Abstract

In rat prefrontal cortex (the prelimbic area of medial frontal cortex), the induction of long-term depression (LTD) and long-term potentiation (LTP) of glutamatergic synapses is powerfully modulated by dopamine. The presence of dopamine in the bathing medium facilitates LTD in slice preparations, whereas in the anesthetized intact brain, dopamine released from dopaminergic axon terminals in the prefrontal cortex facilitates LTP. Dopaminergic facilitation of LTD is at least partly achieved by postsynaptic biochemical mechanisms in which enzymatic processes triggered by dopamine receptor activation cooperate with those triggered by glutamate metabotropic receptor activation. Evidence suggests that dopamine facilitates LTP also in the slice condition. In this case, dopamine receptors must be pre-stimulated (‘primed’) before the application of high-frequency stimuli in the presence of dopamine. This procedure may mimic baseline stimulation of dopamine receptors that occurs under physiological conditions.

Dopamine Modulates Glutamatergic Transmission in the Prefrontal Cortex

Dopamine plays important roles in the function of primate prefrontal cortex (PFC) (Sawaguchi and Goldman-Rakic, 1991, 1994; Goldman-Rakic, 1995; William and Goldman-Rakic, 1995) and the rodent medial frontal cortex (Glowinski et al., 1984), which is believed by many to be the functional counterpart of primate dorsal/lateral prefrontal cortex (particularly the prelimbic area of the medial frontal cortex) (Floresco et al., 1997; Zahrt et al., 1997; Birrell and Brown, 2000). In monkeys, interruption of dopaminergic transmission in dorsolateral PFC by focal D1 antagonist application impairs spatial working memory (Sawaguchi and Goldman-Rakic, 1991, 1994) and exaggerates or inhibits (depending on the dose) the delay period activity of PFC neurons during the working memory task (William and Goldman-Rakic, 1995). Dopamine neurons in substantia nigra and ventral tegmental area (VTA) show increases of firing in response to salient or appetitive stimuli (Ljungberg et al., 1992; Mirenowicz and Schultz, 1996) or to conditioned stimuli predicting reward (Schultz et al., 1993). In the latter case (Schultz et al., 1993), one of the task phases in which the dopamine neurons showed the increases is actually a delay period of a spatial task. These results therefore raise the possibility that at least in certain behavioral phases, a phasic dopamine release coincides with the activity of PFC neurons to tune neuronal transmission at these neurons. Similarly in rats, normal working memory requires optimal levels of dopamine in the prelimbic area (i.e. rat PFC) (Zahrt et al., 1997; Mizoguchi et al., 2000), and some VTA neurons and PFC deep layer neurons were shown to increase their activity at the same behavioral phases in an appetitive operant task (Kosobud et al., 1994).

Modulation of PFC glutamatergic transmission by dopamine has been studied at the cellular level. For example, it was shown that at least D1 subtype of dopamine receptors co-localize with glutamate receptors on dendritic spines and shafts of pyramidal neurons in monkey frontal layers II and V (Smiley et al., 1994; Bergson et al., 1995). Electrophysiologically, the D1 agonist was shown to reduce excitatory transmission in collateral synapses between a pair of layer V pyramidal neurons (Gao et al., 2001). Pyramidal neuron collateral transmission is believed to participate in the generation of the sustained delay period activity (Goldman-Rakic, 1995). Interestingly, collateral transmission between layer III pyramidal neurons in monkey PFC slices was unaffected by dopamine (Urban et al., 2002), while dopamine reduced excitatory transmission in the presumably projection fiber synapses on the same neurons (Urban et al., 2002). In rat PFC slices, dopamine inhibits glutamatergic transmission at layer V pyramidal neurons after stimulation of the superficial (Law-Tho et al., 1994, 1995; Otani et al., 1998, 1999) or deep layer fibers (Law-Tho et al., 1994). The deep layer afferents probably contain projection fibers from the hippocampus (Jay and Witter, 1991), which is involved in working memory (Floresco et al., 1997) and schizophrenia pathogenesis (Lipska and Weinberger, 2002). Several in vivo studies confirm that the synaptic transmission in the hippocampo-PFC monosynaptic connection is inhibited by dopamine (Jay et al., 1995b; Gurden et al., 1999; Floresco and Grace, 2003).

