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Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats

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Abstract

Rationale

Like amphetamine, a locomotor-activating dose of 3,4-methylenedioxymethamphetamine (MDMA) predominantly excites striatal single-unit activity in freely moving rats. Although both D1- and D2-like dopamine (DA) receptors play important roles in this effect, MDMA, unlike amphetamine, strongly increases both DA and serotonin (5-HT) transmission.

Objectives

This study was conducted to investigate the 5-HT receptor mechanisms underlying the striatal effects of MDMA.

Methods

We recorded the activity of >200 single units in the striatum of awake, unrestrained rats in response to acute MDMA administration (5 mg/kg) combined with the selective blockade of either 5-HT2A or 5-HT2C/B receptors.

Results

Prior administration of SR-46349B (a 5-HT2A antagonist 0.5 mg/kg) blocked nearly all MDMA-induced striatal excitations, which paralleled its significant attenuation of MDMA-induced locomotor activation. Conversely, prior administration of SB-206553 (a 5-HT2C/B antagonist 2.0 mg/kg) had no effect on the amount of MDMA-induced locomotor activation or the distribution of single-unit responses to MDMA. However, a coefficient-of-variation analysis indicated significantly less variability in the magnitude of both MDMA-induced neuronal excitations and inhibitions in rats that were pretreated with SB-206553 compared to vehicle. Analysis of concurrent single-unit activity and behavior confirmed that MDMA-induced striatal activation was not merely due to behavioral feedback, indicating a primary action of MDMA.

Conclusion

These results support and extend our previous findings by showing that 5-HT2A and 5-HT2C/B receptors differentially regulate the expression of MDMA-induced behavioral and striatal neuronal responses, either directly or through the modulation of DA transmission.

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Acknowledgements

This work was supported by the National Institutes of Health (DA 02451). MDMA was generously provided by the National Institute on Drug Abuse. SR-46349B was kindly provided by Sanofi Synthelabo Recherche. The authors wish to thank Dr. Dale Sengelaub for his expertise and generous assistance in histological and photomicrograph preparation. We also thank Paul Langley for technical support, Faye Caylor for editorial assistance, and Kelly Walsh for electrode bundle construction and behavioral scoring.

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  1. Department of Psychology and Program in Neural Science, Indiana University, 1101 East 10th Street, Bloomington, IN, 47405, USA

    Kevin T. Ball & George V. Rebec

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Ball, K.T., Rebec, G.V. Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats. Psychopharmacology 181, 676–687 (2005). https://doi.org/10.1007/s00213-005-0038-z

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