Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.
Background and PurposeVarenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption.Experimental ApproachRats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).Key ResultsMicroinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.Conclusion and ImplicationsFollowing long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.
MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, is a popular drug often taken in environments rich in audio and visual stimulation, such as clubs and dance parties. The present experiments were conducted to test the notion that auditory stimulation influences the rewarding effects of MDMA. In Experiment 1, a conditioned place preference (CPP) procedure was conducted in which rats received MDMA (1.5 mg/kg, s.c.) in a distinctive environment accompanied by music (65–75 dB), white noise (70 dB), or no added sound. Animals were pretreated with saline on alternating days in an alternate environment. Results revealed CPP in animals exposed to white noise during MDMA trials. For Experiment 2, rats from Experiment 1 had access to operant levers that delivered intravenous MDMA (0.5 mg/kg/inj) or saline (0.1 ml) on alternate days in the presence or absence of the same types of auditory stimuli as previously experienced. After three each of MDMA and non-reinforced (saline) sessions, animals were tested for NAcc DA and 5-HT responses to MDMA (1.5 mg/kg) or saline under the same stimulus conditions. Findings revealed that NAcc DA and 5-HT increased after an MDMA injection, and both DA and 5-HT were significantly highest in animals exposed to music during the test session. These results indicate that paired sensorial stimuli can engage the same systems activated during drug use and enhance neurochemical and behavioral responses to MDMA administration.
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