Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice.

Deleting the tailless (TLX) gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacological control over aggression and study the role of serotonin (5-HT)(2A/C) receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous (+/-) or homozygous (-/-) for the TLX gene and wild-types (+/+) using a resident-intruder paradigm. No +/+ mice were aggressive, 36% of +/- TLX and 100% of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine (0.1-1.5mg/kg, ip), ketanserin (0.3-1.25 mg/kg, ip), and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI] (0.5-2.0 mg/kg, ip). Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT(2A/C) receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (±)DOI, a 5-HT(2A/C) receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT(2A/C) receptors.

Differences in aggressive behavior and in the mesocorticolimbic DA system between A/J and BALB/cJ mice.

The neurotransmitters DA and serotonin are known to be important modulators of aggression, but endogenous differences in these systems between aggressive and nonaggressive animals are poorly understood. To examine this issue, the mesocorticolimbic DA and serotonin systems of two mouse strains that differ in aggressive behavior, BALB/cJ and A/J, were analyzed using high performance liquid chromatography and quantitative receptor autoradiography. Significant differences in both serotonergic and dopaminergic systems were found between aggressive and nonaggressive mice. The nonaggressive A/J mice exhibited higher DA utilization in the nucleus accumbens and prefrontal cortex, higher D1 receptor expression in the rostral pole of the accumbens, and lower D2 receptor expression throughout the accumbens, as compared with aggressive BALB/cJ mice. Although correlative in nature, these data suggest that differences in mesocorticolimbic DA and serotonin systems may contribute to endogenous differences in aggression.

The rewarding effect of aggression is reduced by nucleus accumbens dopamine receptor antagonism in mice.

RATIONALE: Dopamine (DA) receptors within the nucleus accumbens (NAc) are implicated in the rewarding properties of stimuli. Aggressive behavior can be reinforcing but the involvement of NAc DA in the reinforcing effects of aggression has yet to be demonstrated. OBJECTIVE: To microinject DA receptor antagonists into the NAc to dissociate their effects on reinforcement from their effects on aggressive behavior and general movement. MATERIALS AND METHODS: Male Swiss Webster mice were implanted with guide cannulae aimed for the NAc and tested for aggressive behavior in a resident-intruder procedure. Aggressive mice were then conditioned on a variable-ratio 5 (VR-5) schedule with presentation of the intruder as the reinforcing event. The D1- and D2-like receptor antagonists SCH-23390 and sulpiride were microinfused (12-50 ng) before the mice responded on the VR-5 schedule and attacked the intruder. Open-field activity was also determined following the highest doses of these drugs. RESULTS: SCH-23390 and sulpiride dose-dependently reduced VR responding but did not affect open-field activity. The 50-ng SCH-23390 dose suppressed response rates by 40% and biting behaviors by 10%; other aggressive behaviors were not affected. The 25 and 50 ng sulpiride doses almost completely inhibited VR responding; the 50-ng dose suppressed biting by 50%. CONCLUSIONS: These results suggest that both D1- and D2-like receptors in the ventral striatum are involved in the rewarding properties of aggression, but that D1-like receptors may be related to the motivation to earn reinforcement as opposed to aggressive behavior.

Varied effects of conventional antiepileptics on responding maintained by negative versus positive reinforcement.

We analyzed the effects of four conventional antiepileptic drugs (AEDs) - carbamazepine (CBZ), ethosuximide (ETH), phenytoin (PHT), and valproate (VPA) - on operant behavior maintained by negative or positive reinforcement contingencies. Rats were trained to lever press on a free-operant avoidance schedule or variable-interval (VI) schedule of appetitive reinforcement. Dose-effect functions were separately established on each reinforcement contingency for CBZ (12.5-100 mg/kg), ETH (25-200 mg/kg), PHT (12.5-50 mg/kg), and VPA (50-400 mg/kg). CBZ and PHT reduced responding on free-operant avoidance and VI appetitive reinforcement tasks, with positively reinforced behavior reduced at lower drug dosages than negatively reinforced responding. ETH and VPA reduced responding on the VI appetitive reinforcement task, but did not alter behavior maintained on the free-operant avoidance schedule. Our results suggest that conventional AEDs vary in their effect on operant behavior, depending on the type of reinforcement process maintaining responding.