Effects of opioid antagonists and their quaternary derivatives on locomotor activity and fixed ratio responding for brain self-stimulation in rats.

Rats were implanted with stimulating electrodes aimed at the midbrain-central gray area (MID-CG) and trained to lever press for brain stimulation (ICSS) on a fixed ratio:30 (FR:30) schedule of reinforcement. When response rates were stable, animals were administered either naloxone hydrochloride, naltrexone hydrochloride, naloxone methobromide or naltrexone methobromide in a dose range of 0.1-30 mg/kg. Fifteen minutes after the subcutaneous administration of either drug or vehicle, animals were tested for 45 min in the ICSS procedure and changes in response rates following drug administration were compared with those following vehicle administration. Both naloxone and naltrexone hydrochloride produced graded decreases in responding over the entire dose range, while naloxone and naltrexone methobromide did not alter response rates at any dose level. In a separate testing procedure, 30 mg/kg naloxone and naltrexone hydrochloride produced modest reductions in motor activity, while the methobromide derivatives did not. These results demonstrated that the fixed ratio procedure was sensitive to changes in responding for ICSS produced by opioid antagonists, and this effect depends upon the entry of these opioid antagonists into the brain.