Abstract

Dopamine receptors are significantly involved in hippocampus-based cognitive processes. Whereas the involvement of D1-like receptors in hippocampal plasticity has been described, the role of D2-like receptors remains to be clarified. Therefore, we investigated the contribution of D2-like receptors to synaptic transmission, long-term potentiation (LTP) and depotentiation in the dentate gyrus of freely moving rats. Male Wistar rats underwent chronic implantation of a recording electrode in the granule cell layer, a stimulating electrode in the medial perforant path and a cannula in the ipsilateral cerebral ventricle (to enable drug administration). The D2-like receptor agonists quinpirole and noraporphine dose-dependently inhibited basal synaptic transmission. Agonist priming of D2-like receptors with a drug concentration which had no effect on synaptic transmission inhibited depotentiation but did not affect LTP. The agonist effects on depotentiation were prevented by the D2-like antagonist remoxipride. Remoxipride itself did not influence basal synaptic transmission or depotentiation. Interestingly, ‘weak’ LTP (<4 h) but not ‘strong’ LTP (>24 h) was inhibited by prior application of remoxipride. These results suggest a specific role for dopamine D2-like receptors in the regulation of both depotentiation and LTP in vivo and offer an important and novel insight as to the involvement of these receptors in processes related to learning and memory.

Introduction

Neuronal plasticity comprises phenomena such as long-term potentiation (LTP) (Bliss and Lomo, 1973), long-term depression (LTD) (Dudek and Bear, 1992) and depotentiation (Barrionuevo et al., 1980; Staubli and Lynch, 1990), that are believed to represent the cellular mechanisms which underlie information storage in the mammalian brain (Bear, 1996). A key factor in the regulation of long-term plastic changes in synaptic weight is the differential involvement of kinases and phosphatases (Stanton, 1996; Tokuda and Hatase, 1998). Whereas the maintenance of a persistent use-dependent enhancement of synaptic efficacy, in the form of a robust LTP, critically requires kinase-dependent phosphorylation (Cheng et al., 1994; Lisman, 1994; Pettit et al., 1994; Tokuda and Hatase, 1998), a persistent reduction in synaptic weight as represented by LTD or depotentiation seems to critically depend upon dephosphorylation (Mulkey et al., 1993, 1994; O’Dell and Kandel, 1994; Tokuda and Hatase, 1998).

One important step in triggering dephosphorylation is the disinhibition of protein phosphatase-1 (Mulkey et al., 1994; Wagner and Alger, 1996) via negative regulation of cAMP-dependent protein kinase A. Levels of cAMP are tightly controlled by the activity of adenylyl cyclase (AC). Extensive studies by this group have shown that neurotransmitter receptors which are coupled to AC play a decisive role in the bidirectional modulation of synaptic plasticity in the dentate gyrus (DG). Group II metabotropic glutamate receptors (mGluRs), which are negatively coupled to AC, are, for example, critically involved in depotentiation in the DG of freely moving rats and furthermore modulate LTP expression in this region (Kulla et al., 1999). In addition, it was shown that group III mGluRs (which are negatively coupled to AC) and serotonin 5-HT4 receptors (which are positively coupled to AC) diversely regulate the expression of depotentiation and LTP in the DG (Kulla and Manahan-Vaughan, 2000a, 2002).

The dopaminergic system plays a pivotal role in short- (Bach et al., 1999; Goldman-Rakic, 1999; Wilkerson and Levin, 1999) and long-term memory (Schultz et al., 1993; Izquierdo et al., 1998). Determination of the role of dopamine receptors in synaptic plasticity in vivo is therefore of major interest in elucidating the relationship between plasticity and cellular information storage. On the basis of their biochemical and pharmacological properties, five distinct dopamine receptors have been isolated and divided into two subfamilies, the D1-like dopamine receptors (D1 receptors), which are positively coupled to AC, comprising the D1 and D5 receptors, and the D2-like dopamine receptors, which are mainly negatively coupled to AC, comprising the D2, D3 and D4 receptors (Seeman and Van Tol, 1994; Goldman-Rakic, 1999; Vallone et al., 2000). The dorsal hippocampus receives direct dopaminergic input from the ventral tegmental area and dopaminergic receptors have been identified as being localized in the hippocampus (Grilli et al., 1988; Bouthenet et al., 1991; Kohler et al., 1991; Goldsmith et al., 1994; Yokoyama et al., 1995; Khan et al., 1998, 2000; Stanwood et al., 2000).

Several studies have elucidated the involvement of D1-like receptors in hippocampal synaptic plasticity. In the hippocampal CA1 region, antagonism of D1-like receptors inhibits LTP in vitro and in vivo (Frey et al., 1990, 1991), whereas pharmacological activation of D1-like receptors enhances LTP expression in vitro (Otmakhova and Lisman, 1998). In anesthetized rats it was shown that antagonism of D1-like receptors inhibits LTP and that pharmacological activation of these receptors, together with a weak tetanus, induces a potentiation in the DG (Kusuki et al., 1997). In contrast, it was shown, in freely moving rats, that antagonism of D1-like receptors does not affect LTP in the DG and that pharmacological activation of these receptors also has no influence on LTP (Kulla and Manahan-Vaughan, 2000b). These differences may, however, be associated with a change in the induction threshold for LTP which occurs in rats under anesthesia (Riedel et al., 1994).

In contrast, the role of the D2-like receptors in hippocampal LTP, LTD or depotentiation has not yet been characterized. D2-like receptors have been shown to be involved in hippo-campus-dependent learning tasks (Wilkerson and Levin, 1999). Pharmacological activation of D2-like receptors mediates deficits in a spatial recognition memory task (Lena et al., 2001) and modulates passive avoidance learning (Sigala et al., 1997), whereas pharmacological antagonism of D2-like receptors has been reported to mediate an enhancement and impairment of retention in the water maze depending upon the drug concentration and route of administration (Setlow and McGaugh, 1999, 2000). Furthermore, the D2-like receptors have been identified as a major target for substances acting as drugs in the treatment of psychotic disorders such as schizophrenia (Rowley et al., 2001). LTP is widely believed to comprise the cellular mechanism underlying spatial memory. Depotentiation serves to return potentiated synapses to pre-LTP levels and thus may play a role in forgetting or in aborting the creation of a memory engram. As spatial memory is impaired by application of D2-like receptor ligands it may be the case that these forms of synaptic plasticity are also modulated by these receptors. This study therefore set about to determine the role of D2-like receptors in LTP and depotentiation in the DG of freely moving rats.

Materials and Methods

Electrode Implantation

Seven-to-eight week old male Wistar rats underwent electrode implantation into the DG as described previously (Manahan-Vaughan et al., 1998). Briefly, under sodium pentobarbitone anesthesia (Nembutal, 40 mg/kg i.p.; Serva, Germany) animals underwent implantation of a monopolar recording and a bipolar stimulating electrode (made from 0.1 mm diameter Teflon-coated stainless steel wire). A drill hole was made (1.5 mm diameter) for the recording electrode (2.8 mm posterior to bregma, 1.8 mm lateral to the midline) and a second drill hole (1 mm diameter, 6.9 mm posterior to bregma and 4.1 mm lateral to the midline) for the stimulating electrode. The dura was pierced through both holes and the recording and stimulating electrodes lowered into the DG granule cell layer and the medial perforant path, respectively. Recordings of evoked field potentials via the implanted electrodes were taken throughout surgery to facilitate localization of the required potentials. Potentials evoked by medial perforant path stimulation were distinguished from potentials evoked by lateral perforant path stimulation by the following criteria (based on McNaughton and Barnes, 1977; Abraham and McNaughton, 1984): a field excitatory post-synaptic potential (fEPSP) peak latency of ∼3.0 ms and half-width of ∼5.0 ms and occurrence of the population spike (PS) within the first positive deflection of the fEPSP.

A cannula was also implanted into the lateral cerebral ventricle, through which drug application was made. Once verification of the location of the electrodes was complete, the entire assembly was sealed and fixed to the skull with dental acrylic (Paladur; Heraeus Kulzer GmbH, Germany). The animals were allowed between 7 and 10 days to recover from surgery before experiments were conducted. Throughout the experiments the animals could move freely. Experiments were consistently conducted at the same time of day (commencing at 8.00 a.m.). Baseline experiments to confirm stability of evoked responses were routinely carried out (for at least 24 h) before LTP or depotentiation experiments were conducted. Where possible, the animals served as their own controls. Thus, basal synaptic transmission (in the absence of injection) was monitored over a 24 h period in all animals to confirm stability of evoked responses. Subsequently, a control experiment (e.g. depotentiation or basal synaptic transmission) was carried out in the presence of vehicle injection and approximately 1 week later the same experiment was carried out in the same animal in the presence of a drug injection. Post-mortem histological analysis of the localization of electrodes was conducted to verify correct electrode placement. The data from any animals which exhibited misconfigurations were discarded from the study.

