ACUTE AND CHRONIC EFFECTS OF FLUPENTIXOL ON THE DISCRIMINATIVE STIMULUS AND REINFORCING EFFECTS OF COCAINE IN RHESUS-MONKEYS

It has been proposed that the relatively nonselective dopamine recepto r antagonist flupenthixol may be useful in the treatment of cocaine de pendence. Drugs used in the treatment of cocaine dependence are admini stered chronically; however, most preclinical studies have examined on ly the acute effects of flupenthixol treatment on the effects of cocai ne. Consequently, the purpose of the present study was to compare the effects of acute and chronic treatment with flupenthixol (0.0032-0.032 mg/kg) on the discriminative stimulus and reinforcing effects of coca ine in rhesus monkeys. One group of six monkeys was trained to discrim inate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinfo rced, drug discrimination procedure. A second group of four monkeys wa s trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocain e and food availability. Neither acute nor chronic treatment with a lo w dose of flupenthixol (0.0032 mg/kg) significantly altered the discri minative stimulus or reinforcing effects of cocaine. Higher doses of f lupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of bot h the discriminative stimulus and reinforcing effects of cocaine, shif ting the dose-effect curves for both cocaine discrimination and cocain e self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased res ponse rates. Similarly, doses of flupenthixol that decreased cocaine s elf-administration also often decreased rates of food-maintained respo nding. Consequently, nonselective behavioral effects of flupenthixol m ay have contributed to its effects on cocaine discrimination and self- administration. Moreover, the effects of flupenthixol on cocaine discr imination and self-administration diminished over time. After only 3 t o 5 days of chronic treatment, flupenthixol did not consistently shift the cocaine discrimination dose-effect curve to the right. Similarly, rates of cocaine self-administration that were initially decreased by flupenthixol often recovered partially or completely during a 10-day regimen of chronic flupenthixol treatment. These results suggest that flupenthixol may have limited utility in the longterm treatment of coc aine dependence.