Acquisition of MDMA self‐administration: pharmacokinetic factors and MDMA‐induced serotonin release

Abstract

The current study aimed to elucidate the role of pharmacokinetic (PK) parameters and neurotransmitter efflux in explaining variability in (±) 3, 4-methylenedioxymethamphetamine (MDMA) self-administration in rats. PK profiles of MDMA and its major metabolites were determined after the administration of 1.0 mg/kg MDMA (iv) prior to, and following, the acquisition of MDMA self-administration. Synaptic levels of 5-hydroxytryptamine (5HT) and dopamine (DA) in the nucleus accumbens were measured following administration of MDMA (1.0 and 3.0 mg/kg, iv) using in vivo microdialysis and compared for rats that acquired or failed to acquire MDMA self-administration. Effects of the 5HT neurotoxin, 5,7 dihydroxytryptamine (5, 7-DHT), on the acquisition of MDMA and cocaine self-administration were also determined. In keeping with previous findings, approximately 50% of rats failed to meet a criterion for acquisition of MDMA self-administration. The PK profiles of MDMA and its metabolites did not differ between rats that acquired or failed to acquire MDMA self-administration. MDMA produced more overflow of 5HT than DA. The MDMA-induced 5HT overflow was lower in rats that acquired MDMA self-administration compared with those that did not acquire self-administration. In contrast, MDMA-induced DA overflow was comparable for the two groups. Prior 5,7-DHT lesions reduced tissue levels of 5HT and markedly increased the percentage of rats that acquired MDMA self-administration and also decreased the latency to acquisition of cocaine self-administration. These data suggest that 5HT limits the initial sensitivity to the positively reinforcing effects of MDMA and delays the acquisition of reliable self-administration.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Data set has been published (Bauer et al, 2013b). rate-increasing effects are mediated by DA, whereas abuse-limiting rate-decreasing effects are mediated by 5HT. This conclusion is consistent with results from other ICSS studies (Lin et al, 1997) and with a large literature of drug self-administration data to suggest that DA mediates reinforcing effects of releasers, whereas 5HT limits expression of reinforcing effects (Wee and Woolverton, 2006;Bradbury et al, 2013). In summary then, ICSS frequency-rate procedures permit simultaneous detection and study of effects that can either promote or limit abuse potential, and "% baseline stimulations" provides a useful summary measure for integration of these effects and prediction of their impact on drug reinforcement in selfadministration procedures.…”

Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats

“…Thereafter, infusions of MDMA (1.0 mg/kg/infusion) or vehicle (3 unit heparin) were delivered according to a fixed ratio 1 schedule of reinforcement. As in our previous studies (Do and Schenk, 2013;Bradbury et al, 2014), testing continued for 25 daily sessions, or until the session during which the total cumulative amount of self-administered MDMA reached 90 ± 5 infusions, whichever came first. For rats that met this criterion the dose of MDMA was subsequently decreased to 0.5 mg/kg/infusion and testing continued until a total intake of 165 mg/kg was reached (an additional 150 infusions).…”

“…When MDMA-stimulated 5HT was measured using in vivo microdialysis, groups of rats that subsequently self-administered to criterion had a smaller 5HT response than those that failed to meet the criterion (Bradbury et al, 2014). The idea that 5HT limits the acquisition of MDMA was further reinforced by results of experiments that directly manipulated 5HT neurotransmission.…”

“…The idea that 5HT limits the acquisition of MDMA was further reinforced by results of experiments that directly manipulated 5HT neurotransmission. Both neurotoxic lesions (Bradbury et al, 2014) and a mutation that prevented function of the 5HT transporter (Oakly et al, 2014) increased the reinforcing efficacy of MDMA in rats: the latency to acquisition of self-administration was decreased and the number of rats that met the criterion for acquisition of self-administration was increased.…”

Altered Insula Connectivity under MDMA

“…The potent action of MDMA at the serotonin transporter-compared with other stimulants (Bradbury et al, 2014)-is believed to be responsible for much, but not all, of MDMA's unique phenomenology (Liechti and Vollenweider, 2001;van Wel et al, 2011). Common psychological features of the MDMA experience include heightened arousal and perception, pro-sociability, enhanced mood, and feelings of euphoria.…”