Measurement of Evoked Potentials

Responses were evoked by stimulating at low frequency (0.025 Hz, 0.1 ms stimulus duration, 10 000 Hz sample rate). For each time point, five evoked responses were averaged. Both fEPSP slope and PS amplitude were monitored. The amplitude of PS was measured from the peak of the first positive deflection of the evoked potential to the peak of the following negative potential. fEPSP slope was measured as the maximal slope through the five steepest points obtained on the first positive deflection of the potential. By means of input/output curve determination the maximum PS amplitude was found for each individual animal and all potentials employed as baseline criteria were evoked at a stimulus intensity which produced 40% of this maximum.

Two protocols were used for the induction of LTP. The first protocol was used to induce LTP which endured for over 24 h and involved administration of a tetanus of 200 Hz, (10 bursts of 15 stimuli, 0.2 ms stimulus duration, 10 s interburst interval). The second protocol was used to generate LTP which endured for up to 4 h and involved application of a tetanus of 100 Hz (4 bursts of 1 stimulus, 1 s stimulus duration, 5 min interburst interval).

Depotentiation was generated using three different protocols. Following induction of LTP with 200 Hz tetanization, low frequency stimulation (LFS) at 5 Hz (600 pulses) was given either 5 or 1 min later to induce depotentiation. In the third protocol, LFS at 5 Hz (300 pulses) was given 5 min after 100 Hz stimulation. In each case significant depotentiation was recorded. The stimulus amplitude for all protocols was the same as that used for recordings.

Where experiments comprised monitoring of basal synaptic transmission recordings were conducted for a total of 5.5 h followed by 60 min of further recordings (at 15 min intervals), 24 h after drug or vehicle injection had occurred (see the protocol for compounds and drug treatment below). In LTP experiments, drug or vehicle injection occurred following monitoring of basal synaptic transmission for 30 min. A tetanus was applied 30 min after injection had occurred, with measurements taken at t = 2, 5, 10 and 15 min and then at 15 min intervals (post-tetanization) up to 4 h, with an additional four measurements, taken at 15 min intervals, after 24 h. In depotentiation experiments, a recording of evoked potentials was taken 2 min after tetanization. LFS was then applied for a total of 5 min after tetanization. Five minutes after LFS recordings of evoked potentials were recommenced and conducted at t = 5, 10 and 15 min and then at 15 min intervals (post-LFS) up to 4 h with additional recordings for 60 min 24 h later. (Where LFS was given 1 min after 200 Hz tetanization a recording was taken 10 s after tetanization and the 2 min recording was not conducted. From 5 min after LFS, evoked potentials were recorded as described above.)

Compounds and Drug Treatment

The D2-like receptor agonist (R)-(–)-2,10,11-trihydroxy-N-propyl-noraporphine HBr (noraporphine) was obtained from Sigma RBI (Taufkirchen, Germany). The D2-like receptor agonist (4aR-trans)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline (quin-pirole) and the D2-like receptor antagonist (S)-(–)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide (remoxipride) were obtained from Tocris Cookson Ltd (Bristol, UK). For injection, drugs were dissolved in double-distilled water. Compounds or vehicle were injected in a 5 μl volume over a 6 min period via a Hamilton syringe. Agonist injection was carried out 30 min prior to tetanization and antagonist injection occurred a further 30 min prior to agonist application, to enable diffusion from the lateral cerebral ventricle to the hippocampus to occur (Manahan-Vaughan et al., 1998).

Throughout the experiments, injections were administered following measurement of the baseline for 30 min. Baseline recordings were then conducted for a further 4.5 h (and an additional 60 min recording 24 h later). Where LTP induction was implemented, tetanization was given 30 min after injection and responses were followed for 4 h with a further 60 min recording taken 24 h after tetanization had occurred.

Data Analysis

The baseline fEPSP or PS data were obtained by averaging the response to stimulating the perforant path, to obtain five sweeps at 0.025 Hz, every 5 or 15 min as described above. The data were then expressed as mean percentage pre-injection baseline reading ± SEM. Statistical significance was estimated using analysis of variance (ANOVA) with repeated measures, followed by post-hoc Student’s t-tests. The probability level interpreted as statistically significant was P < 0.05.

Results

The D2-like Receptor Agonist Quinpirole Elicits a Dose-dependent Effect on Evoked Responses in the DG of Freely Moving Rats

Basal synaptic transmission in the presence of vehicle (n = 16) was stable with regard to both PS amplitude and fEPSP slope throughout the recording period (Fig. 1). The selective D2-like receptor agonist quinpirole dose-dependently decreased the PS amplitude but had no influence on fEPSP slope (Fig. 1A,B,E). Whereas 2.5 μg quinpirole (n = 8) exerted no statistically significant effects on either fEPSP slope or PS amplitude compared with controls (n = 16), raising the concentration in the range 5–20 μg significantly reduced the PS amplitude but not the fEPSP slope. ANOVA confirmed the absence of a statistical difference in fEPSP slope values compared with controls for 2.5, 5, 7.5, 10 and 20 μg (n = 8) (Table 2).

Application of 2.5 μg quinpirole had no detectable influence on the PS amplitude compared with baseline controls (Fig. 1, Table 1). For concentrations from 5 to 20 μg (n = 8) a statistical difference in PS amplitude compared with controls was evident from t = 20 min postinjection (t-test: 5 μg, P = 0.049; 7.5 μg, P = 0.001; 10 μg, P < 0.0001; 20 μg, P < 0.0001) and persisted for >24 h. ANOVA confirmed the significant effects of quinpirole on the PS amplitude (Table 1)

The Dopamine D2-like Receptor Agonist Noraporphine Elicits a Dose-dependent Effect on Evoked Responses in the DG of Freely Moving Rats

Confirmation that the depressive effects on PS amplitude seen with quinpirole were elicted through agonist activation of D2-like receptors was obtained using a second D2-like receptor agonist, noraporphine. Administration of 1.25 μg noraporphine (n = 16) had no influence on basal synaptic transmission with regard to either PS amplitude or fEPSP slope (Fig. 1CE). Raising the concentration in the range 2.5–20 μg elicted no significant change in fEPSP slope compared with controls (n = 16). ANOVA analysis for all concentrations from 1.25 to 20 μg confirmed these results with regard to fEPSP slope (Table 2).

Application of 1.25 μg noraporphine elicited no statistically significant alteration in the PS amplitude compared with baseline controls (Table 1). However, increasing the agonist concentration in the range 2.5–20 μg significantly reduced PS amplitude (Fig. 1CE). This reduction could be observed as early as 10 min post-injection (t-test values as compared to controls: 2.5 μg, P = 0.039; 5 μg, P = 0.01; 10 μg, P < 0.008; 20 μg, P < 0.0001) and persisted over the 25 h monitoring period. These results were confirmed by ANOVA analysis (Table 1).

The Dopamine D2 Receptor Antagonist Remoxipride Dose-dependently Prevents the Inhibitory Effects of the D2-like Receptor Agonist Quinpirole on PS Amplitude

Whereas 2.5 μg of the D2-like receptor agonist quinpirole exerted no influence on basal synaptic transmission, higher concentrations of the agonist left the fEPSP slope unaffected but decreased the PS amplitude. To clarify that this effect was D2-like receptor mediated, the D2-like receptor antagonist remoxipride was applied prior to the agonist.

Quinpirole, when given in a concentration of 20 μg markedly reduced the PS amplitude (Fig. 1A,B). Remoxipride was applied at a concentration of 10 μg (n = 8) 30 min prior to the injection of 20 μg quinpirole (n = 8). Whereas the combined application of 10 μg remoxipride and 20 μg quinpirole did not cause any alterations in the fEPSP slope compared with 20 μg quinpirole baseline recordings or controls (Fig. 2B), the reduction in the PS amplitude was attenuated (Fig. 2A). Increasing the concentration of remoxipride to 50 μg (n = 8) prior to 20 μg quinpirole completely blocked the reduction in the PS amplitude without affecting fEPSP slope (Fig. 2A,B).

ANOVA analysis confirmed the absence of any effects on the fEPSP during baseline recordings of either 20 μg quinpirole, the combined application of 10 μg remoxipride prior to 20 μg quinpirole or 50 μg remoxipride prior to 20 μg quinpirole compared with controls (Table 2). Whereas 20 μg quinpirole reduced the PS amplitude (24 h post-injection, 30 ± 3%), this reduction was significantly attenuated by prior application of 10 μg remoxipride (24 h post-injection, 53 ± 10%, P = 0.04) and was completely blocked when the concentration of remoxipride was increased to 50 μg (24 h post-injection, 98 ± 7%), showing no statistical difference to control baseline recordings (for ANOVA see Table 1).

