Repeated exposure to the 5-HT 1b/1a agonist, RU 24969, facilitates the acquisition of MDMA self-administration

Aronsen, Dane; Bukholt, Natasha; Schenk, Susan

doi:10.1016/j.drugalcdep.2015.07.944

“…Destruction of 5-HT terminals via 5,7dihydroxytryptamine (5,7-DHT) lesions produced a similar effect (Bradbury et al, 2013). Furthermore, a down-regulation of 5HT1a and 5HT1b receptors resulting from repeated exposure to the 5HT1a/1b receptor agonist RU 24969 also facilitated the acquisition of MDMA self-administration (Aronsen et al, 2016). 5HT antagonists (5HT1a, 5HT1b, 5HT2a) failed to alter MDMA self-administration (Schenk et al, 2016) supporting the idea that other neural mechanisms must be involved.…”

Section: Mdmamentioning

confidence: 66%

“…While both are amphetamine analogues, methamphetamine and MDMA have different pharmacological profiles, at least following acute administration (Baumann et al, 2002(Baumann et al, , 2005. However, repeated MDMA exposure produced selective deficits in 5HT neurotransmission and it has been suggested that these deficits might contribute to the acquisition of MDMA self-administration (Aronsen et al, 2016;Bradbury et al, 2014;Highgate and Schenk, 2018;Oakley et al, 2014;Schenk, 2011). Methamphetamine exposure can also produce deficits in 5HT neurotransmission (Volz et al, 2007), but 5HT does not appear to play a prominent role in methamphetamine self-administration.…”

Section: Comparison Of Methamphetamine and Mdmamentioning

confidence: 99%

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

Maan¹

0

View full text Add to dashboard Cite

Rationale. 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine are two amphetamine derivatives with contrasting pharmacological profiles. Therefore, self- administration profiles might be expected to reflect these differences. Objectives. This study compared the latency and proportion to acquire self-administration, maintenance of self-administration, and within-session response patterns. Methods. Rats were given extended access (8-hour daily sessions) to either methamphetamine, MDMA or vehicle self-administration over a period of 10 consecutive days. A criterion based on the performance of the vehicle control group was used to determine acquisition of reliable MDMA and methamphetamine self-administration. In conjunction, for MDMA self-administration the infusion dose was halved for each rat that achieved a total of 85mg/kg for the remaining sessions. Temporal patterns of responding were assessed using hourly data of the first day of self-administration, the day following acquisition, and the final day of self-administration. Results. A greater proportion of rats in the methamphetamine group acquired self- administration and self-administration was acquired with a shorter latency compared to the MDMA group. Responding maintained by methamphetamine on day one was high. By the third day a pattern developed that was maintained throughout testing. The greatest proportion of responding occurring within the first hour of each daily test session. A progressive escalation of intake was also observed within the methamphetamine group. Responding maintained by MDMA was low on the first day, but by day 5 responding had increased with most of the responding within the session occurring during the first three hours. On day 10 the greatest amount of responding occurred during the first hour. No escalation of intake as a function of test day was observed for MDMA self-administration.

show abstract

“…Psychopharmacology, 233 (7), 1323-1330. DOI 10.1007/s00213-016-4226-9 Aronsen, Bukholt, & Schenk (2016). Repeated administration of the 5-HT with permission from the publisher (Appendix A).…”

Section: General Introductionmentioning

confidence: 99%

The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

Aronsen¹

Self Cite

0

View full text Add to dashboard Cite

Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse. Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed. Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed. Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors. Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.

show abstract

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

Maan¹

0

View full text Add to dashboard Cite

Rationale. 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine are two amphetamine derivatives with contrasting pharmacological profiles. Therefore, self- administration profiles might be expected to reflect these differences. Objectives. This study compared the latency and proportion to acquire self-administration, maintenance of self-administration, and within-session response patterns. Methods. Rats were given extended access (8-hour daily sessions) to either methamphetamine, MDMA or vehicle self-administration over a period of 10 consecutive days. A criterion based on the performance of the vehicle control group was used to determine acquisition of reliable MDMA and methamphetamine self-administration. In conjunction, for MDMA self-administration the infusion dose was halved for each rat that achieved a total of 85mg/kg for the remaining sessions. Temporal patterns of responding were assessed using hourly data of the first day of self-administration, the day following acquisition, and the final day of self-administration. Results. A greater proportion of rats in the methamphetamine group acquired self- administration and self-administration was acquired with a shorter latency compared to the MDMA group. Responding maintained by methamphetamine on day one was high. By the third day a pattern developed that was maintained throughout testing. The greatest proportion of responding occurring within the first hour of each daily test session. A progressive escalation of intake was also observed within the methamphetamine group. Responding maintained by MDMA was low on the first day, but by day 5 responding had increased with most of the responding within the session occurring during the first three hours. On day 10 the greatest amount of responding occurred during the first hour. No escalation of intake as a function of test day was observed for MDMA self-administration.

show abstract

Repeated exposure to the 5-HT 1b/1a agonist, RU 24969, facilitates the acquisition of MDMA self-administration

Cited by 3 publications

References 0 publications

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

Contact Info

Product

Resources

About