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Abstract
Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.
Highlights
The entactogen psychostimulant drugs 3,4-methylenedioxy methamphetamine (MDMA), 3,4-methylenedioxymethcathi none (Methylone) and 3,4-methylenedioxypentedrone (Pentylone) are commonly abused substances
The mean number of infusions obtained by rats trained on vehicle saline (N = 8) decreased across sections, whereas infusions obtained by rats trained on pentylone, methylone, or MDMA increased across the 14session acquisition interval with the lowest mean drug-intake observed in the MDMA group and highest in the Pentylone group (Figure 2A)
The post hoc test confirmed that infusions were significantly increased compared to the first session in the Methylone (Sessions 8–14), Pentylone (Sessions 5–14), and MDMA groups (Sessions 9, 11–14); no significant differences in infusions were confirmed within the Vehicle trained group
Summary
The entactogen psychostimulant drugs 3,4-methylenedioxy methamphetamine (MDMA), 3,4-methylenedioxymethcathi none (Methylone) and 3,4-methylenedioxypentedrone (Pentylone) are commonly abused substances. Previous intravenous self-administration (IVSA) studies in male rats indicated that MDMA exhibits low efficacy as a reinforcer, leading to low overall drug intake and high inter-subject variability compared with, e.g., cocaine or methamphetamine (Dalley et al, 2007; Bradbury et al, 2014; Creehan et al, 2015). This has long been assumed to be a consequence of the pharmacological selectivity of MDMA for serotonin transporter inhibition and efflux, compared with the closely related methamphetamine. There is evidence that under some circumstances, the serotonin transporter selective entactogen class stimulants can produce compulsive drug seeking behavior in rodent IVSA
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