title: L-type Ca²⁺ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory.
abstract: 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.
authors.affiliation: Department of Neuroscience and Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Degoulet
authors.affiliation: Department of Neuroscience and Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Stelly
authors.affiliation: Department of Neuroscience and Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.|Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K-C
authors.initials: KC
authors.lastname: Ahn
authors.affiliation: Department of Neuroscience and Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Morikawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D004347:Drug Interactions; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D018683:Excitatory Amino Acid Agents; D018377:Neurotransmitter Agents; D003042:Cocaine; D017275:Isradipine