Dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of the midbrain form the nigrostriatal and mesocorticolimbic dopaminergic pathways that, respectively, project to dorsal and ventral striatum (including prefrontal cortex). These midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinson's disease, and incentive-motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. Although it cannot be disputed that excitatory and inhibitory amino acid-based neurotransmitters, such as glutamate and GABA, play a vital role in modulating activity of midbrain dopaminergic neurons, recent evidence suggests that acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons. In close coordination with glutamatergic and GABAergic activity, these excitatory cholinergic projections activate nicotinic and muscarinic acetylcholine receptors within the substantia nigra and ventral tegmental area to modulate dopamine transmission in the dorsal/ventral striatum and prefrontal cortex. Additionally, acetylcholine-containing interneurons in the striatum also constitute an important neural substrate to provide further cholinergic modulation of forebrain striatal dopaminergic transmission. In this review, we examine neurological and psychopathological conditions associated with dysfunctions in the interaction of acetylcholine and dopamine and conventional and new pharmacological approaches to treat these disorders.

Deep Brain Stimulation (DBS) provides therapeutic benefit for several neuropathologies including Parkinson's disease (PD), epilepsy, chronic pain, and depression. Despite well established clinical efficacy, the mechanism(s) of DBS remains poorly understood. In this review we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies, e.g., human electrometer and closed-loop smart devices, for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.

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Muscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M5−/−) mice are less sensitive to the reinforcing properties of addictive drugs. Here we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M5−/− mice backcrossed to the C57BL/6NTac strain. Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M5−/− mice, while the effects of cocaine were similar in M5−/− and wildtype mice. Consistent with the behavioral results, amphetamine- but not cocaine-elicited dopamine release in nucleus accumbens was enhanced in M5−/− mice. The different effects of amphetamine and cocaine in M5−/− mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs.

This study determined the role of ventral tegmental area acetylcholine and glutamate receptors in modulating laterodorsal tegmentum stimulation-evoked dopamine efflux in the nucleus accumbens. Rapid changes in dopamine oxidation current were measured at carbon fiber microelectrodes using fixed potential amperometry in urethane anesthetized male mice. Intraventral tegmental area infusions of the muscarinic acetylcholine receptor antagonist scopolamine, the nicotinic acetylcholine receptor antagonist mecamylamine, or the ionotropic glutamate receptor antagonist kynurenate significantly diminished dopamine efflux in the nucleus accumbens evoked by brief electrical stimulation of the laterodorsal tegmentum. These findings suggest that acetylcholine and ionotropic glutamate receptors influence rapid dopaminergic activity and thus the communication of behaviorally relevant information from ventral tegmental area dopamine cells to forebrain areas.