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

Abstract

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.

Figure 1

Mean dopamine and glutamate levels in 10-min microdialysis samples taken before, during, and after the final heroin self-administration day in animals that had received 14 previous days of self-administration training. Before the microdialysis tests, animals were housed and dialyzed at low rates in the test chamber overnight. On the test morning, the infusion rate was increased and baseline samples taken; then (at t=0), the response lever was inserted into the chamber and heroin became available for 4 h. The times of lever insertion and retraction are indicated by dashed vertical gray lines. Initial lever presses usually occurred within 3 min of lever insertion; the animals pressed at ∼20 min intervals thereafter, receiving ∼300 ng/h of heroin, by the end of the session. Traces a–f below the graph show the temporal pattern of responding for each animal. Vertical hash marks on each timeline indicate the times (relative to the graph above) of each earned injection for each animal.

Figure 2

The effects of VTA ionotropic glutamate receptor blockade on response rates (a) and glutamate (b) and dopamine (c) levels during a single initial extinction test that followed 2 weeks of self-administration training. Insertion of the response lever was at time=0, marked by the dashed vertical gray lines. Three independent groups were tested: two receiving the ionotropic glutamate receptor blocker kynurenic acid (Kyn: 0.1 or 1.0 mM by reverse dialysis), and one receiving only the Kyn vehicle (aCSF). The response lever was inserted at t=0, indicated by dashed vertical gray lines. Kyn significantly attenuated responding and dopamine but not glutamate levels during extinction.

Figure 3

The effects of mild footshock stress and Kyn (1.0 nM) on responding (a) and VTA glutamate (b) and dopamine levels (c) after 2 weeks of self-administration training, followed by 3 weeks of extinction testing. Response levers were inserted into the testing chambers at the end of the 10-min period of intermittent footshock.

Figure 4

Probe placements are indicated by the straight, black, angled vertical line segments at the base of each brain drawing. The number of lines is less than the number of animals because of overlap in the placements. Drawings were adapted from the atlas of Paxinos and Watson (1998); the numbers on the right side of the drawings indicate the distance (in millimeters) posterior to bregma.