1. ¹Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO, USA
2. ²Department of Cellular & Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

Correspondence: Professor DS Zahm, Department of Pharmacological and Physiological Science, St Louis University School of Medicine, 1402 S. Grand Blvd., St Louis, MO 63104, USA. Tel: +1 314 977 8003; Fax: +1 314 977 6411; E-mail: zahmds@slu.edu

³Current address: NIH/NIDA, Behavioral Neuroscience Branch, Baltimore, MD, USA.

Received 24 September 2007; Revised 29 October 2007; Accepted 2 November 2007; Published online 19 December 2007.

Abstract

Blockade of monoamine transporters by cocaine should not necessarily lead to certain observed consequences of cocaine administration, including increased firing of ventral mesencephalic dopamine (DA) neurons and accompanying impulse-stimulated release of DA in the forebrain and cortex. Accordingly, we hypothesize that the dopaminergic-activating effect of cocaine requires stimulation of the dopaminergic neurons by afferents of the ventral tegmental area (VTA). We sought to determine if afferents of the VTA are activated following cocaine administration. Rats were injected in the VTA with retrogradely transported Fluoro-Gold and, after 1 week, were allowed to self-administer cocaine or saline via jugular catheters for 2 h on 6 consecutive days. Other rats received a similar amount 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.