Lasting Neural Traces in the PFC

The above results suggest that a dopamine action in the PFC is tuning or stabilization of ongoing glutamatergic transmission to regulate online information processing. However, the other well-known cellular effect of dopamine in the PFC is its powerful modulation on the induction of long-term plasticity in glutamatergic synapses. This effect is as important, because the PFC appears to be involved not only in online processes but also in the formation of long-term memory. For example, a transient disturbance of PFC function by transcranial magnetic stimulation impairs the formation of episodic long-term memory in humans (Rossi et al., 2001, 2003). At cellular levels, the early study in monkeys (Fuster, 1973) remarked that sustained activity of PFC neurons as seen in trained animals does not occur in the animals untrained in the delayed-response paradigm. Also in monkeys, it was shown that during the progress of an associative learning, the response-related PFC activity appeared progressively earlier in a trial (Assad et al., 1998), indicating an underlying plastic process. In rats, learning in an operant discrimination task was accompanied by persistent increases or decreases in PFC neuron activity (Mulder et al., 2000). In mice, the persistence of the memory for conditioned fear and its successful extinction were nicely correlated with a lasting decrease and increase in the thalamo-PFC synaptic responses, respectively (Herry and Garcia, 2002). Based on these and other lines of evidence, we recently discussed a role for the PFC in long-term memory and the involvement of synaptic plasticity and its dopaminergic modulation in the memory formation (Otani, 2002, 2003).

Long-term Synaptic Plasticity in Rat PFC Neurons

Pioneering Works

Pioneering in vitro studies on LTP and LTD in rat PFC (Hirsch and Crepel, 1990, 1991, 1992) showed that the application of 50 or 100 Hz tetanic stimuli to layer I-II afferent fibers in the presence of γ-aminobutyric acid A (GABA-A) antagonist bicuculline induce LTP or LTD of monosynaptic glutamatergic responses in the portion of layer V pyramidal neurons. Both LTP and LTD are dependent on postsynaptic Ca2+ increases (Hirsch and Crepel, 1992). For LTP, but not LTD, at least part of the critical Ca2+ enter through NMDA (N-methyl-d-aspartate) receptor-linked ion channels, because the NMDA receptor antagonist AP5 (dl-2-amino-5-phosphonopentanoic acid) selectively blocks LTP and unmasks underlying LTD (Hirsch and Crepel, 1991).

NMDA receptor-dependency of LTP was also shown by Vickery et al. (1997) in the identical preparation. In this case, they applied stimuli mimicking hippocampal theta burst (four shocks at 100 Hz, repeated 10 times in every 200 ms) and showed LTP induction in ∼60% of the neurons tested. AP5 significantly reduced this LTP. It is known that in hippocampal neurons, the short burst (four shocks) ‘primes’ the stimulated dendrites so that a successive burst arriving 200 ms later optimally activates the voltage-dependent NMDA receptor-channel complex (Larson and Lynch, 1988). Thus, the 10 times repetitive applications of the burst (Vickery et al., 1997) should strongly activate NMDA receptors to induce LTP.

Anatomically, there is a monosynaptic projection from ventral CA1/subiculum to the prelimbic area in the rat (Jay and Witter, 1991). Therefore, theta-patterned discharge of hippocampal neurons may excite prelimbic synapses to induce NMDA-dependent LTP under, for example, exploratory behavioral conditions (O’Keefe and Nadel, 1978). Although the effect of theta burst stimuli to the hippocampo-PFC synapses has not been tested, LTP in this connection was induced by brief 250 Hz tetanic stimuli (Laroche et al., 1990), and it was shown to be NMDA-dependent (Jay et al., 1995a).

Dopaminergic Facilitation of Prefrontal LTD

As discussed above, application of tetanic stimuli (50 or 100 Hz) induced LTP or LTD in the layer I-II to layer V pyramidal neuron glutamatergic synapses in rat PFC slices (Hirsch and Crepel, 1990, 1991, 1992). Law-Tho et al. (1995) found that the presence of dopamine (50–100 µM) in the bathing medium during tetanic stimuli facilitates LTD and inhibits LTP. Dopamine application alone only transiently depressed the synaptic responses. Subsequent studies (Otani et al., 1998, 1999) fixed the train parameter as 50 Hz, 2 s (four times at 0.1 Hz), and showed that while the tetanic stimuli alone do not induce lasting plasticity, application of the stimuli in the presence of dopamine consistently induces LTD (Fig. 1). Dopamine acts through both D1 and D2 dopamine receptors for the induction of this LTD (Otani et al., 1998). The dopamine-facilitated LTD does not require NMDA receptors but requires postsynaptic depolarization and postsynaptic Ca2+ increases (Otani et al., 1998), consistent with the earlier studies (Hirsch and Crepel, 1991, 1992).

Mechanisms of Dopamine-facilitated LTD

Enhancement of Postsynaptic Excitability by Dopamine

It was shown that dopamine enhances late postsynaptic depolarization during the LTD-inducing 50 Hz stimuli while it reduces postsynaptic responses evoked by low-frequency stimuli (Otani et al., 1998; Otani and Kolomiets, 2003). Dopamine also increases the number of spikes upon depolarizing current injection (Penit-Soria et al., 1987; Yang and Seamans, 1996) through D1 receptor activation (Yang and Seamans, 1996). Underlying mechanisms of this effect may be the enhancement of tetrodotoxin-sensitive slowly-inactivating persistent Na+ current (INaP) and the attenuation of slowly inactivating, outwardly rectifying K+ current (Yang and Seamans, 1996). Dopamine action on the INaP may require protein kinase C (PKC) (Gorelova and Yang, 2000).