The Dopamine D2-like Receptor Antagonist Remoxipride Blocks the Inhibitory Effects of the Dopamine D2-like Receptor Agonist Noraporphine on the PS Amplitude

Application of 50 μg of the D2-like receptor antagonist remoxipride prior to 20 μg of the D2 receptor agonist quinpirole completely blocked the inhibitory effects of the agonist on PS amplitude. The same antagonist concentration was therefore applied prior to the D2 receptor agonist noraporphine. In this case, no influence on the fEPSP slope was seen but a significant block of the reduction in the PS amplitude by 20 μg nora-porphine was obtained (Fig. 2C,D). Thus, when 50 μg of the antagonist remoxipride was applied 30 min prior to 20 μg of the agonist noraporphine (n = 8) no difference compared with control baseline recordings (n = 16) could be detected, either with regard to fEPSP slope or PS amplitude (for ANOVA see Tables 1, 2).

Agonist Priming of Dopamine D2 Receptors by Either Noraporphine or Quinpirole Has No Influence on LTP in the DG of Freely Moving Rats

It was shown that 2.5 μg of the D2-like receptor agonist quinpirole did not affect basal synaptic transmission, with regard to either fEPSP slope or PS amplitude (Fig. 1). It was of interest whether this priming concentration of the agonist had any detectable influence on LTP when applied 30 min prior to its induction.

In the DG, robust LTP, which endured for >24 h, was induced by delivering 200 Hz high frequency tetanization (HFT, 10 bursts of 15 stimuli, 0.2 ms stimulus duration) to the medial perforant path (Fig. 3A,B). In controls injected with vehicle 5 min post-HFT, synaptic transmission was enhanced (fEPSP slope, 130 ± 3%; PS amplitude, 228 ± 15%) and persisted for >24 h, when fEPSP slope was 128 ± 4% and PS amplitude was 222 ± 13%.

Application of a priming concentration of 2.5 μg of the dopamine D2 receptor agonist quinpirole 30 min prior to HFT (n = 8) did not alter the magnitude or time course of LTP with regard to either fEPSP slope or PS amplitude in comparison with vehicle controls (Fig. 3A,B). Five minutes post-HFT the fEPSP slope value was 131 ± 3% and the PS amplitude value was 235 ± 17%; 24 h post-HFT the fEPSP slope value was 127 ± 8% and the PS amplitude value was 228 ± 15%.

The absence of a detectable effect of agonist priming by the D2 agonist quinpirole on LTP could be reproduced by applying a priming concentration of the D2 agonist noraporphine prior to HFT. It was shown previously that 1.25 μg of the D2 agonist noraporphine did not exert any effect on basal synaptic transmission (Fig. 1). When a concentration of 1.25 μg noraporphine was applied 30 min prior to HFT, no effect on LTP was observed in comparison with vehicle controls (Fig. 3A,B). ANOVA analysis confirmed the absence of detectable differences between controls and the application of the priming concentrations of the D2 receptor agonists quinpirole (2.5 μg) and noraporphine (1.25 μg) (see Table 1).

To examine whether the tetanization strength and thus the intensity of the LTP response would alter the response to D2 receptor agonism, we induced LTP using a weaker HFT protocol (see Materials and Methods). Induction of LTP using 100 Hz LFT resulted in LTP which endured for ∼4 h in the DG (n = 6) (Fig. 3C,D). Application of noraporphine (1.25 μg, n = 6) 30 min prior to HFT had no significant effect on the evoked responses obtained. Five minutes after HFT the PS value was 195 ± 17%, compared with 201 ± 20% in controls. Four hours after HFT the PS value was 132 ± 15%, compared with 114 ± 13% in controls (for ANOVA see Tables 1, 2).

Depotentiation in the DG of Freely Moving Rats is Inhibited by Agonist Priming of D2-like Receptors with the Agonist Quinpirole

Low frequency stimulation (LFS) at 5 Hz (600 pulses) given 5 min after application of HFT resulted in a significant depotentiation of LTP in vehicle-injected animals (Fig. 4).

Although 2.5 μg of the D2-like receptor agonist quinpirole did not elicit any effect on basal synaptic transmission (Fig. 1), a significant inhibition of depotentiation was obtained by this agonist concentration (n = 10) (Fig. 4A,E). Whereas no change in the initial depression occurred, a significant impairment of depotentiation was seen with regard to both PS amplitude and fEPSP from t = 105 min post-LFS (fEPSP, 125 ± 5%, P < 0.001; PS amplitude, 190 ± 10%, P < 0.0001) compared with vehicle-injected controls (n = 8; fEPSP, 106 ± 2%; PS amplitude, 116 ± 8%). This inhibition of depotentiation was persistent: 24 h post-LFS the quinpirole-injected group showed significantly higher values with regard to both fEPSP slope (135 ± 5%, P < 0.0001) and PS amplitude (228 ± 12%, P < 0.0001) compared with controls (fEPSP slope, 107 ± 3%; PS amplitude, 134 ± 7%). ANOVA confirmed the statistically significant difference between depotentiation in vehicle and quinpirole animals (Tables 1, 2).

Application of the D2-like receptor antagonist remoxipride (50 μg, n = 8) in the presence of vehicle elicited no independent effects on depotentiation compared with vehicle-injected controls (n = 8) (Fig. 4A). ANOVA confirmed this observation (Tables 1, 2).

The inhibition of depotentiation caused by injection of 2.5 μg quinpirole was prevented, however, when 50 μg remoxipride was injected 30 min before quinpirole application (n = 10), resulting in a depotentiation that was not significantly different from controls (n = 8) (Fig. 4A) (ANOVA, Tables 1, 2).

Depotentiation in the DG of Freely Moving Rats is Inhibited by Agonist Priming of D2-like Receptors with the Agonist Noraporphine

To confirm that the inhibition of depotentiation elicited by quinpirole was mediated by agonist priming of D2-like receptors, the D2-like receptor agonist noraporphine was applied in a concentration that did not elicit any effect on basal synaptic transmission.

Depotentiation was inhibited when 1.25 μg of the D2 receptor agonist noraporphine (n = 10) was injected 30 min prior to the induction protocol (Fig. 4B). Whereas the magnitude and time course of the initial depression was unaffected, the inhibition of depotentiation was statistically significant with regard to both fEPSP slope and PS amplitude from t = 90 min post-LFS (P = 0.001) and persisted for >24 h, compared with controls (n = 8). ANOVA confirmed the statistically significant difference between depotentiation in control and noraporphine-injected animals (Tables 1, 2).

When a concentration of 50 μg remoxipride was injected 30 min prior to the application of 1.25 μg of the agonist noraporphine (n = 10), the inhibition of depotentiation was completely prevented, resulting in a depotentiation that in its magnitude and time course was not different to vehicle controls (Fig. 4B) (ANOVA, Tables 1, 2).

In order to determine whether the latency between HFT and LFS is a factor in the modulation by D2 agonists of depotentiation a protocol was implemented where LFS was given 1 min (rather than 5 min) after HFT. In previous work we reported that the shorter the latency between HFT and LFS the greater the magnitude of depotentiation in the DG in vivo (Kulla et al., 1999). This observation was confirmed in the present study. LFS given 1 min after HFT (in the presence of vehicle) resulted in a depotentiation which 24 h after induction elicited evoked potentials which were not significantly different from pre-HFT basally evoked responses (n = 6). Application of noraporphine (1.25 μg, n = 4) 30 min prior to HFT and LFS resulted in a significant inhibition of depotentiation which became apparent 90 min after LFS was given (t-test, P < 0.01) (for ANOVA see Tables 1, 2) (Fig. 4C). Application of remoxipride (50 μg, n = 6) 30 min before the depotentiation protocol had no effect on the expression of depotentiation (data not shown).

The question arose as to whether the agonist modulation of depotentiation would be different if a milder induction was implemented. Thus, we induced LTP with 100 Hz HFT (see Materials and Methods) and 5 min later applied LFS at 5 Hz (300 pulses). This milder protocol induced LTP (in the presence of vehicle) which endured for 4 h (Fig. 4D) and which was significantly reversed by LFS (n = 7). Under these conditions, application of noraporphine (1.25 μg, n = 5) significantly impaired depotentiation (Fig. 4D) (for ANOVA see Tables 1, 2). Effects became apparent at t = 225 min after LFS (t-test, P < 0.05). Application of remoxipride (50 μg, n = 6) 30 min before this depotentiation protocol had no effect on the expression of depotentiation (data not shown).

