Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses

Abstract

When given systemically to rats and humans, the drug of abuse 3,4 methylenedioxymethamphetamine (ecstasy, MDMA) elicits hyperthermia, hyperactivity, tachycardia, and hypertension. Chemically stimulating the dorsomedial hypothalamus (DMH), a brain region known to be involved in thermoregulation and in stress responses, causes similar effects. We therefore tested the hypothesis that neuronal activity in the DMH plays a role in MDMA-evoked sympathetic and behavioral responses by microinjecting artificial CSF or muscimol, a neuronal inhibitor, into the DMH prior to intravenous infusion of saline or MDMA in conscious rats. Core temperature, heart rate, mean arterial pressure and locomotor activity were recorded by telemetry every minute for 120 min. In rats previously microinjected with CSF, MDMA elicited significant increases from baseline in core temperature (+1.3+/-0.3 degrees C), locomotion (+50+/-6 counts/min), heart rate (+142+/-16 beats/min), and mean arterial pressure (+26+/-3 mmHg). Microinjecting muscimol into the DMH prior to MDMA prevented increases in core temperature and locomotion and attenuated increases in heart rate and mean arterial pressure. These results indicate that neuronal activity in the DMH is necessary for the sympathetic and behavioral responses evoked by MDMA.

Figure 1. Effect of microinjection of muscimol into the DMH on temperature and locomotor activity to intravenous MDMA

Changes from baseline over time (minutes) in (A) core temperature and (B) locomotion after microinjecting (t= −5 min) CSF (100nl) or muscimol (80 pmol/100 nl) into the DMH followed by (t = 0 min) intravenous administration of MDMA (7.5 mg/kg) or saline. *significantly different from baseline; ‡significantly different from all other groups at the specified time point. ANOVA and LSD, p < 0.05.

Figure 2. Effect of microinjection of muscimol into the DMH on cardiovascular responses to intravenous MDMA

Changes over time (minutes) in (A) heart rate and (B) mean arterial pressure after microinjecting into the DMH (t= −5 min) CSF (100nl) or muscimol (80 pmol/100 nl) followed by (t = 0 min) intravenous administration of MDMA (7.5 mg/kg) or saline. *significantly different from baseline; ‡significantly different from all other groups at the specified time point. ANOVA and LSD, p < 0.05.

Figure 3. Sites of injection into the DMH

Schematic coronal sections of the rat brain adapted from the atlas of Paxinos and Watson (1998) illustrating approximate sites of injections into the DMH. Numbers indicate distance from bregma in millimeters. Open symbols represent experiments in which animals were infused with intravenous saline after microinjections of 100 nl of CSF (open circles) or 80 pmol of muscimol (open squares) into the DMH. Filled symbols represent experiments in which animals were infused with intravenous MDMA (7.5 mg/kg) after microinjections with either 100 nl of CSF (closed circles) or 80 pmol of muscimol (closed squares). The numbers of animals in each group is given in parenthesis.