The effect of amfonelic acid or nisoxetine in combination with morphine on brain-stimulation reward

Many drugs of abuse, including stimulants such as cocaine and amphetamine, and opioids like morphine and heroin, will lower threshold at which rats will work to receive electrical stimulation to the medial forebrain bundle-lateral hypothalamic region (MFB-LH). This effect is even greater when the two classes of drugs are coadministered. The underlying mechanisms by which this occurs are not completely understood, however there is considerable evidence suggesting that the catecholamines play a major role in mediating the reinforcing effects of these drugs. The present study was conducted to investigate the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a highly selective norepinephrine uptake blocker, alone and in combination with morphine, on the reward threshold for rewarding electrical intracranial stimulation. As in previous studies, morphine, as well as amfonelic acid, lowered the reward threshold with the amfonelic acid causing greater threshold lowerings than that of morphine. When a low (ineffective) dose of amfonelic acid was administered concomitantly with morphine, the threshold lowerings observed were larger than those seen with either drug alone and were often more than additive. Nisoxetine alone had no effect on the reward threshold and produced inconsistent results when combined with morphine. These findings support the thesis that amfonelic acid has abuse potential, and that its reinforcing effects may, in fact, be even greater than that of the opioids. Further, these results support the hypothesis that dopamine plays a more critical role in mediating brain-stimulation reward than dose norepinephrine.