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 Ca2+ 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.

L‐type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes

“…A new study supporting our data finds that the LTCC blocker isradipine, injected directly into the rat VTA, blocks acquisition of cocaine CPP (potentially via Ca v 1.3 channels as Ca v 1.3 is the predominant subunit expressed in VTA neurons; Rajadhyaksha et al 2004). They further extend these findings to demonstrate that isradipine can enhance extinction of cocaine CPP and block cocaine-induced reinstatement (Degoulet et al 2016), a model of relapse to drug taking behaviour. Similarly, the LTCC blockers nifedipine and isradipine, infused into the VTA, attenuate cue-induced cocaine seeking in the rat cocaine self-administration model (Nunes et al 2015).…”

“…They further extend these findings to demonstrate that isradipine can enhance extinction of cocaine CPP and block cocaine‐induced reinstatement (Degoulet et al . ), a model of relapse to drug taking behaviour. Similarly, the LTCC blockers nifedipine and isradipine, infused into the VTA, attenuate cue‐induced cocaine seeking in the rat cocaine self‐administration model (Nunes et al .…”

Isradipine enhancement of virtual reality cue exposure for smoking cessation: Rationale and study protocol for a double-blind randomized controlled trial

“…Even in the absence of the addictive drug, exposure to cues is sufficient to trigger dopamine release, which plays a role in motivation, thus promoting drug-seeking behavior [9]. These mechanisms are highly conserved across species and play a central role in cigarette addiction where strong associations are formed between smoking and a variety of sensory cues, including proximal (e.g., cigarettes, lighters, ashtrays), contextual (e.g., social and physical environments in which smoking commonly occurs), or interoceptive (e.g., negative mood state) [10][11][12]. Among smokers who quit, strong cravings can be triggered by drug-associated cues even after periods of abstinence and beyond the withdrawal phase [13][14][15][16][17].…”

Type‐1 astrocyte‐like stem cells harboring Cacna1d gene deletion exhibit reduced proliferation and decreased neuronal fate choice

“…Both Ca v 1.2 and Ca v 1.3 subserve a host of physiological functions including activity‐dependent gene regulation (Striessnig, Pinggera, Kaur, Bock, & Tuluc, ; Wheeler et al, ), modulation of synaptic plasticity (Degoulet, Stelly, Ahn, & Morikawa, ; Moosmang, ), neuronal differentiation (D'Ascenzo et al, ; Deisseroth et al, ; Völkening, Schonig, Kronenberg, Bartsch, & Weber, ), and control of electrical excitability (Geier, Lagler, Boehm, & Kubista, ). Isoform‐specific properties of Ca v 1.2 and Ca v 1.3 have been identified with respect to biophysical properties and subcellular localization (reviewed in (Striessnig et al, ).…”

“…LTCCs modulate fundamental brain processes such as context‐dependent behaviors, learning and memory (Davis & Bauer, ; Degoulet et al, ; McKinney, Sze, White, & Murphy, ; Moosmang, ; Seoane, Massey, Keen, Bashir, & Brown, ), depression‐ and anxiety‐related behaviors (Dao et al, ; Kabir, Martinez‐Rivera, & Rajadhyaksha, ; Lee et al, ; Striessnig et al, ), and addiction (Degoulet et al, ; Ford, Wolf, & Hu, ; Giordano et al, ). They also appear to play an important pathophysiological role in Parkinson's disease, autism, Alzheimer's dementia, and epilepsy (Amano et al, ; Anekonda & Quinn, ; Bhat et al, ; Chan et al, ; Dragicevic et al, ; Liao & Soong, ; Pinggera et al, ; Stiglbauer et al, ).…”