Expression of c-fos mRNA in the basal ganglia associated with contingent tolerance to amphetamine-induced hypophagia.

Tolerance to the hypophagic effect of psychostimulants is contingent on having access to food while intoxicated. Rats given chronic injections of such drugs with access to food learn to suppress stereotyped movements, which interfere with feeding. In contrast, controls given the drug after food access do not learn to suppress stereotypy and, therefore, do not become tolerant. To determine the role of the basal ganglia in this phenomenon, we used in situ hybridization to measure the expression of c-fos mRNA, a marker for neural activation, in the brains of tolerant and nontolerant rats. Rats given chronic amphetamine injections prior to food access learned to suppress stereotyped movements, whereas yoked controls given the drug after feeding did not. Following an acute injection of amphetamine, both of these groups had higher levels of c-fos mRNA than saline-treated controls throughout the striatum, in the nucleus accumbens core, the ventral pallidum and layers V-VI of the motor cortex. In contrast, tolerant rats, which had learned to suppress stereotypy, had higher levels of c-fos mRNA than both amphetamine- and saline-treated controls in the entopeduncular nucleus, globus pallidus, subthalamic nucleus, pedunculopontine nucleus, nucleus accumbens shell, olfactory tubercle, somatosensory cortex, and layers II-IV of motor cortex. These data suggest that the learned suppression of amphetamine-induced stereotypy involves the activation of dorsal striatal pathways previously implicated in response selection as well as the ventral striatum, long implicated in appetitive motivation and reinforcement.