A single exposure to restraint stress induces behavioral and neurochemical sensitization to stimulating effects of amphetamine: involvement of NMDA receptors.

Evidence indicates that repeated exposure to stressful events sensitizes the motor and addictive effects of drugs of abuse in rats. Regarding a single exposure to one restraint stress, previous findings have shown that it is sufficient to induce behavioral sensitization to stimulating and reinforcing properties of abuse drugs (e.g., amphetamine and morphine), as measured by locomotor activity and conditioned place preference, respectively. It is well known that enhanced dopaminergic neurotransmission in the nucleus accumbens and striatum plays a critical role in the development and/or expression of repeated stress-induced or drug-induced sensitization. In addition, involvement of NMDA receptors has been implicated in its development. However, whether sensitization induced by a single restraint stress exposure represents the same neurobiologic phenomenon is unknown. We studied the following issues: (a) influence of a single restraint exposure on the stimulating effects of amphetamine on dopamine release by microdialysis from striatum and (b) involvement of glutamatergic pathways, specifically those innervating striatum, on stress-induced sensitization to amphetamine, by administering MK-801 ip (0.1 mg/kg) or intrastriatally (1 microg/0.5 microL) previous to an acute restraint stress. For microdialysis studies (a) or intrastriatal administration of MK-801 (b), Wistar rats (250-330 g) were implanted stereotactically under anesthesia with a guide cannula in the striatum. After 2 days, animals were immobilized for 2 hours in a Plexiglas device. Control animals remained in their home cages. The following day we evaluated the stimulating effect of amphetamine on (a) dopamine release from striatum or (b) locomotor activity. In studies (a), dialysis probes were inserted into the guide cannula, and baseline dopamine levels were collected for 2 hours before a challenge of amphetamine (1.5 mg/kg i.p.). Dialysates were then collected by 3 hours. Amphetamine challenge induced a significantly higher increase in dopamine release and locomotor activity in animals previously subjected to one restraint stress exposure, relative to that observed in the no-restraint stress group. MK-801 administered i.p. or intrastriatally blocked the restraint stress-induced sensitization to amphetamine. First, our results point out that a single restraint stress exposure is a pertinent stimulus to induce sensitization of amphetamine's stimulating effects on dopaminergic neurotransmission in the striatum. Secondly, NMDA-glutamatergic receptors, specifically those placed in the striatum, are implicated in the development of stress restraint-induced sensitization.