The Dopamine D2 Receptor Antagonist Remoxipride Has No Effects on Basal Synaptic Transmission in the DG of Freely Moving Rats

The effects of application of the D2-like receptor antagonist remoxipride on basal synaptic transmission and LTP and depotentiation were investigated.

Neither fEPSP slope nor PS amplitude were significantly altered in comparison with baseline controls (n = 8) when 50 μg remoxipride was applied (n = 8) (Fig. 5A,B). ANOVA analysis confirmed the absence of statistically significant differences (Tables 1, 2).

The Dopamine D2 Receptor Antagonist Remoxipride Inhibits Weak but not Robust LTP in the DG of Freely Moving Rats

LTP was induced in the DG using protocols which generated potentiated responses which endured for either 4 (100 Hz HFT) or >24 h (200 Hz HFT) (Fig. 5C,D). Application of 50 μg remoxipride (n = 8) did not alter the magnitude or time course of the robust 200 Hz-generated LTP with regard to either fEPSP slope or PS amplitude in comparison with vehicle controls (n = 7) (for ANOVA see Tables 1, 2). However, when remoxipride was applied prior to application of 100 Hz HFT a significant impairment of LTP was seen (n = 7, Fig. 5C,D). These effects became evident immediately after HFT was given, when a reduction in the initial potentiation was seen. Thus, at t = 5 min post-LFS, PS amplitude was 120 ± 10%, compared with 201 ± 9% in controls (P = 0.001). By 75 min post-HFT evoked potentials had returned to basal levels. These effects were confirmed by ANOVA (see Tables 1, 2).

Discussion

This study demonstrates that depotentiation is inhibited by concentrations of D2-like receptor agonists which have no significant effect on basal synaptic transmission or LTP. Dose-dependent agonist effects on synaptic transmission were also observed. Pharmacological antagonism of D2-like receptors does not influence either basal synaptic transmission or depotentiation. Interestingly, however, antagonism of D2-like receptors leads to a significant impairment of weak but not robust LTP. The observation that application of D2-like receptor agonists inhibits depotentiation at concentrations which have no effect on synaptic plasticity suggest a possible role for these receptors in metaplasticity (Abraham and Bear, 1996). Furthermore, the inhibition of LTP by a D2-like receptor antagonist provides an interesting link with behavioral studies which support a role for this receptor in learning.

Contribution of D2 Receptors to LTP

Application of the D2-like receptor antagonist remoxipride in this study served two purposes: firstly, to confirm that the agonist effects seen were mediated by activation of D2-like receptors and, secondly, to investigate whether activation of D2-like receptors is a critical prerequisite for induction of either LTP or depotentiation in vivo.

Remoxipride has a reported Ki of ∼300 nM at D2 receptors and Ki of ∼1600 and ∼2800 nM at D3 and D4 receptors, respectively (Seeman and Van Tol, 1994). In the present study it demonstrated a dose-dependent inhibition of the agonist effects on depotentiation and basal synaptic transmission elicited by quinpirole and noraporphine. These findings are consistent with an activation of D2-like receptors by these agonists.

In the present study, pharmacological antagonism of D2 receptors elicited an inhibition of weak but not robust LTP. Application of the antagonist on its own did not elicit significant alterations in basal synaptic transmission, suggesting that a tonic activation of D2-like receptors does not contribute to basal synaptic transmission in the DG.

The differential effects of remoxipride on weak and robust LTP may reflect, on the one hand, a contribution of D2 receptors to LTP which is induced by a more physiological induction protocol (100 versus 200 Hz stimulation). On the other hand, it may suggest that activation of D2 receptors is more critically required when LTP of a more fragile nature is induced. The D2 receptor may serve, therefore, to reinforce or prolong LTP. This possibility would tie in with behavioral learning observations (see ‘Integration with Cognitive Studies’ below).

These findings suggest that dopamine D2 receptors play a significant role in the regulation of LTP in the DG in vivo. These observations are in agreement with studies conducted in the CA1 region in vitro, where pharmacological antagonism of D2-like receptors resulted in an inhibition of the maintenance of LTP (Frey et al., 1989). Interestingly, these findings contrast with the regulation of LTP by dopamine D1/D5 receptors: whereas pharmacological antagonism of D1/D5 receptors results in inhibition of LTP in the CA1 region (Frey et al., 1991; Otmakhova and Lisman, 1996), no effect is seen with regard to DG LTP (Kulla and Manahan-Vaughan, 2000b). These subregion-specific differences may perhaps be explained by the differential localization of the dopamine receptor subtypes (Bouthenet et al., 1991; Köhler et al., 1991;Yokoyama et al., 1995; Khan et al., 1998) and their corresponding coupling to AC.

Contribution of D2 Receptors to Depotentiation

Depotentiation comprises a reversal of tetanization-induced LTP and is expressed when low frequency stimulation (LFS) is applied within 5 min after LTP induction of afferent fibers (Staubli and Lynch, 1990; Staubli and Chun, 1996; Kulla et al., 1999). Although depotentiation and LTD appear to share common signaling mechanisms in that both are dependent upon changes in intracellular calcium levels and subsequent induction of protein phosphatases (Mulkey et al., 1993; O’Dell and Kandel, 1994), depotentiation differs from LTD in some respects. For example, in vivo LTD can be induced at any time point in naive and potentiated synapses (Manahan-Vaughan, 1997), whereas depotentiation requires a recent potentiation of synaptic strength (Staubli and Lynch, 1990; Staubli and Chun, 1996; Kulla et al., 1999). Pharmacological studies have shown that the global mGluR antagonist LY 341495 significantly inhibits the expression of depotentiation in hippocampal slices, whereas LTD is unaffected by the antagonist (Bortolotto et al., 1999). Differing dose-dependent responses of depotentiation and LTD to group II mGluR antagonists have also been reported (Manahan-Vaughan, 1997; Kulla et al., 1999). In addition, age-dependent differences in inducibility and differing involvement of GABA receptors in LTD and depotentiation have been described (Wagner and Alger, 1996). Interestingly, it has been reported that activation of D2-like receptors results in an inhibition of LTD in the CA1 region in vitro (Chen et al., 1996). The lack of agonist effects on depotentiation seen in the present study may correspond to subregion-specific differences, but may also highlight further differences between LTD and depotentiation.

In the current study we investigated the involvement of D2-like receptors in depotentiation. Concentrations of D2-like receptor agonists which had no effect on basal synaptic transmission significantly impaired the expression of depotentiation but did not alter LTP. These effects were seen using the stronger (200 versus 5 Hz 600 times) and weaker (100 Hz versus 5 Hz 300 times) protocols, which suggests an intrinsic involvement of D2 receptors in the regulation of depotentiation. The mechanism of this effect is unclear. One possibility is that an acceleration of LTP stabilization mechanisms is triggered by D2 agonism. To address this hypothesis we conducted experiments where LFS was given 1 min (as opposed to 5 min) after HFT, when LTP should be more vulnerable to reversal by LFS. Under these conditions an inhibition of depotentiation was still seen, which would in fact support the possibility that D2 agonism may accelerate the stabilization of LTP.

The critical involvement of AC-coupled receptors in depotentiation has previously been shown (Kulla et al., 1999; Kulla and Manahan-Vaughan, 2000a,b, 2002). It was demonstrated that pharmacological activation of group II mGluRs, which are predominantly presynaptically localized and negatively coupled to AC, enhances depotentiation, whereas antagonists of group II mGluRs inhibit the expression of depotentiation. This would suggest that activation of group II mGluRs is required for induction of depotentiation. Other AC-coupled neurotransmitter receptors seem to be less essential, as pharmacological antagonism of group III mGluRs, serotonin 5-HT4 receptors or dopamine D1 receptors has no effect on the expression of depotentiation (or LTP) (Kulla and Manahan-Vaughan, 2000a,b, 2002).

Interestingly, AC-coupled receptors appear to modulate depotentiation in the DG of freely moving rats in quite different ways. Whereas agonist activation of group II or III mGluRs (which are predominantly presynaptically expressed and negatively coupled to AC) results in an enhancement of depotentiation, agonist activation of dopamine D1/D5 receptors, which are predominantly postsynaptically expressed and negatively coupled to AC, inhibits depotentiation in the DG of freely moving rats (Kulla et al., 1999; Kulla and Manahan-Vaughan 2000a,b, 2002). Pharmacological activation of serotonin 5-HT4 receptors (which are positively coupled to AC) inhibits depotentiation.

