Neural Activity Associated with Tolerance to Amphetamine Hypophagia

There is a growing body of literature indicating that drug effects are influenced by the
context in which they are taken, and that neuroadaptations resulting from chronic drug
use are similarly context dependent. Contingent tolerance to amphetamine-induced
hypophagia is mediated by the learned suppression of stereotyped behaviors, and is an
example of a drug-environment interaction. This form of behavioral tolerance depends
upon instrumental learning, by which rats learn a strategy to suppress drug-induced
stereotypies that interfere with feeding. Considerable progress has been made in
understanding contingent tolerance at the behavioral level; little is known about the
neural mechanisms underlying contingent tolerance. Therefore, the purpose of this study
was to delineate neural circuitry involved in contingent tolerance. The differential
activation of neurons expressing the immediate early gene c-fos was analyzed throughout
the brains of amphetamine-tolerant and non-tolerant rats, using the Before-After
paradigm; the amphetamine tolerant group received injections of amphetamine (2.0
mg/kg) before access to milk, after-amphetamine and after-saline groups (i.e., nontolerant)
received injections of amphetamine after access to milk, and the saline group received saline at both time points. The experimental design permitted us to identify
structures uniquely involved in tolerance from those associated with drinking milk,
having a history of amphetamine, or receiving an injection of amphetamine on the final
test. The unique finding reported here is that when amphetamine is given in an
environment containing food, patterns of c-fos are very different than when the drug is
given in an environment without food. Results showed that amphetamine-tolerant
animals had significant increases in c-fos in a set of interconnected structures throughout
the brain, as compared with non-tolerant and saline rats. These data supported the
hypothesis that structures associated with the dorsal striatum mediate the response
selection of feeding and the inhibition of stereotypies, while the ventral striatum, via
instrumental learning, reinforces the selection and inhibition of competing motor
behaviors. Results also support the idea that the mechanisms of tolerance involve several
neural subsystems that function to modulate motor, motivational, and reward-based
learning. Specifically, the learned suppression of stereotypies involves the tolerance
"Response Selection," "Reinforcement," and "Instrumental Learning" subsystems.