Cholinergic modulation of mesolimbic dopamine function and reward
Highlights
► Acetylcholine interacts with dopamine in the mesolimbic system. ► CNS cholinergic pathways influence motivation for both natural and drug rewards. ► Both ACh and DA are involved in modulating compulsive behaviors. ► Therapeutic targets for obesity and addiction should include cholinergic systems.
Introduction
More than three decades of research into the neurobiological substrates of reward have focused attention on the nucleus accumbens (NAc), a ventromedial component of the basal ganglia, as a key structure in the neural systems responsible for translating motivation to action [1], [2], [3], [4]. The preponderance of this research effort has centered on dopamine (DA) as the primary neurotransmitter in this regard. Many laboratories have contributed to our understanding of the role of DA in motivated behavior, and certainly the efforts of Dr. Bartley Hoebel in his laboratory at Princeton have been particularly noteworthy. Studies by Hoebel and colleagues have demonstrated increases in the release of DA in the NAc as a function of a variety of behaviors including feeding [5], [6], rehydration [7], models of binge eating [8], [9] and hypothalamic stimulation [10]. Moreover, his laboratory has been instrumental in demonstrating that many drugs with abuse liability (including cocaine, amphetamine, opiates, nicotine and alcohol) share a common mechanism in their ability to elevate DA levels in the NAc.
Of the many perspectives Hoebel brought to the study of neurochemical modulation of motivated behavior, perhaps the most salient for this review – and one that inspired much of the work presented herein – has been his view (along with that of Dr. Pedro Rada) that acetylcholine constitutes an integral component of the mesolimbic system [11]. Cholinergic pathways interact with key regions in the brain reward circuit, as illustrated in Fig. 1. ACh projections from the nucleus basalis provide input to cortical and subcortical regions of the hippocampus and amygdala. These projections may play a role in learning and memory processes that are implicated in drug-induced dysfunctions like craving and relapse [12], [13]. From the DA cell body region of the ventral tegmental area (VTA), DA terminals synapse on medium spiny gamma-aminobutyric acid (GABA)-containing cells and a smaller population of large, aspiny acetylcholine (ACh)-containing interneurons in the NAc [14]. Cholinergic interneurons have large dendritic arbors and an extensive network of axons that contact many cell bodies and terminals within both the core and shell subdivisions of the NAc [15], [16]. Thus, in conjunction with DA inputs from VTA, ACh interneurons can modulate the activity of the GABA projection neurons, the primary output neurons of the NAc [17], [18].
Cholinergic cells in the laterodorsal tegmental nucleus (LDTg) and the posterior component of the pedunculopontine tegmental nucleus (PPTg) project to the VTA [19], [20] where they modulate the activity of DA neurons and reward processing [21], [22], [23], [24], [25], [26]. The anterior portion of the PPTg sends cholinergic projections to the substantia nigra [20]. Together with glutamate fibers, the ACh connection from the LDTg to the VTA forms a loop between the midbrain DA cells, the pons and the prefrontal cortex. The ACh input onto DA cell bodies (in the VTA) is therefore a critical link for gating information flow through the mesocorticolimbic and mesostriatal systems.
Several lines of evidence suggest that stimulation of both nicotinic and muscarinic cholinergic receptors can affect mesolimbic DA levels and modify the reinforcing value of self-administered drugs. In this regard, the action of nicotine (the prototypical agonist at nicotinic ACh receptors) on the mesolimbic DA system has been studied extensively (for review see Ref. [27]) as has its interaction with other drugs of abuse such as alcohol [28], [29] and cocaine [30], [31]. These studies demonstrate that nicotinic activation increases extracellular DA in the NAc, stimulates locomotor activity with repeated exposure, and potentiates the reinforcing value of cocaine.
