Given the multiple origins and discrete projections of CNS cholinergic neurons and their involvement in a myriad of cognitive functions, the relationship between cocaine and ACh is predictably complicated. Acutely, cocaine administration increases ACh in the VTA, NAc, and dorsal striatum. Elevations in VTA ACh concentrations following acute cocaine occur via neuronal projections from the mesopontine nuclei and heighten cocaine’s rewarding effects, primarily through the M5 receptor, by complementing DA neuronal input in a feed-forward manner. In contrast, NAc and dorsal striatal increases in ACh are produced via VTA DA afferents upon striatal ACh interneurons. Striatal ACh release (under the modulating influence of D1 and D2 receptors) appears to increase cocaine’s rewarding effects but decrease cocaine-associated conditioned learning. The chronic administration of cocaine also appears to result in fewer ACh receptors upon abstinence, although the direction of these changes is dependent on cocaine dose, duration, time since last administration, and brain region assessed. nAChRs facilitate the initiation of VTA cocaine-induced sensitization, whereas NAc mAChRs inhibit NAc sensitization.
Cocaine reinforces different types of learning by initiating the storage of new information and strengthening neural pathways through the process of synaptic plasticity. Since cocaine also increases extracellular levels of ACh and ACh turnover rates within the hippocampus, high levels of hippocampal ACh during cocaine use may facilitate the encoding of explicit drug-related information. The acquisition of cocaine-related associations thought to underlie craving is altered by cholinergic release in both the amygdala and striatum, although the direction of change effected is uncertain. Although ACh likely plays a role in the cocaine-related deficits observed in executive functioning, this relationship has yet to be demonstrated and remains a critical area of investigation.
In summary, a plethora of studies now clearly document that the cholinergic system is involved to a great extent in both the experience of cocaine and the conditioned association of cocaine with salient stimuli. This association is complicated by the multiple origins of cholinergic neurons, the unique aspects of striatal cholinergic neurons, and the presence of inhibitory and excitatory ACh subtypes. Our review was also focused on mACh receptor systems with only limited attention on the nACh receptors. Internal and external feedback systems, specific for each cholinergic system, further complicate interpretation. Thus, clarification of the role of ACh in cocaine addiction requires increasing use of agonists and antagonists specific for receptor subtype, as well as animals bred with specific subtype deficits.
The above-reviewed studies do not involve humans, with the exception of a few. These preclinical studies, however, strongly support a role of ACh receptor systems in the progression of cocaine from initial reward to the maintenance of addictive-like behaviors. Complementary clinical laboratory studies to examine the link between chronic cocaine use and ACh receptor alterations, as well as pharmacological trials to assess the utility of cholinomimetics in the treatment of cocaine dependence, are now required. Initially, neuroimaging studies can be used to investigate alterations in ACh receptor systems in cocaineaddicted subjects. SPECT, PET, and functional magnetic resonance imaging (fMRI) techniques have been used to great advantage in the investigation of cholinergic functioning in other populations, particularly in Alzheimer’s disease (Volkow et al, 2001
). For example, PET and SPECT ligands are available to assess extracellular ACh, ACh receptors, and brain function (ie brain blood flow and glucose utilization) as well as markers of cholinergic cell viability (vesicular transporters, AChE) (Zubieta et al, 1998
). Radioligands can be used to identify mAChRs (Volkow et al, 2001
) and nAChRs (Ma et al, 2002
), and more recently developed tracers can select for M2
receptor subtypes (Furey et al, 2000
). These techniques may also be used to explore cocaine-related deficits in executive function, such as learning tasks relevant to the addictive process, in the presence or absence of cholinergic agonist or antagonists. For example, Furey et al (2000)
have utilized fMRI to explore cognitive-induced alterations in neural activation during a working memory task concurrent with the infusion of physostigmine. Given the importance of ACh in modulating the tonic and clonic release of DA, the concurrent functional assessment of DA and ACh systems during acute cocaine administration, withdrawal, and extended abstinence in addicted patients may elucidate the convergent interaction and relevant disruptions in these two complementary systems.
