GABA(A) receptors in the dorsal raphé nucleus of mice: escalation of aggression after alcohol consumption

Abstract

Rationale: The dorsal raphé nucleus (DRN), the origin for serotonin (5-HT) in forebrain areas, has been implicated in the neural control of escalated aggression. Gamma aminobutyric acid type-A (GABA(A)) and type-B (GABA(B)) receptors are expressed in the DRN and modulate 5-HT neuronal activity, and both play a role in the behavioral effect of alcohol.

Objective: The purpose of this study is to examine the interaction between drugs acting on GABA receptors in the DRN and alcohol in their effects on aggressive behaviors.

Method: Male CFW mice, housed with a female, were trained to self-administer ethanol (1.0 g/kg) or water via an operant conditioning panel in their home cage. Immediately after they drank either ethanol or water, the animals were microinfused with a GABAergic drug into the DRN, and their aggressive behaviors were assessed 10 min later. Muscimol (0.006 nmol), a GABA(A) receptor agonist, escalated alcohol-heightened aggression but had no effect in the absence of ethanol. This effect of muscimol was prominent in the animals that showed alcohol-heightened aggression, but not the animals that reduced or did not change aggressive behavior after ethanol infusion compared to water. On the other hand, the GABA(B) agonist baclofen (0.06 nmol) increased aggressive behavior similarly in both water and ethanol conditions. Antagonists of the GABA(A) and GABA(B) receptors, bicuculline (0.006 nmol) and phaclofen (0.3 nmol) respectively, did not suppress heightened-aggressive behavior induced by ethanol self-administration.

Conclusion: GABA(A) receptors in the DRN are one of the neurobiological targets of alcohol-heightened aggression. Activation of the GABA(B) receptors in the DRN also produced escalated aggression, but that is independent of the effect of alcohol.

Fig. 1

Injection sites in the DRN. a Representative mouse coronal brain section (20×) that was stained with cresyl violet. b Schematic representation of injection sites for experiment 1 (GABA_A) and experiment 2 (GABA_B) in mouse coronal brain section (Paxinos and Franklin 2001). Circles indicate injection sites within the DRN and triangles represent injection sites outside the DRN

Fig. 2

GABA_A receptor modulation in the DRN and alcohol-heightened aggression. a The effect of intra-DRN microinjection of GABA_A receptor agonist muscimol (Mus) on the frequency of attack bites after water or 1.0 g/kg of alcohol (EtOH) consumption. Asterisk indicates significant difference from the vehicle within the same condition (p<.05). b The effect of intra-DRN microinjection of the GABA_A receptor antagonist, bicuculline (Bic), on the frequency of attack bites after water or EtOH consumption. Asterisk indicates significant main effect of alcohol

Fig. 3

Interaction between muscimol microinjection into the DRN and alcohol-heightened aggression in AHA and ANA individuals. a AHA individuals (n=4), left side (Pre), attack bites before the cannula implantation after water or 1.0-g/kg alcohol self-administration. Right side (Post), attack bites after water or 1.0-g/kg alcohol self-administration and vehicle microinjection into the DRN. b ANA individuals (n=4) that were designated as such before surgery and consistently showed no change or reduced attack bites after alcohol self-administration and intra-DRN vehicle treatment. c The effect of muscimol in AHA individuals on attack bites after either water or alcohol consumption. d The effect of muscimol in ANA individuals on attack bites after water or alcohol consumption. Asterisks indicate significant difference from vehicle within same condition (p<.05)

Fig. 4

GABA_B receptor modulation in the DRN and alcohol-heightened aggression. a The effect of intra-DRN microinjection of the GABA_B receptor agonist, baclofen (Bac), on the frequency of attack bites after water or 1.0 g/kg of alcohol (EtOH) consumption. b The effect of intra- DRN microinjection of the GABA_B receptor antagonist, phaclofen (Pha), on the frequency of attack bites after water or EtOH consumption. Asterisks 2indicate significant difference from the vehicle within the same condition (p<.05)