Differential Effects of D2 Receptor Activation on PS and fEPSP

The pharmacological activation of D2-like receptors by higher concentrations of the D2-like receptor agonists quinpirole and noraporphine resulted in a decrease in PS amplitude but did not affect fEPSP, which suggests a somatic mode of action of these agonists in the higher concentration ranges used. A somatic mode of action would, however, be contradictory to the widely documented dendritic localization of D2 receptors, but could correspond to the somatic localization of D3 and/or D4 receptors (Khan et al., 1998; Stanwood et al., 2000). In general, D4 receptors are expressed at greater density in the hippocampus than D2 or D3 receptors. Furthermore, D3 receptors are expressed at lower densities and with a more restricted distribution pattern than D2 receptors (Bouthenet et al., 1991; Khan et al., 1998; Stanwood et al., 2000). Thus the dose-dependent inhibition of PS amplitude following agonist application may correspond to an activation of D4 receptors. Quinpirole, for example, has a dissociation constant (Ki) of 4.8 nM on D2 receptors, whereas the Ki at D3 and D4 receptors are ∼24 and∼30 nM, respectively (Seeman and Van Tol, 1994). An activation of D3 receptors may also explain the reduction in PS seen with higher agonist concentrations. D3 receptor-mediated opening of K+ channels would result in a strong decrease in excitability (Shafer and Levant, 1998), which could be reflected in a decrease in PS amplitude, whereas fEPSP would remain unchanged.

The agonist effects on depotentiation were obtained using concentrations which had no effect on basal synaptic transmission. Given the lower Ki for quinpirole at D2 receptors compared with D3 and D4 receptors, it is possible that these effects were mediated by D2 receptors. D2 receptors are localized exclusively dendritically (Bouthenet et al., 1991; Bruinink and Bischoff, 1993; Khan et al., 1998). Although D3 receptors are found on hippocampal cell bodies, a dendritic localization has also been reported (Khan et al., 1998; Stanwood et al., 2000). A modulation of depotentiation through joint activation of D2 and D3 receptors cannot therefore be excluded.

D2-like Receptors and Metaplasticity

Metaplasticity (Abraham and Bear, 1996) comprises the ability of synapses to generate different, or differing levels of, synaptic plasticity (in response to an identical plasticity-inducing stimulus) as a consequence of a previous synaptic event which in itself did not cause an alteration in synaptic strength. The previous synaptic event could comprise a stressful or arousing behavioral event (Xu et al., 1997; Manahan-Vaughan and Braunewell, 1999), patterned afferent stimulation (Christie and Abraham, 1992; Wexler and Stanton, 1993; Holland and Wagner, 1998) or pharmacological activation of neurotransmitter receptors (Manahan-Vaughan et al., 1996; Cohen et al., 1998; Wang and Wagner, 1999). It has been shown that activation of D2 receptors can enhance neuronal excitability in the hippocampus (Smialowski and Bijak, 1987). In the present study, however, D2-like receptor agonist concentrations which were subthreshold for eliciting effects on basal synaptic transmission produced a significant inhibition of depotentiation. Thus, it is possible that D2-like receptors are involved in metaplasticity of depotentiation. These effects may contribute to reinforcement of LTP (via suppression of depotentiation) and therefore enhanced memory consolidation.

Integration with Cognitive Studies

The findings of the present study provide a strong link with previous work with regard to behavioral learning. D2-like receptors have been implicated in early memory consolidation processes (Packard and White, 1989, 1991; White et al., 1993). In our study, we found that impairment of LTP caused by antagonism of D2-like receptors became evident within minutes of LTP induction, consistent with a critical role for these receptors in early consolidation of LTP. A role for D2-like receptors in memory retention has also been proposed, however (Setlow and McGaugh, 1999, 2000). Here it was shown that cerebral application of the D2-like receptor antagonist sulpiride leads to impairment of spatial memory retention in the water maze, whereas subcutaneous application of the same compound leads to retention enhancement. The differences may perhaps be explained by a dose-dependent direct antagonism of central D2-like receptors in the former case and by facilitation of striatal dopamine release via inhibition of presynaptic autoreceptors (leading to enhanced activation of D2-like receptors) in the latter case (Setlow and McGaugh, 2000). Our finding that robust (24 h) LTP is not influenced by D2-like receptor antagonism may reflect the recruitment of other modulating factors in the induction and stabilization of LTP, such as a greater recruitment of voltage gated calcium channels during LTP induction (Grover and Teyler, 1990) or increasing participation of metabotropic glutamate receptors during LTP consolidation (Manahan-Vaughan et al., 1996; Cohen et al., 1998), which might render the D2-like receptor contribution to LTP less significant. Alternatively, the weaker induction parameter used to generate D2 receptorsensitive LTP may reflect a physiological and therefore more relevant form of LTP in freely moving animals.

Interestingly, we observed that agonist activation of D2-like receptors leads to inhibition of depotentiation. This finding suggests that D2-like receptors can reinforce LTP expression by suppressing the induction of depotentiation. It has been reported that D2-like receptor activation enhanced memory performance in rats whereas D2-like receptor antagonism causes impairment. These findings were later confirmed by others (Gasbarri et al., 1993; Wilkersin and Levin, 1999). It may be the case that the inhibition of depotentiation seen in our study relates to the enhancement of learning caused by D2-like receptor activation.

Conclusions

In conclusion, D2-like receptors appear to play a modulatory role in synaptic plasticity in the DG of freely moving rats. A critical involvement of this neurotransmitter receptor in DG synaptic plasticity is supported by the finding that D2-like receptor antagonist application selectively inhibited LTP but not depotentiation. On the other hand, agonist activation of D2-like receptors inhibited depotentiation. The modulatory action on depotentiation was elicited by concentrations of the agonist which had no effect on basal synaptic responses and therefore were not associated with a direct effect on synaptic transmission; rather this effect appears to occur as a result of a direct regulation of the expression of depotentation, which may correspond to metaplasticity of depotentiation. This finding is in agreement with previous reports by this group on the involvement of AC-coupled receptors in depotentiation in the DG of freely moving rats (Kulla et al., 1999; Kulla and Manahan-Vaughan 2000a,b, 2002). The regulation of depotentiation by D2 receptor activation may serve to maintain synaptic faciliation in recently potentiated pathways and thereby help consolidate information storage. These findings add support to a role for dopamine as a modulator of synaptic plasticity and implicate D2-like receptors in processes related to learning and memory.

We are grateful to Jens Klausnitzer, BTA, for technical assistance. This work was supported by a Deutsche Forschungsgemeinschaft grant (SFB 515/ B8) to D.M.-V.

Table 1

ANOVA with repeated measures of population spike amplitudes following treatment with the dopamine D2 receptor agonists quinpirole and noraporphine and the antagonist remoxipride prior to assessment of basal synaptic transmission, LTP or depotentiation in freely moving rats

