Serotonin type-1A receptors modulate adolescent, cocaine-induced offensive aggression in hamsters.

Hamsters repeatedly exposed to cocaine throughout adolescence display highly escalated offensive aggression compared to saline-treated littermates. Recently, we have shown that serotonin neural signaling and development play an important role in adolescent cocaine-induced offensive aggression. This study examined whether the adolescent cocaine-induced aggressive response was modulated by serotonin type 1A (5HT1A) receptors. To test this, adolescent male Syrian hamsters were administered cocaine hydrochloride (0.5 mg/kg, i.p.) throughout adolescent development (P27-57) and then tested for offensive aggression after the administration of the 5HT(1A) receptor agonist R(+)-8-OH-DPAT (0.1, 0.3, 0.6, 1.0, 1.25 mg/kg, i.p.). R(+)-8-OH-DPAT dose-dependently reduced cocaine-induced offensive aggression, with a significant reduction observed at 0.3 mg/kg for most of the offensive responses measured. Animals treated with higher doses of R(+)-8-OH-DPAT (0.6-1.25 mg/kg) prior to testing showed significant reductions in all measures of offensive aggression and social interest towards intruders (i.e., contact time), indicating more general behavioral inhibition. Adolescent cocaine-treated animals did not differ in body weight from controls, suggesting that the increased aggression was not due to increased body mass. These data support a role for 5HT1A signaling in adolescent cocaine-induced aggression.

Persistent activation of select forebrain regions in aggressive, adolescent cocaine-treated hamsters.

Hamsters repeatedly exposed to cocaine throughout adolescence display highly escalated offensive aggression compared to saline-treated littermates. The current study investigated whether adolescent cocaine exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent cocaine-treated hamsters and saline-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, saline-treated controls, aggressive cocaine-treated hamsters showed persistent increases in the number of FOS-ir cells in several aggression regions, including the anterior hypothalamus, nucleus circularis, lateral hypothalamus (i.e., the hypothalamic attack area), lateral septum, and medial and corticomedial amygdaloid nuclei. Conversely, aggressive cocaine-treated hamsters showed a significant decrease in FOS-ir cells in the medial supraoptic nucleus, bed nucleus of the stria terminalis, and central amygdala when compared with controls. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the paraventricular hypothalamic nucleus, or in a number of non-aggression areas. These results suggest that adolescent cocaine exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the hypothalamus) may facilitate the development of the aggressive phenotype in adolescent cocaine-exposed animals is presented.

Repeated cocaine exposure during adolescence alters glutamic acid decarboxylase-65 (GAD65) immunoreactivity in hamster brain: correlation with offensive aggression.

Male Syrian hamsters (Mesocricetus auratus) treated with low-dose (0.5 mg/kg/day) cocaine throughout adolescence (P27-P56) display highly escalated offensive aggression. The current study examined whether adolescent cocaine exposure influenced the immunohistochemical localization of glutamic acid decarboxylase-65 (GAD65), the rate-limiting enzyme in the synthesis of gamma-aminobutyric acid (GABA), a fast-acting neurotransmitter implicated in the modulation of aggression in various species and models of aggression. Hamsters were administered low doses of cocaine throughout adolescence, scored for offensive aggression using the resident-intruder paradigm, and then examined for changes in GAD65 immunoreactivity in areas of the brain implicated in aggression control. When compared with saline-treated control animals, aggressive cocaine-treated hamsters showed significant differences in the area covered by GAD65 puncta in several notable aggression regions, including the anterior hypothalamus, the medial and central amygdaloid nuclei, and the lateral septum. However, no differences in GAD65 puncta were found in other aggression areas, such as the bed nucleus of the stria terminalis, the ventrolateral hypothalamus, and the corticomedial amygdala. Together, these results suggest that altered GABA synthesis and function in specific aggression areas may be involved in adolescent cocaine-facilitated offensive aggression.

Serotonin type 3 receptors stimulate offensive aggression in Syrian hamsters.

Hamsters repeatedly exposed to cocaine during adolescence display high levels of offensive aggression compared to saline-treated littermates. The escalated offensive phenotype observed in adolescent cocaine-treated animals is modulated by serotonin (5-HT) signaling and can be suppressed by inhibiting 5-HT type 3 receptors, suggesting that these receptors might play an important role in the aggression-stimulating effects of adolescent cocaine exposure. The current study examined this hypothesis and extended earlier studies investigating the relationship between 5HT(3) receptor neural signaling and the offensive response patterns of aggressive, adolescent cocaine-treated animals compared to non-aggressive, saline-treated littermates. Adolescent cocaine-treated hamsters and saline-treated littermates were tested for offensive aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron) or the 5-HT(3) agonist 1-(m-chlorophenyl)-biguanide hydrochloride (mCPBG). Tropisetron significantly reduced the high levels of offensive responding observed in adolescent cocaine-treated animals, whereas treatment with the 5-HT(3) receptor agonist mCPBG failed to affect the escalated offensive response. Conversely, tropisetron failed to affect very low, baseline levels of aggressive responding seen in adolescent saline-treated animals, while 5-HT(3) receptor activation via mCPBG triggered highly escalated levels of offensive aggression in these animals. Together, these data support a stimulatory role for 5-HT(3) neural signaling in offensive aggression.