Chronic administration of stimulant drugs induces behavioral and neural adaptations resulting in either tolerance or sensitization. Both of these effects are influenced by the environmental context in which the drug is given. For example, tolerance to the "anorexic" effect of amphetamine is contingent on having access to food (sweetened milk) while intoxicated. To understand the behavioral mechanism responsible for this effect, we used intraoral delivery of milk to isolate the effect of the drug on the consummatory phase of feeding (licking, swallowing) while eliminating the appetitive phase (approach and orientation). This behavioral dissection revealed that amphetamine had little effect on the consummatory phase of feeding, suggesting that the locus of its effect on feeding is the appetitive phase. Further analysis revealed that amphetamine suppresses food intake by inducing stereotyped movements, which are incompatible with the appetitive phase of feeding. By making intraoral infusions of milk contingent on maintaining a stationary head posture, we demonstrated that rats can learn to inhibit stereotyped movements in order to feed. Thus, at the behavioral level, contingent tolerance can be explained by the fact that when rats are given amphetamine and access to food, they learn to suppress stereotyped movements in order to feed. Such learning does not occur when rats are given the drug without access to food because they lack an incentive to do so.
As a first approach to understanding the neural mechanisms involved in the learned suppression of stereotypy, we measured levels of c-fos mRNA, a marker for neural activation, in the brains of tolerant and nontolerant rats. Tolerant rats had higher levels of c-fos mRNA in select regions of the basal ganglia, somatosensory cortex and motor cortex, as well as in the nucleus accumbens shell and olfactory tubercle. Thus, the suppression of stereotyped movements is associated with the activation of major components of the dorsal striatal output pathways and the mesolimbic dopamine system. Current research is focused on understanding the role each of these structures play in contingent tolerance.
Wolgin, D.L. (2000). Contingent tolerance to amphetamine hypophagia: New insights into the role of environmental context in the expression of stereotypy. Neuroscience & Biobehavioral Reviews, 24, 279-294.
Wolgin, D.L. & Jakubow, J.J. (2004). Tolerance to amphetamine hypophagia: A real-time depiction of learning to suppress stereotyped movements in the rat. Behavioral Neuroscience, 118, 470-478.
Bachand, K.D., Guthrie, K.M. & Wolgin, D.L. (2009). Expression of c-fos mRNA in the basal ganglia associated with contingent tolerance to amphetamine-induced hypophagia. Behavioural Brain Research, 198, 388-396.