The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.

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The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell patch-clamp recordings from freshly dissociated neurons, we found that nucleus accumbens neurons are less excitable in cocaine withdrawn rats because of a novel form of plasticity: reduced whole-cell sodium currents. Three days after discontinuation of repeated cocaine injections, nucleus accumbens neurons recorded in brain slices were less responsive to depolarizing current injections, had higher action potential thresholds, and had lower spike amplitudes. Freshly dissociated nucleus accumbens neurons from cocaine-pretreated rats exhibited diminished sodium current density and a depolarizing shift in the voltage-dependence of sodium channel activation. These effects appear to be related to enhanced basal phosphorylation of sodium channels because of increased transmission through the dopamine D1 receptor/cAMP-dependent protein kinase pathway. The effects of repeated cocaine administration were not mimicked by repeated injections of the local anesthetic lidocaine and were not observed in neurons within the motor cortex, indicating that they did not result from local anesthetic actions of cocaine. Because nucleus accumbens neurons are normally recruited to coordinate response patterns of movement and affect, the decreased excitability during cocaine withdrawal may be related to symptoms such as anergia, anhedonia, and depression.

Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of autoreceptors in such conditions has remained elusive. The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.