Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA(A) receptor blockade?
Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel's conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1-5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA(A)/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.
Söderpalm
B
B
Department of Pharmacology, Institute of Physiology and Pharmacology, Göteborg University, Sweden. bo.soderpalm@clavicula.mednet.gu.se
Svensson
A I
AI
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000374:Aggression / Q000187:drug effects* / Q000502:physiology; D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D004326:Drinking; D018757:GABA Modulators / Q000494:pharmacology; D007175:Impulsive Behavior / Q000188:drug therapy; D008297:Male; D009270:Naloxone / Q000494:pharmacology* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology
D001386:Azides; D018757:GABA Modulators; D009292:Narcotic Antagonists; D011963:Receptors, GABA-A; D018490:Serotonin Agents; D001569:Benzodiazepines; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D009270:Naloxone; C042957:Ro 15-4513; D000654:Amobarbital