Treatment n Within factor P Between factor P 
In the case of agonist injection, comparison was made with vehicle-injected controls; in the case of antagonist/agonist injection, comparison was made with vehicle/agonist-injected controls (as described in Results). 
Basal transmission      
    Quinpirole 2.5 μg F(1,41) = 0.53 <0.97 F(1,41) = 0.88 <0.34 
    Quinpirole 5 μg F(1,41) = 1.32 <0.12 F(1,41) = 519.03 <0.0001 
    Quinpirole 7.5 μg F(1,41) = 2.62 <0.0001 F(1,41) = 1412.46 <0.0001 
    Quinpirole 10 μg F(1,41) = 6.45 <0.0001 F(1,41) = 3385.96 <0.0001 
    Quinpirole 20 μg F(1,41) = 12.79 <0.001 F(1,41) = 5105.94 <0.0001 
    Noraporphine 1.25 μg 16 F(1,41) = 0.95 <0.54 F(1,41) = 3.98 <0.06 
    Noraporphine 2.5 μg 16 F(1,41) = 5.43 <0.0001 F(1,41) = 1182.16 <0.0001 
    Noraporphine 5 μg 16 F(1,41) = 6.17 <0.0001 F(1,41) = 1799.49 <0.0001 
    Noraporphine 10 μg 16 F(1,41) = 8.99 <0.0001 F(1,41) = 3961.39 <0.0001 
    Noraporphine 20 μg 16 F(1,41) = 17.46 <0.001 F(1,41) = 5594.41 <0.0001 
    Remoxipride 10 μg/quinpirole 20 μg F(1,41) = 0.36 <0.99 F(1,41) = 113.72 <0.0001 
    Remoxipride 50 μg/quinpirole 20 μg F(1,41) = 0.64 <0.92 F(1,41) = 0.02 <0.89 
    Remoxipride 50 μg/noraporphine 20 μg F(1,41) = 0.43 <0.99 F(1,41) = 0.97 <0.32 
    Remoxipride 50 μg/vehicle F(1,41) = 0.65 <0.91 F(1,41) = 0.49 <0.48 
LTP (200 Hz)      
    Quinpirole 2.5 μg F(1,41) = 0.19 <1 F(1,41) = 0.92 <0.47 
    Noraporphine 1.25 μg F(1,41) = 0.18 <1 F(1,41) = 0.9 <0.48 
    Remoxipride 50 μg F(1,41) = 0.13 <1 F(1,41) = 0.45 <0.50 
LTP (100 Hz)      
    Noraporphine 1.25 μg F(1,35) = 0.85 <0.39 F(1,35) = 0.708 <0.78 
    Remoxipride 50 μg F(1,35) = 6.53 <0.04 F(1,35) = 2787.27 <0.0001 
LFS 5 min after 200 Hz      
    Quinpirole 2.5 μg 10 F(1,41) = 6.31 <0.0001 F(1,41) = 276.14 <0.0001 
    Remoxipride 50 μg/vehicle F(1,41) = 0.35 <0.99 F(1,41) = 0.11 <0.73 
    Remoxipride 50 μg/quinpirole 2.5 μg 10 F(1,41) = 0.19 <1 F(1,41) = 0.45 <0.5 
    Noraporphine 1.25 μg 10 F(1,41) = 5.55 <0.0001 F(1,41) = 289.68 <0.0001 
    Remoxipride 50 μg/noraporphine 1.25 μg 10 F(1,41) = 0.58 <0.95 F(1,41) = 0.29 <0.58 
LFS 1 min after 200 Hz      
    Noraporphine 1.25 μg F(1,35) = 9.09 <0.024 F(1,35) = 269.5 <0.0001 
LFS 5 min after 100 Hz      
    Noraporphine 1.25 μg F(1,35) = 2.51 <0.04 F(1,35) = 142.63 <0.01 
Treatment n Within factor P Between factor P 
In the case of agonist injection, comparison was made with vehicle-injected controls; in the case of antagonist/agonist injection, comparison was made with vehicle/agonist-injected controls (as described in Results). 
Basal transmission      
    Quinpirole 2.5 μg F(1,41) = 0.53 <0.97 F(1,41) = 0.88 <0.34 
    Quinpirole 5 μg F(1,41) = 1.32 <0.12 F(1,41) = 519.03 <0.0001 
    Quinpirole 7.5 μg F(1,41) = 2.62 <0.0001 F(1,41) = 1412.46 <0.0001 
    Quinpirole 10 μg F(1,41) = 6.45 <0.0001 F(1,41) = 3385.96 <0.0001 
    Quinpirole 20 μg F(1,41) = 12.79 <0.001 F(1,41) = 5105.94 <0.0001 
    Noraporphine 1.25 μg 16 F(1,41) = 0.95 <0.54 F(1,41) = 3.98 <0.06 
    Noraporphine 2.5 μg 16 F(1,41) = 5.43 <0.0001 F(1,41) = 1182.16 <0.0001 
    Noraporphine 5 μg 16 F(1,41) = 6.17 <0.0001 F(1,41) = 1799.49 <0.0001 
    Noraporphine 10 μg 16 F(1,41) = 8.99 <0.0001 F(1,41) = 3961.39 <0.0001 
    Noraporphine 20 μg 16 F(1,41) = 17.46 <0.001 F(1,41) = 5594.41 <0.0001 
    Remoxipride 10 μg/quinpirole 20 μg F(1,41) = 0.36 <0.99 F(1,41) = 113.72 <0.0001 
    Remoxipride 50 μg/quinpirole 20 μg F(1,41) = 0.64 <0.92 F(1,41) = 0.02 <0.89 
    Remoxipride 50 μg/noraporphine 20 μg F(1,41) = 0.43 <0.99 F(1,41) = 0.97 <0.32 
    Remoxipride 50 μg/vehicle F(1,41) = 0.65 <0.91 F(1,41) = 0.49 <0.48 
LTP (200 Hz)      
    Quinpirole 2.5 μg F(1,41) = 0.19 <1 F(1,41) = 0.92 <0.47 
    Noraporphine 1.25 μg F(1,41) = 0.18 <1 F(1,41) = 0.9 <0.48 
    Remoxipride 50 μg F(1,41) = 0.13 <1 F(1,41) = 0.45 <0.50 
LTP (100 Hz)      
    Noraporphine 1.25 μg F(1,35) = 0.85 <0.39 F(1,35) = 0.708 <0.78 
    Remoxipride 50 μg F(1,35) = 6.53 <0.04 F(1,35) = 2787.27 <0.0001 
LFS 5 min after 200 Hz      
    Quinpirole 2.5 μg 10 F(1,41) = 6.31 <0.0001 F(1,41) = 276.14 <0.0001 
    Remoxipride 50 μg/vehicle F(1,41) = 0.35 <0.99 F(1,41) = 0.11 <0.73 
    Remoxipride 50 μg/quinpirole 2.5 μg 10 F(1,41) = 0.19 <1 F(1,41) = 0.45 <0.5 
    Noraporphine 1.25 μg 10 F(1,41) = 5.55 <0.0001 F(1,41) = 289.68 <0.0001 
    Remoxipride 50 μg/noraporphine 1.25 μg 10 F(1,41) = 0.58 <0.95 F(1,41) = 0.29 <0.58 
LFS 1 min after 200 Hz      
    Noraporphine 1.25 μg F(1,35) = 9.09 <0.024 F(1,35) = 269.5 <0.0001 
LFS 5 min after 100 Hz      
    Noraporphine 1.25 μg F(1,35) = 2.51 <0.04 F(1,35) = 142.63 <0.01 
Table 2

ANOVA with repeated measures of field excitatory postsynaptic potential (fEPSP) slope values following treatment with the dopamine D2 receptor agonists quinpirole and noraporphine and the antagonist remoxipride prior to assessment of basal synaptic transmission, LTP or depotentiation in freely moving rats

