Cues specifically unpaired with amphetamine can inhibit the expression of sensitization to amphetamine

The ability of cues specifically unpaired with amphetamine to inhibit the expression of sensitization was assessed. Rats in one group (Paired) received amphetamine injections in the test chambers while rats in another group (Unpaired) received saline. On the following day Paired rats received saline in their home cage while Unpaired rats received amphetamine. Rats in a third group (Control) received saline in both environments; this procedure was repeated five times. Thus, in Unpaired animals, amphetamine was explicitly unpaired with the test chambers in which all experimental data were collected. On the test day, 10-14 days after the last amphetamine exposure injection, Paired rats showed enhanced locomotor activity and dopamine overflow in the nucleus accumbens in response to a challenge injection of amphetamine, while Unpaired rats showed locomotor activity and dopamine overflow similar to that observed in Control rats, even though the Unpaired rats had received the same number and dose of amphetamine injections as the Paired rats. This effect was extinguished by subjecting Unpaired rats to saline injections in their home cage after repeated exposure to amphetamine and before testing for environment-specific sensitization. Following this procedure known to extinguish conditioned inhibition, Unpaired rats displayed sensitized responding comparable to Paired rats in the test environment. These findings suggest that in Unpaired rats, cues previously unpaired with the drug can acquire the ability to subsequently inhibit the expression of both locomotor sensitization and enhanced nucleus accumbens dopamine overflow. Interestingly, the decreased glutamate and gamma-aminobutyric acid overflow also observed in the nucleus accumbens of Unpaired rats during testing for sensitization suggests that these neurotransmitter systems may be important in mediating the sensitized response to amphetamine. Additional experiments were aimed at determining the contribution of the medial prefrontal cortex, basolateral amygdala, and the ventral subiculum to the inhibition of the sensitized locomotor response; activation of the medial prefrontal cortex was necessary for the expression of conditioned inhibition. In conclusion, we have established that stimuli explicitly unpaired with amphetamine can become powerful enough to prevent the expression of sensitized behavioral and neurochemical responding to amphetamine in an animal model of addiction.