The Role of Acetylcholine in Cocaine Addiction

Abstract

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Accumbens dopamine-acetylcholine balance in approach and avoidance

“…d-Fenfluramine combined with phentermine, given systemically, increases extracellular ACh in the NAc at a dose that inhibits both eating and cocaine self-administration [31,33,34]. ACh enhancement by acetylcholinesterase inhibitors blocks cue-induced heroin seeking [35] and blocks cocaine and heroin conditioned place preference, which is reversed by selective ablation of ACh neurons [36].…”

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

“…Acetylcholine (ACh) mediates reinforcement, satiation, the acquisition of conditional associations that underlie drug craving and drug sensitization, the development of stimulus response associations in habit learning, and drug procurement through its effects on arousal and attention (Williams and Adinoff, 2008). In addition, ACh and its target receptors are prominent in subcortical and cortical structures important to drug reward, self-administration, and the addictive use of substances.…”

“…Preclinical evidence of a function for ACh in drug-related behaviors has been strongest for cocaine (see review in Williams and Adinoff, 2008). Striatal (Berlanga et al, 2003;Crespo et al, 2006;Mark et al, 1999) and hippocampal (Imperato et al, 1996;Smith et al, 2004a;Smith et al, 2004b) increases in ACh are associated with the acquisition of cocaine; in rodents, the run time (how fast an animal runs to obtain a contingent stimulus) is inversely correlated to nucleus accumbens (NAc) ACh release during cocaine acquisition (Crespo et al, 2006), NAc ACh neuronal activation is directly correlated with the amount of cocaine self-administered (Berlanga et al, 2003), and cholinergic input into the amygdala has a function in the cognitive processes involved in the learning and memory of drugassociated cues (Schroeder and Packard, 2004;See et al, 2003).…”

“…Indirect evidence also suggests that the relevance of ACh to attentional (Robbins, 2002;Sarter et al, 2003) and decision-making (Chen et al, 2004;Ragozzino and Choi, 2004) processes may impact the observed deficits that many cocaine-addicted subjects show in these neurocognitive domains (Adinoff et al, 2007;Horner et al, 1996;Jovanovski et al, 2005). Substance-induced alterations in cholinergic systems, therefore, could reasonably be expected to alter both reward and cognitive systems relevant to the addictive process (Williams and Adinoff, 2008). …”

“…The relevance of the nAChR to nicotine (Mansvelder et al, 2003) and, more recently, cocaine (Williams and Adinoff, 2008) dependence have been well described. Of equal interest, however, is the impact of the mACh receptor on cocaine-induced reward and administration.…”