Search

The purpose of this study was to evaluate the agonist and antagonist properties of pentazocine, an opioid mixed agonist-antagonist analgesic, in relation to prototypic opioid agonist and antagonist drugs in opioid-dependent human subjects. Pentazocine (45 and 60 mg), naloxone (0.1 and 0.2 mg), morphine (20, 40 and 60 mg) and saline placebo were administered intramuscularly to six male volunteers maintained on methadone (30 mg/24 hr p.o.), following a double-blind, randomized block order design. Drugs were administered 20 hr after the last dose of methadone. Subject-reported effects and physiological measures were collected before drug administration and during 4 hr postadministration. Morphine produced significant dose-related increases in subjective measures characteristic of mu agonist effects, decreased pupil diameter and was classified as an opioid agonist. Naloxone precipitated a dose-related opioid withdrawal syndrome which was measurable on several subject-rated measures, and significantly increased pupil diameter. Subjects consistently identified naloxone as an antagonist. Pentazocine precipitated a withdrawal syndrome, but the effects were not dose-dependent, and produced symptoms of confusion and dysphoric changes that were not observed after naloxone administration. Pentazocine was classified as an antagonist by some individuals, and as alcohol or hallucinogen by others. The results of the present study indicate that pentazocine acts in humans as a partial mu agonist with a non-mu component of activity.

It has been proposed that the relatively nonselective dopamine receptor antagonist flupenthixol may be useful in the treatment of cocaine dependence. Drugs used in the treatment of cocaine dependence are administered chronically; however, most preclinical studies have examined only the acute effects of flupenthixol treatment on the effects of cocaine. 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 to cocaine in rhesus monkeys. One group of six monkeys was trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced, drug discrimination procedure. A second group of four monkeys was trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocaine and food availability. Neither acute nor chronic treatment with a low dose of flupenthixol (0.0032 mg/kg) significantly altered the discriminative stimulus or reinforcing effects of cocaine. Higher doses of flupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of both the discriminative stimulus and reinforcing effects of cocaine, shifting the dose-effect curves for both cocaine discrimination and cocaine self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased response rates. Similarly, doses of flupenthixol that decreased cocaine self-administration also often decreased rates of food-maintained responding. Consequently, nonselective behavioral effects of flupenthixol may have contributed to its effects on cocaine discrimination and self-administration. Moreover, the effects of flupenthixol on cocaine discrimination and self-administration diminished over time. After only 3 to 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 long-term treatment of cocaine dependence.

These studies were designed to evaluate the effects of the putative dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013–1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01–1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01–0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032–0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1–0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D3/D2 dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.

The effects of 100 mg of intranasal cocaine (COC) in acute alcohol intoxication (1 g/kg) was assessed in nine experienced and non-dependent healthy volunteers in a double-blind, controlled, randomized, cross-over clinical trial. Alcohol alone impaired psychomotor performance, whereas COC alone produced subjective effects related to euphoria and well-being, improved the reaction time and increased heart rate and blood pressure. The combination of COC and alcohol induced a nonsignificant decrease in the subjective feelings of drunkeness, an increase in COC-induced euphoria, a significant improvement in alcohol-related changes in psychomotor performance and a marked increase in heart rate. Subjects experienced subjective and performance effects that could be self-interpreted as more pleasant compared to the effects of alcohol alone. When alcohol was given simultaneously, COC plasma levels were higher (possibly as a result of an inhibition of hepatic metabolism of COC produced by alcohol), norcocaine plasma levels almost doubled and cocaethylene was detected in plasma, so that its basic pharmacokinetic profile could be described. The simultaneous use of both drugs produced changes in heart rate and blood pressure that could increase the risk of cardiovascular toxicity associated with the use of COC.