Disinhibitory and aggressive behavior in the rat. Neurohumoral mechanisms
Effective pharmacological treatment for impulsive aggression and dysfunctional impulsive behavior is needed. These behavioral disturbences in man and impulsive-like and aggressive behavior in animals may involve serotonin (5-HT), noradrenaline (NA), GABAA receptors and steroid hormones, e.g. testosterone. Depletion of 5-HT consistently produces impulsive-like behavior and, in most investigations, aggressive behavior in animals. Positive and negative GABAA receptor modulators produce impulsive-like behavior and inhibited behavior, respectively. Animals depleted of brain 5-HT are more sensitive to both these behavioral effects. Moreover, several lines of behavioral and neurochemical evidence indicate GABAA receptor antagonistic properties of naloxone.In the present study a punished conflict model was used to study impulsive-like behavior in adult male rats. Impulsive-like behavior in brain 5-HT depleted isolated rats, by means of intracerebroventricular treatment with 5,7-dihydroxytryptamine (5,7-DHT), was reduced by naloxone at doses that did not significantly affect the behavior in sham-lesioned controls. Amobarbital (a positive GABAA receptor modulator) reversed the behavioral effect of naloxone at a dose without effects per se. Moreover, naloxone and Ro 15-4513 (partial inverse benzodiazepine;BDZ agonist) reduced aggression in 5,7-DHT treated residents in a resident intruder test. Sham-depleted animals did not display aggressive behavior. Naloxone reduced GABA-induced 36Cl- uptake in corticohippocampal synaptoneurosomes and shifted the concentration-response curve for GABA-induced 36Cl- uptake to the right. Amobarbital and GABA, but not morphine or flumazenil (BDZ antagonist), reversed the antagonistic effect of naloxone on GABAA receptor function. Furthermore, gonadectomy in connection with the 5,7-DHT treatment reduced both impulsive-like behavior and GABA-induced 36Cl- uptake in synaptoneuro-somes in isolated rats. Testosterone substitution prevented both these effects. Gonadectomy did not affect the behavior in non-lesioned isolated animals. However, in group-housed rats, gonadectomy enhanced inhibited behavior. Testosterone treatment to intact group-housed rats during six, but not 14 days, produced impulsive-like behavior. Testosterone treated rats (14 days) displayed increased sensitivity for flunitrazepam (BDZ)-induced sedation and increased GABA-induced 36Cl- uptake in synaptoneuro-somes. On the other hand, gonadectomized rats were less sensitivity for diazepam (BDZ)-produced sedation and muscle relaxation/ataxia. Thus, naloxone or other weak negative GABAA receptor modulators may represent a new pharmacological principle for the treatment of dysfunctional impulsive behavior. The present data support the hypothesis that both endogenous and exogenous testosterone promote impulsive-like behavior and this effect of testosterone may involve increased activity at GABAA receptors. Clinical studies are warranted to investigate whether testosterone antagonists and/or 5-a-reductase inhibitors are beneficial in the treatment of dysfunctional impulsive behavior. Finally, these data indicate that humans with increased testosterone activity are more sensitive to GABAA induced impulsive behavior, e.g. after intake of BDZs.
Göteborgs universitet/University of Gothenburg
Department of Pharmacology
Avdelningen för farmakologi
Farmakologiska avdelningens föreläsningssal Ragnar Sandberg kl. 13.00
Date of defence