Despite these data, however, it is still unclear whether the enhancement of postsynaptic excitability by dopamine is necessary for LTD induction in deep layer pyramidal neurons of the PFC. First, there are contradictions in the literature. Geijo-Barrientos and Pastore (1995) found a reduction of the INaP by dopamine in layer II–VI regular spiking neurons. Gulledge and Jaffe (1998) found a reduction in the number of spikes in layer V pyramidal neurons by D2 receptors. Maurice et al. (2001) found no effect of dopamine on the INaP in acutely dissociated PFC pyramidal neurons. These results are rather consistent to dopamine effects found in striatal medium spiny neurons (Nicola et al., 2000) (see Concluding Remarks for more discussion). Secondly, more importantly, our recent analysis showed that the dopaminergic enhancement of postsynaptic depolarization during 50 Hz tetanus is blocked by NMDA antagonist AP5 (Otani and Kolomiets, 2003; see also Wang and O’Donnell, 2001), but LTD is inducible in the presence of AP5 (Otani et al., 1998). Thus, the enhancement of depolarization by dopamine during tetanus appears unnecessary for LTD, although it is possible that depolarization enhancement in local dendritic sites was not adequately monitored by somatic electrodes.

But, the NMDA-dependent enhancement of postsynaptic depolarization by dopamine may play roles in online information processing. Recent modeling studies (Durstewitz et al., 2000; Brunel and Wang, 2001) suggest that an increase in NMDA-mediated conductance by dopamine is a major factor to cause the enhancement of signal-to-noise ratio and the stabilization of sustained high-frequency collateral activity during delay period of working memory tasks.

Cooperativity between Dopamine Receptors and mGluRs

Blockade of group I or group II mGluRs during tetanus blocked dopamine-facilitated LTD (Otani et al., 1999). This result suggests that the dopamine receptors and the groups I and II mGluRs cooperate for LTD induction in the PFC. The following lines of evidence showed that this cooperativity involves postsynaptic converging activation of MAP-Ks (mitogen-activated protein kinases) (Valjent et al., 2001) by dopamine receptors and the mGluRs (see Fig. 2A). First, LTD could be induced by combined bath-application of dopamine and the group I and II mGluR agonist ACPD [(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid] (Otani et al., 1999). Secondly, this LTD was blocked by postsynaptic inhibition of MAP-Ks (Otani et al., 1999). Thirdly, Western blot analyses with anti-active MAP-Ks antibody showed that MAP-Ks are activated by dopamine, a group I mGluR agonist, and a group II mGluR agonist (Otani et al., 1999). Fourthly, combined application of dopamine and one of these mGluR agonists synergistically or additively activated MAP-Ks (Otani et al., 1999). Although critical target(s) of the MAP-Ks for LTD induction is still unknown, a study in the hippocampus suggested a link between MAP-Ks and the modification of dendritic spine shape (Wu et al., 2001). Also in the hippocampus, MAP-Ks are necessary for the phosphorylation of CREB (cyclic AMP response element-binding protein) by PKC and protein kinase A (PKA) (Roberson et al., 1999), confirming the importance of the MAP-Ks as a mediator for long-term cellular changes (Valjent et al., 2001; Fig. 2A).

Dopaminergic Facilitation of Prefrontal LTP

In Vivo Studies

Gurden et al. (1999) tested the effect of VTA stimulation on LTP of the hippocampo-PFC monosynaptic projection (Jay and Witter, 1991) in anesthetized rats. First, single VTA stimulation just before a test pulse delivery to the ventral CA1/subiculum reversibly depressed the hippocampo-PFC synaptic responses, consistent with the observation made in vitro that bath-applied dopamine transiently depresses PFC synaptic responses (Law-Tho et al., 1995; Otani et al., 1998, 1999). Second, application of 50 Hz 2 sec stimuli to the VTA 2 sec before 250 Hz tetanus to the ventral CA1/subculum enhanced LTP induced by the 250 Hz tetanus. Third, VTA lesion reduced the magnitude of LTP induced by the 250 Hz tetanus. Gurden et al. (2000) subsequently showed that the hippocampal stimulation evokes dopamine release in the PFC. In terms of the mechanism, it was shown that dopamine stimulates PKA through D1 receptors to facilitate LTP (Gurden et al., 2000). Because LTP in the PFC requires NMDA receptors (Hirsch and Crepel, 1991; Jay et al., 1995a), D1 receptors and NMDA receptors may cooperate in LTP-inducing mechanisms (see Fig. 2B). Interestingly, Baldwin et al. (2002) showed that normal acquisition of appetitive operant conditioning in the rat requires D1 receptors, NMDA receptors, and PKA in the PFC. This agreement at the cellular level supports the idea that LTP-like processes in the PFC may be involved in learning and memory (Herry and Garcia, 2002; Otani, 2002).

