Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine

摘要

Blockade of monoamine transporters by cocaine should not necessarily lead to certain observed consequences of cocaine administration, including increased firing of ventral mesencephalic dopamine neurons and accompanying impulse-stimulated release of dopamine in the forebrain and cortex. Accordingly, we hypothesize that the dopaminergic activating effect of cocaine requires stimulation of dopaminergic neurons by afferents of the ventral tegmental area. We sought to determine if afferents of the ventral tegmental area are activated following cocaine administration. Rats were injected in the ventral tegmental area with retrogradely transported Fluoro-Gold and, after one week, were allowed to self-administer cocaine or saline via jugular catheters for two hours on six consecutive days. Other rats received like amounts of investigator-administered cocaine through jugular catheters. Afterward, the rats were killed and the brains processed immunohistochemically for retrogradely transported tracer and Fos, the protein product of the neuronal activation-associated immediate early gene, c-fos. Forebrain neurons exhibiting both Fos and tracer immunoreactivity were enriched in both cocaine groups relative to the controls only in the globus pallidus and ventral pallidum, which, together, represented a minor part of total forebrain retrogradely labeled neurons. In contrast, both modes of cocaine administration strongly increased double-labeling relative to the controls in the brainstem, specifically in the caudal ventromedial mesencephalon and rostromedial pontine tegmentum. It is concluded that a previously unappreciated activation of pallidal and brainstem afferents may contribute to the modulation of dopaminergic neuronal activity following cocaine administration.