Gender differences in the intravenous self-administration of mu opiate agonists

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Abstract

Gender differences have been observed in a number of aspects of the pharmacology of opiates, including their antinociceptive activity, discriminative stimulus properties, the generation of physical dependence, and their positive reinforcing properties. The current experiments were carried out to rigorously examine whether gender differences exist in the intravenous (IV) self-administration of opiates in an operant conditioning paradigm. Both dose–response analyses and the determination of the strength of the reinforcing properties of opiates using a “breakpoint” analysis were examined. We found strong gender differences in the IV self-administration of two mu opiate agonists—heroin and morphine. At a standard fixed ratio (FR) of responding, females consumed significantly greater amounts of heroin and morphine than did males in a dose-dependent fashion. In addition, females also showed much higher breakpoints than did males: the highest FR breakpoint achieved in females was more than double that observed in males and the frequency distribution of breakpoints was shifted significantly to the right in females when compared to males. These data collectively show that mu opiate agonists may serve as reinforcing agents in females over a broader dose range than males and that they also self-administer considerably more opiates on a milligram per kilogram basis. Finally, we conclude that they will also expend much greater effort in an operant conditioning task to obtain opiate reinforcement.

Section snippets

Humane care of laboratory animals

All of the experiments and protocols employed in these studies were reviewed and approved by the Institutional Animal Care and Use Committee.

Materials

Sprague–Dawley male and female rats, 60 days of age, were purchased from Harlan Sprague Dawley (Indianapolis, IN). Self-administration catheter sets were purchased from Med-Associates (Lafayette, IN). Heroin and morphine-sulfate were generously provided by the National Institute on Drug Abuse (Bethesda, MD).

IV self-administration

Male and female rats, which were food restricted

Effects of opiates on operant rates of responding for food reinforcement

To ascertain whether opiates stimulated or suppressed operant behavior in general, as opposed to a specific effect on self-administration rates, 12 female and 12 male rats were trained to self-administer food pellets using an FR1 schedule of reinforcement; 20 reinforcements were possible during each 40-min daily session. Once the behavior was acquired (>85% correct responses), the rats were shifted to a variable interval (VI) schedule of reinforcement (VI—120 s). In this paradigm, a light above

Dose–response analysis

Fig. 1A and B shows the number of infusions taken in the heroin dose–response analysis. The data are presented as number of infusion versus dose of heroin, expressed as micrograms heroin/200 μl infusion (panel A, which was the standard infusion volume for both males and females), and numbers of infusions versus heroin dose expressed as micrograms/kilogram/infusion to adjust for the large gender differences in body weight (panel B). As can be seen, the number of infusions taken by females was

Discussion

The results of these studies indicate that strong gender differences exist in the IV self-administration of two mu opiate agonists—heroin and morphine. At a standard fixed ratio (FR), females consumed significantly greater amounts of heroin and morphine than did males in a dose-dependent fashion. In addition, females also showed much higher breakpoints for morphine self-administration than did males. These results appear to reflect differences in the potency or efficacy of heroin and morphine

Acknowledgements

This research was supported by a grant from the National Institute on Drug Abuse (TJC), DA-03839.

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