In the first, and as yet preliminary, study to utilize neuroimaging techniques to assess ACh systems in cocaine-addicted subjects, we have used SPECT to identify alterations in ACh systems in abstinent cocaine-addicted subjects. Preliminary findings suggest regional-specific changes in cerebral blood flow following the infusion of physostigmine or scopolamine compared to saline (Adinoff et al, 2005
). To date, the only published studies exploring neural cholinergic systems in this population have reported that ChAT and vesicular ACh transporter (VAChT) concentrations in the autopsied brains of cocaine-addicted subjects did not differ from those of heroin-addicted (VAChT, ChAT) or control subjects (VAChT) (Kish et al, 1999
; Siegal et al, 2004
Ultimately, pharmacologic investigations will be required to explore the relevance of ACh alterations to the addictive process. Although cocaine increases ACh during acute administration, the literature reviewed above, in toto
, suggests that ACh agonists may be the most promising agents in the treatment of cocaine dependence. Cholinomimetics may compensate for the apparent reduction in ACh receptors observed during withdrawal and facilitate the acquisition of non-cocaine-driven behaviors by strengthening the salience of stimuli unassociated with cocaine use. A large number of cholinergic agonists are now available for human use, and pharmaceutical agents that target specific receptor subtypes are rapidly being developed. Some of the most common cholinergic agonists are cholinesterase inhibitors, and donepezil, galantamine, and rivastigmine are presently available for use in humans (Cummings, 2000
; Ellis, 2005
). In a preliminary trial of donepezil using the Cocaine Rapid Efficacy and Safety Trial (CREST) study design, however, dozepezil did not produce significant changes in cocaine use (Winhusen et al, 2005
). Treatment trials of rivastigmine in the treatment of cocaine addiction are ongoing. The relevance of the M5
receptor in cocaine reinforcement (Fink-Jensen et al, 2003
; Thomsen et al, 2005
) suggests that targeting this muscarinic subtype may be of particular importance.
In contrast, a clinical laboratory study revealed that the nicotinic receptor antagonist
mecamylamine decreased craving in cocaine-dependent subjects (Reid et al, 1999
), although its effectiveness in relapse prevention is unknown. This mirrors preclinical work demonstrating that mecamy-lamine suppressed both nicotine and cocaine self-administration (Blokhina et al, 2005
). These studies highlight the difficulty of dissembling the contributions of cocaine vs
nicotine to nAChR changes in cocaine- (and typically nicotine-) addicted individuals. In preclinical studies, the administration of nicotine alters the locomotor effects of cocaine (Collins and Izenwasser, 2004
), the two drugs exhibit cross-tolerance (Desai and Terry, 2003
), nicotine substitutes for cocaine reinforcement (Tessari et al, 1995
), and repeated nicotine exposure enhances cocaine-seeking behavior (Bechtholt and Mark, 2002
). In humans, nicotine increases cue-induced cocaine craving (Reid et al, 1998
). Thus, the frequent co-morbid dependence on nicotine and cocaine, their shared effects on reward systems (Kauer, 2003
), and their apparent interactive effects on the ACh system suggest that the nAChR may be a fruitful area of investigation. The newly available (for nicotine dependence) partial α4
nicotinic agonist, varenicline, may therefore be worthy of investigation for the treatment of cocaine dependence.
Perhaps one of the most promising treatment strategies involves the shared role of both DA and ACh in regulating reward and each other’s synaptic release. From a clinical perspective, this neurobiologic interconnectiveness suggests that a combination of cholinergic and dopaminergic modulation may be the optimal treatment approach for the cocaine-dependent patient. For example, most studies of DA agonists have not provided strong signals in the treatment of cocaine dependence (Adinoff, 2004
). The addition of a cholinomimetic may enhance the effects of a dopaminergic agonist in the NAc. Alternatively, a pharmacologic cocktail of DA agonist and cholinergic antagonist may provide the optimal environment during the early phase of cocaine abstinence. Clearly, other neurotransmitter systems that regulate ACh outflow and pharmacogenetic influences are also potent areas of investigation.
Ultimately, one of the greatest benefits derived from ACh modulation in the treatment of cocaine addiction may stem from its effects on learning and memory processes. These changes may account for some of the more intractable aspects of cocaine addiction, such as craving, sensitization, and conditioned learning. A better delineation of the molecular and cellular changes that occur during chronic cocaine use may provide important insights into the role of ACh in cocaine addiction, assisting in the development of stage- and site-specific pharmacological treatment interventions.