Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.

The lateral habenula is one of the few forebrain areas that project to the midbrain raphe nuclei. Electrical stimulation of the habenula markedly suppressed serotonergic neurons in the midbrain raphe. The suppression was blocked by systemic or microiontophoretic administration of picrotoxin, which suggests that gamma-aminobutyric acid is the inhibitory transmitter in the habenula-raphe pathway. These results support the concept that the habenula may serve a pivotal role in funneling information from the forebrain to the midbrain raphe.

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