Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors

Abstract

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS, producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD₆₇ (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD₆₇ neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression.

Figure 1

Schematic (adapted from Morin & Wood, 2001) and representative photomicrograph of a coronal section of the Syrian hamster brain showing the site of central administration of eticlolpride and SCH-23390 into the anterior hypothalamus. Note in the photomicrograph (from the dorsal to ventral axis), the track of the guide-cannula and the track of the injection needle (arrows) aimed toward the lateral subdivision of the anterior hypothalamus (i.e the LAH). 3v: third ventricle; AH: anterior hypothalamus; mSON: medial supraoptic nucleus; NC: nucleus circularis; oc: optic chiasm.

Figure 2

Composite aggression score of AAS-treated animals after injection of the D2 receptor antagonist eticlopride or the D5 receptor antagonist SCH-23390 (0.1μg -1.0μg/0.5μl) in the anterior hypothalamus. A. Only the highest dose of SCH-23390 suppressed AAS-induced aggression when compared to steroid treated animals administered saline. B. Both moderate (0.1μg) and high (1.0μg) doses of eticloprdie dose-dependently decreased AAS-induced aggression. * p < 0.05, ** p < 0.01 compared to AAS-treated hamsters injected with saline into the AH on test day.

Figure 3

Treatment with AAS throughout adolescence altered GAD₆₇ but not D5 immunofluorescent staining in the LAH. Animals treated with AAS showed a significnat increase in the number of cells positively labeled for GAD₆₇. However no changes were observed in the number of cells expressing D5 receptors between AAS and sesame oil-controls. Interestingly, few neurons were positively labeled with both GAD₆₇ and D5 receptors and were unaltered by AAS-treatment. *p<0.05; Student's t-test, two-tailed (n = 6/group).

Figure 4

Darkfield photomicrographs of a coronal section through the LAH at 20× magnification. Shown are cells positively labeled with GAD₆₇ (green), D5 receptors (red), and double-labeled GAD₆₇/D5 cells (overlay) of sesame oil and AAS treated hamsters.

Figure 5

A model showing the hypothetical modulation of magnocellular AVP release through dopamine and GABA interactions. AAS-induced increases in dopamine from the NC and mSON activate inhibitory D2 receptors expressed on GABAergic neurons in the LAH. These local D2-expressing GABAergic neurons are hypothesized to modulate the release of aggression stimulating AVP. Therefore, AAS-induced increases in dopamine would remove GABAergic inhibition of AVP resulting in increased LAH activity and elevated aggression. (+) excitation; (-) inhibition.