Heroin self-administration experience establishes control of ventral tegmental glutamate release by stress and environmental stimuli.

Heroin and cocaine have very different unconditioned receptor-mediated actions; however, in the brain circuitry of drug-reward and motivation, the two drugs establish common conditioned consequences. A single experience with either drug can change the sensitivity of ventral tegmental area (VTA) dopamine neurons to glutamatergic input. In the case of cocaine, repeated intravenous self-administration establishes de novo VTA glutamate release and dopaminergic activation in response to conditioned stimuli and mild footshock stress. Here we determined whether repeated self-administration of heroin would establish similar glutamate release and dopaminergic activation. Although self-administration of heroin itself did not cause VTA glutamate release, conditioned glutamate release was seen when rats expecting rewarding heroin were given nonrewarding saline in its place. Mild footshock stress also caused glutamate release in heroin-trained animals. In each case, the VTA glutamate release was accompanied by elevations in VTA dopamine levels, indicative of dopaminergic activation. In each case, infusion of the ionotropic glutamate antagonist kynurenic acid blocked the VTA dopamine release associated with VTA glutamate elevation. Although glutamate levels in the extinction and reinstatement tests were similar to those reported in cocaine studies, the effects of heroin self-administration itself were quite different from what has been seen during cocaine self-administration.