The brain pattern of c-fos induction by two doses of amphetamine suggests different brain processing pathways and minor contribution of behavioural traits.

Previous studies have shown that amphetamine (AMPH) markedly activates dopaminergic projection areas, together with some important limbic nuclei. However, a global picture of the brain areas activated is lacking and the contribution of the dose of the drug and individual differences to this global brain activation is not known. In the present experiment, we studied in adult male rats the c-fos expression induced by two doses of AMPH (1.5 and 5 mg/kg sc) in a wide range of brain areas, and investigated the possible contribution of novelty-induced activity and anxiety traits. AMPH administration increased Fos+ neurons in an important number of telencephalic, diencephalic and brainstem areas. Interestingly, the ventral tegmental area (VTA) and the dorsal raphe nucleus were activated by the drug, but c-fos expression was restricted to non-dopaminergic and non-serotoninergic neurons, those activated in the VTA being predominantly GABAergic. The use of the factorial analysis, which grouped the areas in function of the correlation between the number of Fos+ neurons observed in each area, revealed three main factors, probably reflecting activation of various relatively independent brain circuits: the first included medial prefrontal cortex regions, most dorsal and ventral striatal subregions and VTA; the second, raphe nuclei; and the third, the different subdivisions of the paraventricular nucleus of the hypothalamus. Other areas such as the central amygdala did not group around any factor. The finding that an important number of activated areas grouped around specific factors is suggestive of activation of partially independent brain circuits. Surprisingly, a minor contribution of novelty-induced activity and anxiety traits on brain activation induced by AMPH was found. It is possible that normal variability in these traits is poorly related to the effects of AMPH or that c-fos expression is not a good tool to reveal such differences.