Repeated administration of the 5-HT sub(1B/1A) agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT sub(1A) and 5-HT sub(1B) receptor mechanisms

• Published in: Psychopharmacology Vol. 233; no. 8; pp. 1339 - 1347
• Main Authors: Aronsen, Dane, Bukholt, Natasha, Schenk, Susan
• Format: Journal Article
• Language: English
• Published: 01.04.2016
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4225-x

3,4 Methylenedioxymethamphetamine (MDMA) preferentially stimulates the release of serotonin (5-HT) that subsequently produces behavioral responses by activation of post-synaptic receptor mechanisms. The 5-HT sub(1A) and 5-HT sub(1B) receptors are both well localized to regulate dopamine (DA) release, and have been implicated in modulating the reinforcing effects of many drugs of abuse, but a role in acquisition of self-administration has not been determined. This study was designed to determine the effect of pharmacological manipulation of 5-HT sub(1A) and 5-HT sub(1B) receptor mechanisms on the acquisition of MDMA self-administration. The 5-HT sub(1B/1A) receptor agonist, RU 24969 (0.0 or 3.0 mg/kg, bid), was administered for 3 days in order to down-regulate both 5-HT sub(1A) and 5-HT sub(1B) receptors. Following the pretreatment phase, latency to acquisition of MDMA self-administration was measured. Repeated administration of RU 24969 significantly decreased the latency to acquisition and increased the proportion of animals that acquired MDMA self-administration. Dose-effect curves for the 5-HT sub(1A)-mediated hyperactivity produced by the 5-HT sub(1A) agonist, 8-OH-DPAT, and the 5-HT sub(1B)-mediated adipsic response produced by RU 24969 were shifted rightward, suggesting a desensitization of 5-HT sub(1A) and 5-HT sub(1B) receptor mechanisms. These data suggest that the initial reinforcing effects of MDMA are modulated by 5-HT sub(1A) and/or 5-HT sub(1B) receptor mechanisms. The potential impact of these changes on the DAergic response relevant to self-administration and a possible role in conditioned reinforcement pertaining to acquisition of self-administration are discussed.