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.

Figure 1

Limbic and paralimbic regions contain the highest density of acetylcholine (ACh) innervations in the brain. The three primary sources of cholinergic input are (1) the mesopontine nuclei (comprised of the pedunculopontine and laterodorsal tegmental nuclei), which provide ACh innervations to the VTA, SN, and thalamus, (2) the nucleus basalis of Meynert (NBM), which provides the principal ACh input to the cerebral cortex and amygdala, and (3) the medial septal-diagonal band of Broca, which provides primary ACh input to the hippocampus. Striatal ACh interneurons are largely influenced by dopamine (DA) receptors D₁ and D₂. Striatal muscarinic ACh interneurons primarily consist of M₁, M₂, and M₄; M₁ is post-synaptic (M_post in the figure) and excitatory whereas M₂ and M₄ are pre-synaptic and inhibitory (M_pre in the figure). These interneurons synapse with γ-aminobutyric acid (GABA) medium spiny output neurons (MSNs). The ventral striatum, central to the motivations and reward behaviors that underlie drug addiction, projects output neurons to the ventral pallidium (VP) of the globus pallidus (GP) and, in turn, to the mediodorsal (MD) nucleus of the thalamus. The dorsal striatum, involved in the motor processes and conditioned learning of drug addiction, sends projections either directly or indirectly (via the external globus pallidus and subthalamic nucleus) to the internal segment of the globus pallidus and pars recticula of the substania nigra. The GP further projects, through GABAergic neurons, to the mediodorsal (MD) nucleus of the thalamus. Glutaminergic neurons from the MD project to the prefrontal cortex (PFC). Synaptic communication within the reward circuit is conducted via DA (modulatory), acetylcholine (ACh, modulatory), glutamate (GLU, excitatory), and γ-aminobutyric acid (GABA, inhibitory) neurotransmission.