Cholinergic modulation of mesolimbic dopamine function and reward

Abstract

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems.

The Evidence for the Contribution of the Autism Susceptibility Candidate 2 (AUTS2) Gene in Heroin Dependence Susceptibility

“…AUTS2 has been reported to be associated with autism spectrum disorders (ASD) (Sultana et al 2002), mental retardation (FitzPatrick et al 2007), epilepsy (Mefford et al 2010), dyslexia (Girirajan et al 2011), and attention deficit hyperactivity disorder (ADHD) (Elia et al 2010). Furthermore, AUTS2 is highly expressed in the developing cerebral cortex, hippocampus, and amygdala regions often affected by neuropathological changes in drug dependence (Bedogni et al 2010;Baik 2013;Mark et al 2011). AUTS2 expression in the brain has been confirmed to be associated with the alcohol preference in mice (Schumann et al 2011), whereas downregulating the expression of the Drosophila AUTS2 homologue dAUTS2/tay gene reduced the alcohol sensitivity of Drosophila (Schumann et al 2011).…”

Cholinergic modulation of food and drug satiety and withdrawal

“…In this paper, we will focus on the distinct role that cholinergic neurons have in food and drug ingestion, particularly with regard to their unique contributions to the cessation of food and drug intake, as well as their role in aversive aspects that can ensue following overeating or drug use. Moreover, there is a relationship between DA and cholinergic functions in reward-related brain regions that has been reviewed elsewhere [4–6], and a theory has been proposed that the balance of these neurotransmitter levels in the ventral striatum plays a role in motivated behaviors [5,6], much like the theory that exists regarding the role of the balance of DA and ACh in the dorsal striatum in the control of locomotor activity [7]. …”

Citicoline in addictive disorders: a review of the literature

“…Acetylcholine connections from the laterodorsal tegmental nucleus to the ventral tegmental area are thought to form a loop with dopamine cells in the midbrain and the pons and prefrontal cortex. As a result, acetylcholine input into dopamine bodies in the ventral tegmental area might serve an important gating function for the information traveling between mesocorticolimbic and mesostriatal systems (41). Additionally, cholinergic and dopaminergic systems are thought to coordinate reward functioning in the striatum, with various dopamine receptor subtypes controlling acetylcholine transmission as well striatal cholinergic output modulating dopamine output (42).…”