In vitro Studies

Dopaminergic facilitation of LTP was not seen in the in vitro studies (Law-Tho et al., 1995; Otani et al., 1998, 1999). A critical difference between the intact brain and the brain slice preparations may be the lack of baseline stimulation of dopamine receptors in the slice preparation. Dopaminergic axons are severed and probably inactive in the slices, because if it is otherwise, the application of dopamine receptor antagonists should augment the synaptic responses. We detect no such effects (unpublished observations). We suggest that during a few-hour pre-conditioning period, dopamine receptors in the PFC slices are largely unstimulated. By contrast, baseline stimulation of dopamine receptors occurs in the physiological situations, since dopamine levels in the PFC are tonically maintained (Takahata and Moghaddam, 2000) and show repeated increases during behavior (Bassareo and Di Chiara, 1997).

We attempted to partially control this factor by exposing the slices to bath-applied dopamine first (10–15 min; Blond et al., 2002; Fig. 3). When the synaptic responses recovered from the transient inhibitory effect of dopamine (in ∼30 min), dopamine was identically applied for the second time. This second application was coupled to 50 Hz stimuli. This protocol induced LTP, not LTD (Blond et al., 2002; Fig. 3). The second application of dopamine was necessary for LTP induction (Blond et al., 2002).

Still little is known about cellular mechanisms of this LTP. However, it was noted that the transient inhibition of the synaptic responses by the second application of dopamine is always smaller than that by the first application (Blond et al., 2002; Fig. 3). Furthermore, unlike the first application, the second application of dopamine does not enhance postsynaptic depolarization during tetanic stimuli (Otani and Kolomiets, 2003). These results suggest the possibility that although the inhibition of glutamatergic synaptic responses by the first dopamine application is only transient (∼30 min), the first dopamine lastingly changes cellular chemistry so that a delayed dopamine receptor activation combined with identical tetanic stimuli induces LTP, not LTD. We tentatively call the hypothetical lasting dopamine effects as ‘priming’ (e.g. Christie and Abraham, 1992) or ‘metaplastic’ (Abraham and Bear, 1996) effects (Fig. 2B). In this regard, Seamans et al. (2001) showed that D1 receptor stimulation induces enhancement of NMDA receptor-mediated transmission in PFC layer V neurons that manifests slowly (note: this slow effect should be separated from the rapid inhibition of NMDA transmission by dopamine, Law-Tho et al., 1994). Also, Gorelova and Yang (2000) showed that a D1 agonist lastingly decreases first spike latency in layer V neurons. These may be the dopamine-induced metaplastic effects, although if it is the case, postsynaptic depolarization during tetanus in the presence of the second dopamine is expected to be larger than that in the presence of the first dopamine. Our recent analysis suggests the contrary (Otani and Kolomiets, 2003).

Concluding Remarks

Dopaminergic modulation of the function of PFC neurons is still not clearly understood. The reason for the difficulty to pin down clear cellular effects of dopamine appears to be the anatomical, pharmacological, and biochemical diversities of dopamine actions. For example, dopamine has been reported to reduce ongoing glutamatergic transmission in collateral synapses between layer V pyramidal neurons (Gao et al., 2001) and the projection fiber synapses on layer III pyramidal neurons (Urban et al., 2002), but not in the collateral synapses between layer III pyramidal neurons (Urban et al., 2002). Furthermore, dopamine triggers lasting ‘metaplastic’ cellular processes. Therefore, depending on the time elapsed between the beginning of dopamine application and the electrophysiological test, the result may differ dramatically. This may be a main reason for the discrepancy seen in the literature of the dopamine effects on postsynaptic excitability in rat deep layer pyramidal neurons. Thus, one group (Yang and Seamans, 1996; Gorelova and Yang, 2000) found enhancing effects of dopamine on the INaP and neuronal discharge by performing the electrophysiological tests after dopamine or a D1 agonist was washed out of the bath. The other groups (Geijo-Barrientos and Pastore, 1995; Gulledge and Jaffe, 1998) showed opposite results by testing dopamine effects during 1–2 min (Geijo-Barrientos and Pastore, 1995) or 5 min (Gulledge and Jaffe, 1998) bath-application of dopamine. Importantly in this respect, Gorelova and Yang (2000) found a biphasic action of D1 agonist SKF81297 on the first spike latency (their figure 8A3): i.e. an early increase (within 5 min after a brief agonist application) and a late lasting (>20 min) decrease (see also Gulledge and Jaffe, 2001). Taken together therefore, dopamine may indeed have complex actions on cellular excitability in deep layer pyramidal neurons; i.e. initial suppression through D1 and D2 receptors (Gulledge and Jaffe, 1998; Gorelova and Yang, 2000) and subsequent enhancement through D1 receptors (Gorelova and Yang, 2000).

