Drug seeking in response to a priming injection of MDMA in rats: relationship to initial sensitivity to self-administered MDMA and dorsal striatal dopamine

Abstract

In laboratory animals, exposure to priming injections of 3,4-methylenedioxymethamphetamine (MDMA) produced drug seeking following extinction of MDMA self-administration. This study aimed to evaluate whether the magnitude of drug seeking was related to latency to acquisition of MDMA self-administration and increases in striatal dopamine, as measured by in-vivo microdialysis. Rats were given daily access to MDMA self-administration until they earned a total of 240 infusions (total intake of 165 mg/kg MDMA). Twelve of the 20 rats acquired self-administration within the temporal limits of the study and the latency to meet the criterion ranged from 9 d to 37 d. An experimenter-administered injection of MDMA (10.0 mg/kg i.p.) produced drug seeking in these rats, and the number of responses was significantly higher than responses produced by rats that failed to meet the criterion or by yoked control rats that received the drug passively. For rats that met the criterion, drug seeking was negatively correlated with the number of days to self-administer the criterion number of MDMA infusions and positively correlated with MDMA-produced dopamine in the dorsal striatum. Importantly, MDMA-produced dopamine overflow was greater for the rats that met the criterion. These findings suggest that drug seeking is influenced by initial sensitivity to the reinforcing effects of MDMA and to drug-produced increases in striatal dopamine.

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

“…Coincident with the decrease in MDMA-produced 5HT, some studies have shown that there is an increase in MDMA-produced DA (Kalivas et al, 1998;Mayerhofer et al, 2001;Colussi-Mas et al, 2010). We have suggested that this sensitised DA response underlies the development of high levels of MDMA self-administration leading to further, and more persistent, deficits in 5HT (Schenk, 2011).…”

“…Exposure to either repeated, intermittent experimenter-delivered injections (Kalivas et al, 1998) or substantial self-administered (Colussi-Mas et al, 2010) MDMA also increased MDMA-produced DA overflow as measured by microdialysis. Of particular interest, the sensitised rearing response persisted following 14 days of abstinence.…”

“…Effects of MDMA selfadministration on these same measures in rats are, however, lacking. One study failed to observe a change in dialysate levels of MDMAstimulated DA overflow following relatively small amounts of selfadministered MDMA (Reveron et al, 2010) whereas another showed increased DA overflow following more extensive MDMA selfadministration (Colussi-Mas et al, 2010). Another study reported MDMA-produced changes in dialysate levels of DA and 5HT as well as in MDMA-produced hyperactivity, but comparisons to effects of MDMA from saline self-administering rats was not provided so that an indication of changes due specifically to MDMA self-administration was not possible (Feduccia and Duvauchelle, 2008).…”

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

“…The fact that risperidone blocked the acquisition of MDMA-induced CPP in our experiments indicates that DA D 2 /5-HT 2 receptors are critical to one or both of the aforementioned processes. Microdialysis studies have shown an increase in synaptic DA and serotonin in the nucleus accumbens following exposure to MDMA, similarly to that seen with other addictive drugs (Cadoni et al, 2005;Colussi-Mas et al, 2010;Gudelsky and Yamamoto, 2008). A recent study has demonstrated the involvement of serotonin and DA transporters (SERT and DAT, respectively) in MDMA-induced DA release in the striatum, finding it to be blocked only in mice lacking both transporters, but not in those lacking either DAT or SERT (Hagino et al, 2011).…”

Rats preexposed to MDMA display attenuated responses to its aversive effects in the absence of persistent monoamine depletions

“…Rhesus monkeys also display a great deal of individual variability in MDMA self-administration, far more than that observed when responding for cocaine (Fantegrossi et al 2002). Adding further complication to a characterization of MDMA"s rewarding effects, recent reports using extended acquisition periods have reported robust self-administration, even in rats that displayed initial resistance to such acquisition (Dalley et al 2007;Colussi-Mas et al 2010). Complemented by reports from the human literature that have identified subpopulations of long-term, heavy users (Schifano et al 1998;Parrott 2005; see also Kouimtsidis et al 2006), the collective data strongly suggest that MDMA"s abuse potential varies widely among individual users.…”