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This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson’s disease, Huntington’s disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms.

The present paper reviews foundational and contemporary theories of motivated behaviors and the growing body of evidence that they require specific functional interactions within the basal ganglia. Such evidence suggests that unconditioned responses (UR), conditioned responses (CR), goal-directed actions and stimulus-response (S-R) habits are selected in the basal ganglia. Such selection depends on activation of striatal neurons by cortical and subcortical neurons encoding unconditioned stimuli (US), conditioned stimuli (CS), goals and neutral stimuli (S). These neurons project respectively to the medial nucleus accumbens (NAc) shell/olfactory tubercle, NAc core/lateral olfactory tubercle, dorsolateral striatum and dorsomedial striatum. The strength of these synapses is altered when the levels of extracellular dopamine in the basal ganglia undergo phasic increases or decreases, which signal outcomes that are, respectively, better or worse than expected. In addition, dopamine release in response to salient USs and to CSs with incentive salience increases the signal-to-noise ratio of corticostriatal neurotransmission, thus 'energizing' the performance of selected actions. Different actions can be selected in the striatum because the striatal neurons of the so-called direct and indirect pathways can respectively initiate and end actions through pallidum/nigral-thalamic projections to premotor and motor areas of the cortex. According to this view, the basal ganglia is thought to play a role in the action-selection processes needed for the expression of both declarative and procedural memories, but the memories of the contexts, predictive stimuli or neutral stimuli associated with free rewards or with an action's outcomes are stored elsewhere.

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Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.