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Drug addiction is driven, in part, by powerful and enduring memories of sensory cues associated with drug intake. As such, relapse to drug use during abstinence is frequently triggered by an encounter with drug-associated cues, including the drug itself. L-type Ca(2+) channels (LTCCs) are known to regulate different forms of synaptic plasticity, the major neural substrate for learning and memory, in various brain areas. Long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA) may contribute to the increased motivational valence of drug-associated cues triggering relapse. In this study, using rat brain slices, we found that isradipine, a general LTCC antagonist used as antihypertensive medication, not only blocks the induction of NMDAR LTP but also promotes the reversal of previously induced LTP in the VTA. In behaving rats, isradipine injected into the VTA suppressed the acquisition of cocaine-paired contextual cue memory assessed using a conditioned place preference (CPP) paradigm. Furthermore, administration of isradipine or a CaV1.3 subtype-selective LTCC antagonist (systemic or intra-VTA) before a single extinction or reinstatement session, while having no immediate effect at the time of administration, abolished previously acquired cocaine and alcohol (ethanol) CPP on subsequent days. Notably, CPP thus extinguished cannot be reinstated by drug re-exposure, even after 2 weeks of withdrawal. These results suggest that LTCC blockade during exposure to drug-associated cues may cause unlearning of the increased valence of those cues, presumably via reversal of glutamatergic synaptic plasticity in the VTA.

Repeated administration of psychostimulant drugs, such as amphetamine, induces an enhanced behavioral response to subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Current thinking is that the ventral tegmental area, but not the nucleus accumbens, plays a critical role in the development of behavioral sensitization. Here, we report that the concomitant blockade of glutamatergic and nicotinic ionotropic receptors in the core of the nucleus accumbens blocks the development of behavioral sensitization to amphetamine and further abolishes the increase in extracellular dopamine release induced by amphetamine in the nucleus accumbens. These findings demonstrate that the development of behavioral sensitization to amphetamine depends, in addition to the well-known role of the ventral tegmental area, on glutamatergic and nicotinic-dependent mechanisms in the core of the nucleus accumbens and further indicate that the dopaminergic mesolimbic pathway must be viewed as a single coordinated system of critical importance in the development of behavioral sensitization to psychostimulant drugs., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Drug addiction is driven, in part, by powerful drug-related memories. Deficits in social life, particularly during adolescence, increase addiction vulnerability. Social isolation in rodents has been used extensively to model the effects of deficient social experience, yet its impact on learning and memory processes underlying addiction remains elusive. Here, we show that social isolation of rats during a critical period of adolescence (postnatal days 21-42) enhances long-term potentiation of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA). This enhancement, which is caused by an increase in metabotropic glutamate receptor-dependent Ca(2+) signaling, cannot be reversed by subsequent resocialization. Notably, memories of amphetamine- and ethanol-paired contextual stimuli are acquired faster and, once acquired, amphetamine-associated contextual memory is more resistant to extinction in socially isolated rats. We propose that NMDAR plasticity in the VTA may represent a neural substrate by which early life deficits in social experience increase addiction vulnerability., (Copyright © 2013 Elsevier Inc. All rights reserved.)