In conclusion, in order to accurately assess short- and long-lasting cellular effects of dopamine in the PFC, anatomical identification of stimulated axons and neurons, and a good control over the application protocol and the pattern of VTA stimulation must be taken into consideration.

Figure 1. Dopaminergic facilitation of LTD induction in rat PFC (prelimbic) neurons in vitro. (A) Layer V pyramidal neurons of the prelimbic area in coronal slices were penetrated by a sharp micro pipette, and glutamatergic synaptic responses evoked by layer I–II stimulation were recorded. Slope analysis was applied to the initial rising phase (<1 ms from onset), which is monosynaptic component (Hirsch and Crepel, 1990). (B) Application of tetanic stimuli (50 Hz, 2 s, repeated four times in every 10 s) does not itself induce long-lasting synaptic changes. (C) Bath-application of dopamine (100 µM for 10–15 min) induces a transient inhibition of synaptic responses which recovers within 30 min. (D) Combination of the tetanic stimuli and the bath-application of dopamine induces LTD. The synaptic responses taken from the baseline period (1) and 40 min after the coupling (2) are shown in the inset. Adapted from figure 1 of Otani et al. (1999) with permission.

Figure 1. Dopaminergic facilitation of LTD induction in rat PFC (prelimbic) neurons in vitro. (A) Layer V pyramidal neurons of the prelimbic area in coronal slices were penetrated by a sharp micro pipette, and glutamatergic synaptic responses evoked by layer I–II stimulation were recorded. Slope analysis was applied to the initial rising phase (<1 ms from onset), which is monosynaptic component (Hirsch and Crepel, 1990). (B) Application of tetanic stimuli (50 Hz, 2 s, repeated four times in every 10 s) does not itself induce long-lasting synaptic changes. (C) Bath-application of dopamine (100 µM for 10–15 min) induces a transient inhibition of synaptic responses which recovers within 30 min. (D) Combination of the tetanic stimuli and the bath-application of dopamine induces LTD. The synaptic responses taken from the baseline period (1) and 40 min after the coupling (2) are shown in the inset. Adapted from figure 1 of Otani et al. (1999) with permission.

Figure 3. Dopaminergic facilitation of LTP induction in rat PFC layer V pyramidal neurons in vitro. First, dopamine (100 µM) was bath-applied for 10–15 min. After the recovery from the transient inhibition of synaptic responses, dopamine was applied for the second time. This second application of dopamine was coupled to 50 Hz tetanic stimuli. Adapted from figure 1 of Blond et al. (2002) with permission.

Figure 3. Dopaminergic facilitation of LTP induction in rat PFC layer V pyramidal neurons in vitro. First, dopamine (100 µM) was bath-applied for 10–15 min. After the recovery from the transient inhibition of synaptic responses, dopamine was applied for the second time. This second application of dopamine was coupled to 50 Hz tetanic stimuli. Adapted from figure 1 of Blond et al. (2002) with permission.

Figure 2. Schematic drawings showing possible postsynaptic mechanisms underlying LTD and LTP in the rat PFC neurons. (A) Possible mechanism for LTD. When dopamine receptors are in unstimulated (‘non-primed’) state, as in normal slice conditions, dopamine receptor stimulation combined with the stimulation of glutamate receptors by high-frequency synaptic input results in LTD of the AMPA receptor-mediated synaptic transmission. This LTD is NMDA receptor-independent (Otani et al., 1998) but dependent on the activation of groups I and II mGluRs (Otani et al., 1999). A possible consequence of the mGluRs stimulation is activation of PLC, to give rise to internal Ca2+ release and PKC activation (Otani et al., 2002). The increase of postsynaptic Ca2+ concentration may be also achieved through the activation of voltage-dependent Ca2+ channels (Otani et al., 1998). Stimulation of D1 receptors may activate cAMP and PKA, and D2 receptor stimulation may result in arachidonic acid (AA) production (Vial and Piomelli, 1995; Nisson et al., 1998). Although the importance of these dopamine-related second messengers in LTD is yet to be shown, we know that a critical factor for LTD is a joint activation of MAP-Ks (ERK1 and ERK2) by D1 and D2 receptors and the mGluRs (Otani et al., 1999). (B) Possible mechanism for LTP. When dopamine receptors are in pre-stimulated (‘primed’) state, dopamine receptor activation combined with the activation of glutamate receptors results in LTP. The ‘priming’ may occur in the physiological conditions by spontaneous or behaviorally correlated activity of VTA neurons (Bassareo and Di Chiara, 1997; Takahata and Moghaddam, 2000). For in vivo LTP facilitated by VTA stimulation, we know that both NMDA receptor activation and D1 receptor-mediated PKA activation are necessary (Jay, 1995a; Gurden et al., 2000). For the in vitro LTP, our preliminary data also suggest involvement of NMDA receptors. But our recent analysis showed that postsynaptic depolarization during LTP-inducing stimuli in vitro is smaller than that during control stimuli (Otani and Kolomiets, 2003). The involvement of mGluRs and their modulation by dopamine-induced ‘metaplastic’ effects are still hypothetical.