Treatment n Within factor P Between factor P 
In the case of agonist injection, comparison was made with vehicle-injected controls; in the case of antagonist/agonist injection, comparison was made with vehicle/agonist-injected controls (as described in Results). 
aAll quinpirole and all noraporphine baseline data were compared together in one ANOVA. The statistical data presented for the individual concentrations comprises the overall result for comparison with vehicle-injected controls. 
Basal transmission      
    Quinpirole 2.5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065a 
    Quinpirole 5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 7.5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 10 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 20 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Noraporphine 1.25 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70a 
    Noraporphine 2.5 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 5 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 10 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 20 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Remoxipride 10 μg/quinpirole 20 μg F(1,41) = 0.37 <1 F(1,41) = 0.43 <0.78 
    Remoxipride 50 μg/quinpirole 20 μg F(1,41) = 0.38 <1 F(1,41) = 0.45 <0.79 
    Remoxipride 50 μg/noraporphine 20 μg F(1,41) = 0.54 <0.97 F(1,41) = 0.01 <0.96 
    Remoxipride 50 μg/vehicle F(1,41) = 0.51 <0.98 F(1,41) = 0.07 <0.79 
LTP (200 Hz)      
    Quinpirole 2.5 μg F(1,41) = 0.41 <1 F(1,41) = 0.34 <0.70 
    Noraporphine 1.25 μg F(1,41) = 0.43 <1 F(1,41) = 0.36 <0.71 
    Remoxipride 50 μg F(1,41) = 0.75 <0.82 F(1,41) = 11.86 <0.0006 
LTP (100 Hz)      
    Noraporphine 1.25 μg F(1,41) = 0.45 <0.49 F(1,41) = 0.33 <0.70 
    Remoxipride 50 μg F(1,41) = 3.13 <0.0001 F(1,41) = 199.05 <0.0001 
LFS 5 min after 200 Hz      
    Quinpirole 2.5 μg 10 F(1,41) = 3.83 <0.0001 F(1,41) = 206.65 <0.0001 
    Remoxipride 50 μg/vehicle F(1,41) = 0.29 <0.99 F(1,41) = 4.44 <0.03 
    Remoxipride 50 μg/quinpirole 2.5 μg 10 F(1,41) = 0.32 <0.99 F(1,41) = 0.07 <0.79 
    Noraporphine 1.25 μg 10 F(1,41) = 2.34 <0.0002 F(1,41) = 141.37 <0.0001 
    Remoxipride 50 μg/noraporphine 1.25 μg 10 F(1,41) = 0.70 <0.86 F(1,41) = 3.44 <0.06 
LFS 1 min after 200 Hz      
    Noraporphine 1.25 μg F(1,35) = 6.09 <0.03 F(1,35) = 255.5 <0.001 
LFS 5 min after 100 Hz      
    Noraporphine 1.25 μg F(1,35) = 2.11 <0.039 F(1,35) = 122.54 <0.001 
Treatment n Within factor P Between factor P 
In the case of agonist injection, comparison was made with vehicle-injected controls; in the case of antagonist/agonist injection, comparison was made with vehicle/agonist-injected controls (as described in Results). 
aAll quinpirole and all noraporphine baseline data were compared together in one ANOVA. The statistical data presented for the individual concentrations comprises the overall result for comparison with vehicle-injected controls. 
Basal transmission      
    Quinpirole 2.5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065a 
    Quinpirole 5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 7.5 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 10 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Quinpirole 20 μg F(1,41) = 0.30 <1.0 F(1,41) = 2.08 <0.065 
    Noraporphine 1.25 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70a 
    Noraporphine 2.5 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 5 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 10 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Noraporphine 20 μg 16 F(1,41) = 1.07 <0.26 F(1,41) = 0.59 <0.70 
    Remoxipride 10 μg/quinpirole 20 μg F(1,41) = 0.37 <1 F(1,41) = 0.43 <0.78 
    Remoxipride 50 μg/quinpirole 20 μg F(1,41) = 0.38 <1 F(1,41) = 0.45 <0.79 
    Remoxipride 50 μg/noraporphine 20 μg F(1,41) = 0.54 <0.97 F(1,41) = 0.01 <0.96 
    Remoxipride 50 μg/vehicle F(1,41) = 0.51 <0.98 F(1,41) = 0.07 <0.79 
LTP (200 Hz)      
    Quinpirole 2.5 μg F(1,41) = 0.41 <1 F(1,41) = 0.34 <0.70 
    Noraporphine 1.25 μg F(1,41) = 0.43 <1 F(1,41) = 0.36 <0.71 
    Remoxipride 50 μg F(1,41) = 0.75 <0.82 F(1,41) = 11.86 <0.0006 
LTP (100 Hz)      
    Noraporphine 1.25 μg F(1,41) = 0.45 <0.49 F(1,41) = 0.33 <0.70 
    Remoxipride 50 μg F(1,41) = 3.13 <0.0001 F(1,41) = 199.05 <0.0001 
LFS 5 min after 200 Hz      
    Quinpirole 2.5 μg 10 F(1,41) = 3.83 <0.0001 F(1,41) = 206.65 <0.0001 
    Remoxipride 50 μg/vehicle F(1,41) = 0.29 <0.99 F(1,41) = 4.44 <0.03 
    Remoxipride 50 μg/quinpirole 2.5 μg 10 F(1,41) = 0.32 <0.99 F(1,41) = 0.07 <0.79 
    Noraporphine 1.25 μg 10 F(1,41) = 2.34 <0.0002 F(1,41) = 141.37 <0.0001 
    Remoxipride 50 μg/noraporphine 1.25 μg 10 F(1,41) = 0.70 <0.86 F(1,41) = 3.44 <0.06 
LFS 1 min after 200 Hz      
    Noraporphine 1.25 μg F(1,35) = 6.09 <0.03 F(1,35) = 255.5 <0.001 
LFS 5 min after 100 Hz      
    Noraporphine 1.25 μg F(1,35) = 2.11 <0.039 F(1,35) = 122.54 <0.001 
Figure 1.

The dopamine D2-like receptor agonists quinpirole and noraporphine elicit a dose-dependent effect on evoked responses in the DG of freely moving rats. (A,B) Test pulse stimulation when given in the presence of the D2-like receptor agonist quinpirole (2.5 μg, n = 8) does not affect basal PS amplitude (A) or fEPSP slope (B) compared with vehicle-injected controls (n = 8). In contrast, application of quinpirole at the higher concentrations of 5 (n = 8), 7.5 (n = 8), 10 (n = 8) or 20 μg (n = 8) elicits a dose-dependent depression of PS amplitude (A) but not fEPSP slope (B). Line breaks indicate a change in time-scale. (C,D) Test pulse stimulation when given in the presence of the D2-like receptor agonist noraporphine (1.25 μg, n = 16) does not affect basal PS amplitude (A) or fEPSP slope (B) compared with vehicle-injected controls (n = 16). In contrast, application of quinpirole at the higher concentrations of 2.5 (n = 16), 5 (n = 16), 10 (n = 16) or 20 μg (n = 16) elicits a dose-dependent depression of PS amplitude (C) but not fEPSP slope (D). Line breaks indicate a change in time-scale. (E) Original analog traces showing the field potentials evoked by DG pre-injection, 5 min and 24 h following application of (i) vehicle, (ii) 20 μg quinpirole and (iii) 20 μg noraporphine. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 1.

The dopamine D2-like receptor agonists quinpirole and noraporphine elicit a dose-dependent effect on evoked responses in the DG of freely moving rats. (A,B) Test pulse stimulation when given in the presence of the D2-like receptor agonist quinpirole (2.5 μg, n = 8) does not affect basal PS amplitude (A) or fEPSP slope (B) compared with vehicle-injected controls (n = 8). In contrast, application of quinpirole at the higher concentrations of 5 (n = 8), 7.5 (n = 8), 10 (n = 8) or 20 μg (n = 8) elicits a dose-dependent depression of PS amplitude (A) but not fEPSP slope (B). Line breaks indicate a change in time-scale. (C,D) Test pulse stimulation when given in the presence of the D2-like receptor agonist noraporphine (1.25 μg, n = 16) does not affect basal PS amplitude (A) or fEPSP slope (B) compared with vehicle-injected controls (n = 16). In contrast, application of quinpirole at the higher concentrations of 2.5 (n = 16), 5 (n = 16), 10 (n = 16) or 20 μg (n = 16) elicits a dose-dependent depression of PS amplitude (C) but not fEPSP slope (D). Line breaks indicate a change in time-scale. (E) Original analog traces showing the field potentials evoked by DG pre-injection, 5 min and 24 h following application of (i) vehicle, (ii) 20 μg quinpirole and (iii) 20 μg noraporphine. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 2.

The dopamine D2 receptor antagonist remoxipride dose-dependently prevents the inhibitory effects of the D2-like receptor agonists quinpirole and noraporphine on PS amplitude. (A,B) Administration of the D2-like receptor antagonist remoxipride (10 or 50 μg) in the presence of the D2-like receptor agonist quinpirole (20 μg) results in a dose-dependent inhibition of the depressive effects of quinpirole on PS amplitude (A) compared with vehicle-injected controls (n = 8). Whereas 10 μg remoxipride (n = 8) partially prevents the depressive effects of quinpirole (50 μg), application of the antagonist in a concentration of 50 μg (n = 8) completely prevents the inhibitory effects of the agonist on PS amplitude. No agonist or antagonist effects on fEPSP slope (B) occurred. (C,D) Administration of remoxipride (50 μg) in the presence of the D2-like receptor agonist noraporphine (20 μg) results in a significant inhibition of the depressive effects of noraporphine on PS amplitude (A) compared with vehicle-injected controls (n = 8). No agonist or antagonist effects on fEPSP slope (B) occurred. Line breaks indicate a change in time-scale.

Figure 2.

The dopamine D2 receptor antagonist remoxipride dose-dependently prevents the inhibitory effects of the D2-like receptor agonists quinpirole and noraporphine on PS amplitude. (A,B) Administration of the D2-like receptor antagonist remoxipride (10 or 50 μg) in the presence of the D2-like receptor agonist quinpirole (20 μg) results in a dose-dependent inhibition of the depressive effects of quinpirole on PS amplitude (A) compared with vehicle-injected controls (n = 8). Whereas 10 μg remoxipride (n = 8) partially prevents the depressive effects of quinpirole (50 μg), application of the antagonist in a concentration of 50 μg (n = 8) completely prevents the inhibitory effects of the agonist on PS amplitude. No agonist or antagonist effects on fEPSP slope (B) occurred. (C,D) Administration of remoxipride (50 μg) in the presence of the D2-like receptor agonist noraporphine (20 μg) results in a significant inhibition of the depressive effects of noraporphine on PS amplitude (A) compared with vehicle-injected controls (n = 8). No agonist or antagonist effects on fEPSP slope (B) occurred. Line breaks indicate a change in time-scale.

Figure 3.

