Fos After Single and Repeated Self-Administration of Cocaine and Saline in the Rat: Emphasis on the Basal Forebrain and Recalibration of Expression

The effects of addictive psychostimulant drugs on the brain change over repeated administrations. We evaluated a large sample of brain structures, particularly ones comprising basal forebrain macrosystems, and determined in which the immediate-early gene product, Fos, is expressed following a single and repeated self-administrations of cocaine. The caudate-putamen and accumbens, comprising the basal ganglia input structures, and the hypothalamic supraoptic and paraventricular nuclei, lateral and medial habenula, mesopontine rostromedial tegmental nucleus and anterior cingulate cortex exhibited Fos expression enhanced by acute self-administration of cocaine (SAC), but desensitized after repeated administrations. Fos expression was mainly enhanced by acutely self-administered cocaine in basal ganglia output and intrinsic structures and the intermediate nucleus of lateral septum, medial division of the central amygdaloid nucleus and zona incerta, but, in contrast, was sensitized in these structures after repeated administrations. Acute and repeated SAC left Fos expression unaffected or marginally enhanced in most extended amygdala structures, of which nearly all, however, exhibited robustly increased Fos expression after repeated saline self-administration, occasionally to levels exceeding those elicited by cocaine. Thus, self-administered cocaine mainly elicits Fos expression, which persists or increases with repeated administrations in some structures, but declines in others. In addition, Fos expression is sensitized in most extended amygdala structures merely by the act of repeated self-administering. Similar spatiotemporal patterns of cocaine-or saline-elicited Fos expression characterize functionally related clusters of structures, such as, eg, basal ganglia input structures, basal ganglia output structures, extended amygdala and structures in the brainstem to which forebrain macrosystems project. Neuropsychopharmacology (2010) 35, 445-463; doi: 10.1038/npp.2009.149; published online 30 September 2009