Figure 2. Schematic drawings showing possible postsynaptic mechanisms underlying LTD and LTP in the rat PFC neurons. (A) Possible mechanism for LTD. When dopamine receptors are in unstimulated (‘non-primed’) state, as in normal slice conditions, dopamine receptor stimulation combined with the stimulation of glutamate receptors by high-frequency synaptic input results in LTD of the AMPA receptor-mediated synaptic transmission. This LTD is NMDA receptor-independent (Otani et al., 1998) but dependent on the activation of groups I and II mGluRs (Otani et al., 1999). A possible consequence of the mGluRs stimulation is activation of PLC, to give rise to internal Ca2+ release and PKC activation (Otani et al., 2002). The increase of postsynaptic Ca2+ concentration may be also achieved through the activation of voltage-dependent Ca2+ channels (Otani et al., 1998). Stimulation of D1 receptors may activate cAMP and PKA, and D2 receptor stimulation may result in arachidonic acid (AA) production (Vial and Piomelli, 1995; Nisson et al., 1998). Although the importance of these dopamine-related second messengers in LTD is yet to be shown, we know that a critical factor for LTD is a joint activation of MAP-Ks (ERK1 and ERK2) by D1 and D2 receptors and the mGluRs (Otani et al., 1999). (B) Possible mechanism for LTP. When dopamine receptors are in pre-stimulated (‘primed’) state, dopamine receptor activation combined with the activation of glutamate receptors results in LTP. The ‘priming’ may occur in the physiological conditions by spontaneous or behaviorally correlated activity of VTA neurons (Bassareo and Di Chiara, 1997; Takahata and Moghaddam, 2000). For in vivo LTP facilitated by VTA stimulation, we know that both NMDA receptor activation and D1 receptor-mediated PKA activation are necessary (Jay, 1995a; Gurden et al., 2000). For the in vitro LTP, our preliminary data also suggest involvement of NMDA receptors. But our recent analysis showed that postsynaptic depolarization during LTP-inducing stimuli in vitro is smaller than that during control stimuli (Otani and Kolomiets, 2003). The involvement of mGluRs and their modulation by dopamine-induced ‘metaplastic’ effects are still hypothetical.

References

Abraham WC, Bear MF (
1996
) Metaplasticity: the plasticity of synaptic plasticity.
Trends Neurosci
 
19
:
126–
130.
Assad WF, Rainer G, Miller EK (
1998
) Neural activity in the primate prefrontal cortex during associative learning.
Neuron
 
21
:
1399–
1407.
Baldwin AE, Sadeghian K, Kelly AE (
2002
) Appetitive instumental learning requies coincident activation of NMDA and dopamine D1 receptor within the medial prefrontal cortex.
J Neurosci
 
22
:
1063–
1071.
Bassareo V, Di Chiara G (
1997
) Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum.
J Neurosci
 
17
:
851–
861.
Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic PS (
1995
) Regional, cellular, and subcellular variations in the distributions of D1 and D5 dopamine receptors in primate brain.
J Neurosci
 
15
:
7821–
7836.
Birrell JM, Brown VJ (
2000
) Medial frontal cortex mediates perceptual attentional set shifting in the rat.
J Neurosci
 
20
:
4320–
4324.
Blond O, Crepel F, Otani S (
2002
) Long-term potentiation in rat prefrontal slices facilitated by phased application of dopamine
Eur J Pharmacol
 
438
:
115–
116.
Brunel N, Wang X-J (
2001
) Effects of neuromodulation in a cortical network model of object working memory dominated by recurrent inhibition.
J Comput Neurosci
 
11
:
63–
85.
Christie BR, Abraham WC (
1992
) Priming of associative long-term depression in the dentate gyrus by theta frequency synaptic activity.
Neuron
 
9
:
79–
84.
Durstewitz D, Seamans JK, Sejnowski TJ (
2000
) Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex.
J Neurophysiol
 
83
:
1733–
1750.
Floresco SB, Grace AA (
2003
) Gating of hippocampal-evoked activity in prefrontal cortical neurons by inputs from the mediodorsal thalamus and ventral tegmental area.
J Neurosci
 
23
:
3930–
3943.
Floresco SB, Seamans JK, Phillips AG (
1997
) Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay.
J Neurosci
 
17
:
1880–
1890.
Fuster JM (
1973
) Unit activity in prefrontal cortex during delayed-response performance: neuronal correlates of transient memory.
J Neurophysiol
 
36
:
61–
78.
Gao WJ, Krimer LS, Goldman-Rakic PS (
2001
) Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits.
Proc Natl Acad Sci USA
 