In comparison to the rather clear-cut situation for nicotinic activation, the effect of muscarinic drugs on stimulus reinforcement is less clear. There is evidence that muscarinic receptor activation can decrease amphetamine-induced hyperactivity [32] and inhibit amphetamine-induced DA release in the NAc [33]. Conversely, muscarinic antagonists enhance the locomotor stimulating effects of amphetamine and cocaine [32], [34], [35]. Systemic administration of muscarinic agonists and partial agonists has been reported to decrease cocaine self-administration rates in mice [36], whereas co-administration with the muscarinic antagonist, scopolamine decreases cocaine self-administration in rhesus monkeys [37]. In addition, mice lacking the muscarinic M5 type receptor self-administer less cocaine and show reduced cocaine conditioned place preference compared to their wild-type counterparts [38], suggesting that muscarinic receptors may mediate some component of cocaine reward.
Identifying the precise location of cholinergic effects on psychostimulant reward has been difficult because systemic administration of drugs and genetic deletion models affect receptors throughout the nervous system. However, recent work has focused attention on the NAc as a site of interaction between cholinergic mechanisms and cocaine reinforcement [39]. ACh interneurons in the NAc are known to be responsive to cocaine self-administration [40], [41]. Hikida et al. (2001) reported that selective ablation of cholinergic interneurons within the NAc using immunotoxin-mediated cell targeting resulted in increased cocaine-induced locomotor activity and reward value (as measured by conditioned place preference). In contrast, augmentation of ACh levels with acetylcholinesterase inhibitors in lesioned mice had the opposite effect [42], [43]. These studies provide strong evidence that cholinergic cells in the NAc play an important role in modulating the reinforcing value of psychostimulants, but the nature of the cholinergic receptors that are critical for this effect remains unclear.
Section snippets
Acetylcholine–dopamine interactions and ingestive behavior
Seminal studies by Hernandez and Hoebel (1988) demonstrated that food reward increased DA in the NAc as measured by microdialysis [5], and Radhakishun and colleagues reported a similar result in the same year [44]. A key question that remained to be addressed, however, was whether DA output in the NAc was part of a general stimulus-induced arousal process or, alternatively, did DA play a role in the transduction of ingestive reward valence. To address these issues, Hoebel and colleagues
Cholinergic interactions with mesencephalic dopamine systems and drug reward
Work done in the Hoebel laboratory over a decade ago was some of the first to demonstrate a relevant link between ACh in the VTA and feeding related behavior [61]. These findings suggested that an interaction between ACh from pontomesencephalic sources and VTA could also be particularly critical for determining the action of drugs such as cocaine, that increase DA signaling by reuptake blockade. The ability of cocaine to increase extracellular DA is impulse dependent, and the interaction of
Cholinergic antagonist prevents escalation of cocaine self-administration in rats
When rats are allowed increased access time to cocaine for self-administration (from 1-h/day to 6-h/day), they exhibit an escalation in their average daily intake of the drug [64], [65]. Rats maintained on 1-h/day access do not show an escalation. We have replicated this finding in our laboratory (see Fig. 7; red circles, solid line [69]). The escalation of drug intake phenomenon is a potential animal model with strong construct validity for the behavior of some human drug users who, as
Intra-VTA Injection of mecamylamine reduces high-level cocaine intake
A key goal was to identify whether inactivation of cholinergic input to VTA can reduce expression of escalated cocaine intake. In a recent study, we found that microinjection of the nAChR antagonist mecamylamine (60 μg/side) reduced escalated cocaine intake (Fig. 8) but did not reduce cocaine intake below pre-escalation levels. Rats self-administered cocaine for 1 h per day in the pre-escalation phase. The average level of cocaine intake in 1 h access sessions is represented by the dotted line.
Acknowledgments
I (GPM) would like to extend my sincerest gratitude to Dr. Bartley G. Hoebel for his guidance and support throughout the length of this work and all that preceded it. He has been an outstanding role model. The authors would like to thank Tammie Painter for her excellent technical assistance. This work was supported by NIH grants R01 DA14639, T32 DA07262, and P50 DA018165.
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Current address: Dept of Neuroanatomy, University of Utah, Salt Lake City, UT.