Agonist priming of dopamine D2 receptors by either noraporphine or quinpirole has no influence on either robust or weak LTP in the DG of freely moving rats. (A) 200 Hz high frequency tetanization (HFT) (n = 8) results in robust long-term potentiation which persists for 24 h. Application of either quinpirole (2.5 μg, n = 8) or noraporphine (1.25 μg, n = 8) prior to HFT has no effect on the profile of LTP expressed. Line breaks indicate a change in time-scale. (B) Original analog traces showing the field potentials evoked from the DG before 200 Hz HFT, 5 min and 24 h following application of HFT in the presence of (i) vehicle or (ii) quinpirole. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms. (C) 100 Hz HFT (n = 6) results in long-term potentiation enduring for ∼4 h. Application of noraporphine (1.25 μg, n = 6) prior to HFT has no effect on the profile of LTP expressed. Line breaks indicate a change in time-scale. (D) Original analog traces showing the field potentials evoked from the DG before 100 Hz HFT, 5 min and 24 h following application of HFT in the presence of (i) vehicle or (ii) noraporphine. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 3.

Agonist priming of dopamine D2 receptors by either noraporphine or quinpirole has no influence on either robust or weak LTP in the DG of freely moving rats. (A) 200 Hz high frequency tetanization (HFT) (n = 8) results in robust long-term potentiation which persists for 24 h. Application of either quinpirole (2.5 μg, n = 8) or noraporphine (1.25 μg, n = 8) prior to HFT has no effect on the profile of LTP expressed. Line breaks indicate a change in time-scale. (B) Original analog traces showing the field potentials evoked from the DG before 200 Hz HFT, 5 min and 24 h following application of HFT in the presence of (i) vehicle or (ii) quinpirole. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms. (C) 100 Hz HFT (n = 6) results in long-term potentiation enduring for ∼4 h. Application of noraporphine (1.25 μg, n = 6) prior to HFT has no effect on the profile of LTP expressed. Line breaks indicate a change in time-scale. (D) Original analog traces showing the field potentials evoked from the DG before 100 Hz HFT, 5 min and 24 h following application of HFT in the presence of (i) vehicle or (ii) noraporphine. Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 4.

Depotentiation in the DG of freely moving rats is inhibited by agonist priming of dopamine D2-like receptors with the agonist quinpirole or noraporphine. (A,B) Low frequency stimulation (LFS) at 5 Hz (600 pulses) when given 5 min post-HFT (200 Hz) in the presence of vehicle injection (n = 8) results in a significant reversal of LTP. Application of the D2-like receptor agonist quinpirole (2.5 μg, n = 8) prior to HFT and LFS results in a significant inhibition of depotentiation (A). Similarly, administration of the D2-like receptor agonist noraporphine (1.25 μg, n = 8) prior to HFT and LFS causes a significant inhibition of depotentiation (B). Administration of the D2-like receptor antagonist remoxipride (50 μg), prior to application of either quinpirole (2.5 μg, n = 8) or noraporphine (1.25 μg, n = 8), results in a significant prevention of the inhibitory effects of the agonists on depotentiation (A,B). Remoxipride (50 μg, n = 8) has no independent effects on the expression of depotentiation. (C) Reducing the time interval between HFT and LFS generates a more robust form of depotentation. Low frequency stimulation (LFS) at 5 Hz (600 pulses) when given 1 min post-HFT (200 Hz) in the presence of vehicle injection (n = 6) results in a significant reversal of LTP. At 24 h evoked responses reflect pre-HFT basal levels of evoked responses. Application of noraporphine (1.25 μg, n = 4) prior to the induction of depotentiation results in a significant inhibition of depotentiation. Line breaks indicate a change in time-scale. (D) To examine whether depotentiation that is induced by a milder protocol is sensitive to D2-like receptor agonists, LTP was induced with 100 Hz HFT and 5 min later 300 pulses of 5 Hz stimulation were given. Application of this protocol in the presence of vehicle injection (n =7) results in a significant reversal of LTP. Application of noraporphine (1.25 μg, n = 5) prior to the induction of depotentiation results in a significant inhibition of depotentiation. Line breaks indicate a change in time-scale. (E) Original analog traces show the field potentials evoked from the DG before HFT, 2 min post-HFT, 5 min post-LFS and 24 h post-LFS in the presence of (i) vehicle and (ii) noraporphine (1.25 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 4.

Depotentiation in the DG of freely moving rats is inhibited by agonist priming of dopamine D2-like receptors with the agonist quinpirole or noraporphine. (A,B) Low frequency stimulation (LFS) at 5 Hz (600 pulses) when given 5 min post-HFT (200 Hz) in the presence of vehicle injection (n = 8) results in a significant reversal of LTP. Application of the D2-like receptor agonist quinpirole (2.5 μg, n = 8) prior to HFT and LFS results in a significant inhibition of depotentiation (A). Similarly, administration of the D2-like receptor agonist noraporphine (1.25 μg, n = 8) prior to HFT and LFS causes a significant inhibition of depotentiation (B). Administration of the D2-like receptor antagonist remoxipride (50 μg), prior to application of either quinpirole (2.5 μg, n = 8) or noraporphine (1.25 μg, n = 8), results in a significant prevention of the inhibitory effects of the agonists on depotentiation (A,B). Remoxipride (50 μg, n = 8) has no independent effects on the expression of depotentiation. (C) Reducing the time interval between HFT and LFS generates a more robust form of depotentation. Low frequency stimulation (LFS) at 5 Hz (600 pulses) when given 1 min post-HFT (200 Hz) in the presence of vehicle injection (n = 6) results in a significant reversal of LTP. At 24 h evoked responses reflect pre-HFT basal levels of evoked responses. Application of noraporphine (1.25 μg, n = 4) prior to the induction of depotentiation results in a significant inhibition of depotentiation. Line breaks indicate a change in time-scale. (D) To examine whether depotentiation that is induced by a milder protocol is sensitive to D2-like receptor agonists, LTP was induced with 100 Hz HFT and 5 min later 300 pulses of 5 Hz stimulation were given. Application of this protocol in the presence of vehicle injection (n =7) results in a significant reversal of LTP. Application of noraporphine (1.25 μg, n = 5) prior to the induction of depotentiation results in a significant inhibition of depotentiation. Line breaks indicate a change in time-scale. (E) Original analog traces show the field potentials evoked from the DG before HFT, 2 min post-HFT, 5 min post-LFS and 24 h post-LFS in the presence of (i) vehicle and (ii) noraporphine (1.25 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 5.

The dopamine D2 receptor antagonist remoxipride inhibits weak but not robust LTP in the DG of freely moving rats. Basal synaptic transmission is unaffected by the antagonist. (A) 200 Hz HFT in the presence of vehicle (n = 8) results in a robust long-term potentiation which persists for 24 h. Prior application of the D2-like receptor antagonist remoxipride (50 μg, n = 6) has no effect on the expression of LTP (n = 8). Similarly, basal synaptic transmission is unaffected by application of remoxipride (50 μg, n = 8), compared with vehicle-injected controls (n = 8). Line breaks indicate a change in time-scale. (B) Original analog traces showing the field potentials evoked from the DG pre-HFT, 5 min and 24 h following 200 HFT in the presence of (i) vehicle or (ii) remoxipride (50 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms. (C) 100 Hz HFT in the presence of vehicle (n = 7) results in long-term potentiation which persists for ∼4 h. Prior application of the D2-like receptor antagonist remoxipride (50 μg, n = 7) significantly inhibits expression of this weaker form of LTP. Line breaks indicate a change in time-scale. (D) Original analog traces showing the field potentials evoked from the DG pre-HFT, 5 min and 24 h following 100 HFT in the presence of (i) vehicle or (ii) remoxipride (50 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

Figure 5.

The dopamine D2 receptor antagonist remoxipride inhibits weak but not robust LTP in the DG of freely moving rats. Basal synaptic transmission is unaffected by the antagonist. (A) 200 Hz HFT in the presence of vehicle (n = 8) results in a robust long-term potentiation which persists for 24 h. Prior application of the D2-like receptor antagonist remoxipride (50 μg, n = 6) has no effect on the expression of LTP (n = 8). Similarly, basal synaptic transmission is unaffected by application of remoxipride (50 μg, n = 8), compared with vehicle-injected controls (n = 8). Line breaks indicate a change in time-scale. (B) Original analog traces showing the field potentials evoked from the DG pre-HFT, 5 min and 24 h following 200 HFT in the presence of (i) vehicle or (ii) remoxipride (50 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms. (C) 100 Hz HFT in the presence of vehicle (n = 7) results in long-term potentiation which persists for ∼4 h. Prior application of the D2-like receptor antagonist remoxipride (50 μg, n = 7) significantly inhibits expression of this weaker form of LTP. Line breaks indicate a change in time-scale. (D) Original analog traces showing the field potentials evoked from the DG pre-HFT, 5 min and 24 h following 100 HFT in the presence of (i) vehicle or (ii) remoxipride (50 μg). Vertical scale bar corresponds to 5 mV; horizontal scale bar corresponds to 4 ms.

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