PM310. Pregabalin prevents morphine-induced neuroadaptation in VTA DA neurons and reduces morphine self-administration and withdrawal in mice.

Abstract

Gabapentinoid, pregabalin, is widely used to treat epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder. Pregabalin is believed to lack abuse potential, but it is also known to produce an euphoric state in some patients. Dopamine (DA) neurons in the ventral tegmental area (VTA) play a key role in the mechanisms of action of addictive drugs. Particularly, addictive drugs including morphine induce glutamatergic neuroplasticity in VTA DA cells. The goal of this study was to determine whether (1) pregabalin alone can induce persistent neuroadaptations in VTA DA neurons like other addictive drugs and (2) whether it alters reinforcing properties of morphine.

We used whole-cell voltage-clamp recordings to study synaptic responses of VTA DA neurons in slices. Neuroplasticity was assessed as AMPAR/NMDAR-mediated current ratio. Using C57BL/6J mice we examined withdrawal symptoms, locomotor activity and intravenous self-administration.

We first demonstrated that non-sedative doses of pregabalin (50–200 mg/kg, i.p.) did not alter the AMPAR/NMDAR ratio in VTA DA neurons at 24 h after the treatment. Mice did not self-administer it more than saline. Next, we showed that pretreatment with pregabalin (50 mg/kg, i.p) persistently suppressed morphine (10 mg/kg, s.c.) treatment-induced neuroplasticity in the VTA DA neurons. Importantly, the same dose of pregabalin attenuated morphine-induced hyperlocomotion and self-administration of morphine. Furthermore, it also suppressed withdrawal symptoms, such as jumps and tremor episodes in morphine-treated mice.

Our results are consistent with nonaddictive profile of pregabalin, although recently its abuse has been increasing in drug addicts. Gabapentinoids may have potential for development of novel treatment strategies for opioid addiction.