98
:
295–
300.
Geijo-Barrientos, E and Pastore, C (
1995
) The effects of dopamine on the subthreshold electrophysiological responses of rat prefrontal cortex neurons in vitro.
Eur J Neurosci
 
7
:
358–
366.
Glowinski J, Tassin JP, Thierry AM (
1984
) The mesocortico-prefrontal dopaminergic neurons.
Trends Neurosci
 
7
:
415–
418.
Goldman-Rakic P (
1995
) Cellular basis of working memory.
Neuron
 
14
:
477–
485.
Gorelova NA, Yang CR (
2000
) Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro.
J Neurophysiol
 
84
:
75–
87.
Gulledge AT, Jaffe DB (
1998
) Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex.
J Neurosci
 
18
:
9139–
9151.
Gulledge AT, Jaffe DB (
2001
) Multiple effects of dopamine on layer V pyramidal cell excitability in rat prefrontal cortex.
J Neurophysiol
 
86
:
586–
595.
Gurden H, Tassin J-P, Jay TM (
1999
) Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation.
Neuroscience
 
94
:
1019–
1027.
Gurden H, Takita M, Jay TM (
2000
) Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo.
J Neurosci
 
20
:
RC106
.
Herry C, Garcia R (
2002
) Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice.
J Neurosci
 
22
:
577–
583.
Hirsch JC, Crepel F (
1990
) Use-dependent changes in synaptic efficacy in rat prefrontal neurons in vitro.
J Physiol (Lond)
 
427
:
31–
49.
Hirsch JC, Crepel F (
1991
) Blockade of NMDA receptors unmasks a long-term depression in synaptic efficacy in rat prefrontal neurons in vitro.
Exp Brain Res
 
85
:
621–
624.
Hirsch JC, Crepel F (
1992
) Postsynaptic calcium is necessary for the induction of LTP and LTD of monosynaptic EPSPs in prefrontal neurons: an in vitro study in the rat.
Synapse
 
10
:
173–
175.
Jay TM, Witter MP (
1991
) Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin.
J Comp Neurol
 
313
:
574–
586.
Jay TM, Burette F, Laroche S (
1995
a) NMDA receptor-dependent LTP in the hippocampal afferent fibre system to the prefrontal cortex in the rat.
Eur J Neurosci
 
7
:
247–
250.
Jay TM, Glowinski J, Thierry AM (
1995
) Inhibition of hippocampo-prefrontal cortex excitatory responses by the mesocortical DA system.
Neuroreport
 
6
:
1845–
1848.
Kosobud AE, Glenda CH, Chapin JK (
1994
) Behavioral associations of neuronal activity in the ventral tegmental area of the rat.
J Neurosci
 
14
:
7117–
7129.
Laroche S, Jay TM, Thierry A-M (
1990
) Long-term potentiation in the prefrontal cortex following stimulation of the hippocampal CA1/subicular region.
Neurosci Lett
 
114
:
184–
190.
Larson J, Lynch G (
1988
) Role of N-methyl-d-aspartate receptors in the induction of synaptic potentiation by burtst stimulation patterned after the hippocampal theta-rhythm.
Brain Res
 
441
:
111–
118.
Law-Tho D, Hirsch, JC, Crepel F (
1994
) Dopamine modulation of synaptic transmission in rat prefrontal cortex: an in vitro electrophysiological study.
Neurosci Res
 
21
:
151–
160.
Law-Tho D, Desce JM, Crepel F (
1995
) Dopamine favours the emergence of long-term depression versus long-term potentiation in slices of rat prefrontal cortex.
Neurosci Lett
 
188
:
125–
128.
Lipska BK, Weinberger DR (
2002
) A neurodevelopmental model of schizophrenia: neonatal disconnection of the hippocampus.
Neurotox Res
 
4
:
469–
475.
Ljungberg T, Apicella P, Schultz W (
1992
) Responses of monkey dopamine neurons during learning of behavioral reactions.
J Neurophysiol
 
67
:
145–
163.
Maurice N, Tkatch T, Meisler M, Sprunger LK, Surmeier DJ (
2001
) D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons.
J Neurosci
 
21
:
2268–
2277.
Mirenowicz J, Schultz W (
1996
) Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli.
Nature
 
379
:
449–
451.
Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui D-H, Tabira T (
2000
) Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction.
J Neurosci
 
15
:
1568–
1574.
Mulder AB, Nordquist R, Örgüt O, Pennartz CMA (
2000
) Plasticity of neuronal firing in deep layers of the medial prefrontal cortex in rats engaged in operant conditioning. Prog
Brain Res
 
126
:
287–
301.
Nicola SM, Surmeier DJ, Malenka RC (
2000
) Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.
Annu Rev Neurosci
 
23
:
185–
215.
Nisson CL, Hellstrand M, Ekman A, Eriksson E (
1998
) Direct dopamine D2-receptor-mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+-mobilizing agent.
Br J Pharmacol
 
