The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor OX(1), have demonstrated its involvement in behavioral sensitization, conditioned place-preference, self-administration and reinstatement of drugs abuse. There are dense concentrations of hypocretin receptors, in brain regions implicated in drug reinforcement processes, such as the nucleus accumbens, ventral tegmental area and bed nucleus of the stria terminalis Adult male Wistar rats were implanted the stimulating electrodes to the lateral hypothalamus. Simultaneously, the microcanules were implanted into the BNST to inject the OX(1) receptor antagonist. Rats were trained to perform intracranial self-stimulation. The effects of the OX(1)-selective antagonist SB-408124 on brain stimulation-reward (BSR) were measured. SB-408124 injected into the BNST (1µg/1 µl in volume for each injection.) alone had no effect on self-stimulation of lateral hypothalamus. Amphetamine (1 mg/kg i.p.) potentiated BSR, measured as lowering of BSR threshold and enhancing of BSR frequency. Amphetamine-induced stimulatory effects on intracranial self-stimulation was blocked by injections of SB-408124 into BNST. These data demonstrate that OX(1) play an important role in regulating the reinforcing and reward-enhancing properties of amphetamine and suggest that orexin transmission is likely essential for establishing and maintaining the amphetamine habit in human addicts. However, the observations that OX1 antagonism reduce brain reward and block stress- and cue-induced reinstatement of drug-seeking suggests that this class of compounds may be useful additions to stress-reduction and other behavioral therapies in the treatment of substance abuse disorders.