Local cerebral metabolic response to 8-OH-DPAT in Dark Agouti rats is altered by prior exposure to 3,4,-methylenedioxymethamphetamine (MDMA)

Introduction

A single exposure to 3,4,-methylenedioxymethamphetamine (MDMA) induces serotonergic terminal depletion in Dark Agouti (DA) rats ¹ , although by six weeks post-MDMA cerebral function is normalised ² . The compensatory mechanisms that follow initial MDMA-induced effects on cerebral glucose use (LCMRglu) are unclear, although alterations in serotonergic receptors may be involved. In this study we examined the effects of the selective 5-HT1A agonist, 8-OH-DPAT upon LCMRglu in DA rats exposed to MDMA six weeks previously.

Methods

DA rats were injected i. p. with MDMA (15 mg.kg-1) or saline (both n=10). 6 weeks later equal numbers from each group were injected i.v. with 8-OH-DPAT (1 mg.kg-1) or saline 1 minute prior to the measurement of LCMRglu using [14C]-2-deoxyglucose quantitative autoradiography. Data (mean±sem) from 62 brain areas were analysed using t-test with Bonferroni correction (p<0.05).

Results

There were no significant differences between pre-treatment groups in either physiological variables or LCMRglu following acute saline. In both pre-treatment groups 8-OH-DPAT produced significant decreases in MABP (137±3 to 119±4 mmHg in saline and 138±2 to 121±3 mmHg in MDMA), temperature and heart rate. In saline pre-treated rats, 8-OH-DPAT produced widespread reductions in LCMRglu significantly different from control in 28 of the 62 brain areas analysed. Most marked significant decreases were observed in motor areas (entopeduncular nucleus, from 58±9 to 33±3 mmol.100 g.min-1) limbic areas (medial amygdala, 58±7 to 30±4) neocortex (entorhinal cortex, 70±3 to 49±3) and raphé nuclei (median raphé, 87±3 to 66±4; paramedian raphé, 82±3 to 61±4). Significant increases in LCMRglu were observed in just 3 brain areas (frontal cortex layer IV, 109±5 to 140±9; layer VI 90±4 to 107±5). In keeping with previous work (Quate et al, 2004), MDMA pre-treatment produced a statistically significant 33% reduction in 5-HT receptor binding (p<0.05). With the exception of hippocampus, in the MDMA group 8-OH-DPAT-induced reductions in LCMRglu were both less widespread and less marked (range −4 to −45%), in comparison with responses observed in the saline group (−16% to −60%) while 8-OH-DPAT-induced increases in LCMRglu observed in saline animals were potentiated. Significant reductions in LCMRglu were observed in 7 brain areas most markedly in limbic areas (medial amygdala from 61±4 to 33±4 mmol.100 g.min-1; ventral CA1, 62±2 to 41±4). Significant increases in LCMRglu were observed in 11 brain regions predominantly in neocortex (frontal layer IV, 97±3 to 164±6; layer VI, 84±3 to 126±7; sensorimotor layer IV, 105±4 to 162±11; layer VI, 89±3 to133±7) although significant increases were also observed in motor and limbic areas. In hippocampus 8-OH-DPAT produced similar significant reductions in LCMRglu in both groups. (e.g. dorsal CA1, saline: 57±2 to 41±3; MDMA: 55±2 to 45±3).

Conclusions

These results suggest that MDMA-induced serotonergic depletion is followed by changes in 5-HT1A receptor function. However, the effects of these changes are not uniform throughout the brain and may reflect the relative importance of 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, particularly in hippocampus.