124
:
1651–
1658.
O’Keefe J, Nadel L (
1978
)
Hippocampus
  as a cognitive map. Oxford: Clarendon Press.
Otani S (
2002
) Memory trace in prefrontal cortex: theory for the cognitive switch.
Biol Rev
 
77
:
563–
577.
Otani S (
2003
) Prefrontal cortex function, quasi-physiological stimuli, and synaptic plasticity.
J Physiol (Paris)
  (in press).
Otani S, Kolomiets B (
2003
) Induction properties of synaptic plasticity in rat prefrontal neurons In: Prefrontal cortex: from synaptic plasticity to cognition (Otani S, ed.). Boston, MA: Kluwer Aademic Publishers (in press).
Otani S, Blond O, Desce J-M, Crepel F (
1998
) Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex.
Neuroscience
 
85
:
669–
676.
Otani S, Auclair N, Desce J-M, Roisin M-P, Crepel F (
1999
) Dopamine receptors and groups I & II mGluRs cooperate for LTD induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases.
J Neurosci
 
19
:
9788–
9802.
Otani S, Daniel H, Takita M, Crepel F (
2002
) Long-term depression induced by postsynaptic group II mGluRs linked to phospholipase C and intracellular calcium rises in rat prefrontal cortex.
J Neurosci
 
22
:
3434–
3444.
Penit-Soria J, Audinat E, Crepel F (
1987
) Excitation of rat prefrontal cortical neurons by dopamine: an in vitro electrophysiological study.
Brain Res
 
42
:
263–
274.
Roberson ED, English JD, Adams JP, Selcher JC, Kondratick C, Sweatt JD (
1999
) The mitogen-activated protein kinae cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus.
J Neurosci
 
19
:
4337–
4348.
Rossi S, Cappa SF, Babiloni C, Pasqualetti P, Miniussi C, F Carducci, Babiloni F, Rossini PM (
2001
) Prefrontal cortex in long-term memory: an ‘interference’ approach using magnetic stimulation.
Nat Neurosci
 
4
:
948–
952.
Rossi S, Miniussi C, P Rossini M, Babiloni C, Cappa S (2003) Transcranial magnetic stimulation of the prefrontal cortex: a complementary approach to investigate human long-term memory. In: Prefrontal cortex: synaptic plasticity to cognition (Otani S, ed.). Boston, MA: Kluwer Academic Publishers (in press).
Sawaguchi T, Goldman-Rakic PS (
1991
) D1 dopamine receptors in prefrontal cortex: involvement in working memory.
Science
 
251
:
947–
950.
Sawaguchi T, Goldman-Rakic PS (
1994
) The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task.
J Neurophysiol
 
71
:
515–
528.
Schultz W, Apicella P, Ljungberg T (
1993
) Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task.
J Neurosci
 
13
:
900–
913.
Seamans JK, Durstewitz D, Christie BR, Stevens CF, Sejnowski TJ (
2001
) Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons.
Proc Natl Acad Sci USA
 
98
:
301–
306.
Smiley JF, Levey AL, Ciliax BJ, Goldman-Rakic PS (
1994
) D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines.
Proc Natl Acad Sci USA
 
91
:
5720–
5724.
Takahata R, Moghaddam B (
2000
) target-specific glutamate regulation of dopamine neurons in the ventral tegmental area.
J Neurochem
 
75
:
1775–
1778.
Urban NN, Gonzàlez-Burgos G, Henze DA, Lewis DA, Barrionuevo G (
2002
) Selective reduction by dopamine of excitatory synaptic inputs to pyramidal neurons in primate prefrontal cortex.
J Physiol (Lond)
 
539
:
707–
712.
Valjent E, Caboche J, Vanhoutte P (
2001
) Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain.
Mol Neurobiol
 
23
:
83–
99.
Vial D, Piomelli D (
1995
) Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2.
J Neurochem
 
64
:
2765–
2772.
Vickery RM, Morris SH, Bindmann LJ (
1997
) Metabotropic glutamate receptors are involved in long-term potentiation in isolated slices of rat medial frontal cortex.
J Neurophysiol
 
78
:
3039–
3046.
Wang J, O’Donnell P (
2001
) D1 dopamine receptors potentiate NMDA-mediated excitability increases in layer V prefrontal cortical pyramidal neurons.
Cereb Cortex
 
11
:
452–
462.
William GV, Goldman-Rakic PS (
1995
) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.
Nature
 
376
:612.
Wu G-Y, Deisseroth K, Tsien RW (
2001
) Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology.
Nat Neurosci
 
4
:
151–
158.
Yang CR, Seamans JK (
1996
) Dopamine D1 receptor actions in layers V–VI rat prefrontal cortex neurons in vitro: modulation of dendritic–somatic signal integration.
J Neurosci
 
16
:
1922–
1935.
Zahrt J, Taylor JR, Mathew RG, Arnsten AFT (
1997
) Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance.
J Neurosci
 
17
:
8528–
8535.