Repeated exposure to MDMA and amphetamine: sensitization, cross-sensitization, and response to dopamine D1- and D2-like agonists.

RATIONALE: Acute exposure to (±) 3, 4-methylenedioxymethamphetamine (MDMA) produces hyperlocomotion that is preferentially expressed in the periphery of closed chambers. Following repeated administration, however, a sensitized hyperlocomotor response is preferentially expressed in the center of an activity box, so that the response resembles the more generalized activity that is produced by D-amphetamine (AMPH). OBJECTIVES: The present study was designed to determine whether common neuroadaptations underlie the acute and sensitized responses to MDMA and AMPH. METHODS: Rats were pretreated with five daily injections of MDMA (10.0 mg/kg), AMPH (2.0 mg/kg), or saline. Following a 2-day drug-free period, dose-response curves for hyperactivity produced by MDMA (2.5-10.0 mg/kg), AMPH (0.5-2.0 mg/kg), SKF-81297 (1.0-2.0 mg/kg), or quinpirole (0.25-1.0 mg/kg) were obtained. RESULTS: Effects of MDMA and AMPH were increased by pretreatment with both drugs. The sensitized response following MDMA exposure was preferentially expressed in the center compartment, but, following AMPH pretreatment, the sensitized response was observed in both compartments. Cross-sensitization was unidirectional; AMPH pretreatment failed to sensitize to the effects of MDMA, but MDMA pretreatment sensitized to the effects of AMPH. MDMA and AMPH pretreatment produced marginal increases in the effects of SKF-81297. The response to quinpirole was, however, greater following MDMA, but not AMPH, pretreatment. CONCLUSIONS: These data suggest that repeated MDMA exposure produces sensitization via a unique neurochemical effect.

Effects of priming injections of MDMA and cocaine on reinstatement of MDMA- and cocaine-seeking in rats.

Exposure to self-administered drugs is sufficient to produce drug-seeking in animal models. In many cases priming injections of drugs that share discriminative stimulus properties with the self-administered drug also can lead to drug-seeking, suggesting that exposure might precipitate relapse. The present investigation examined the ability of MDMA or cocaine priming injections to reinstate extinguished drug-seeking in rats. Priming injections of cocaine (0-20.0 mg/kg) and MDMA (0.0-10.0 mg/kg) reinstated extinguished drug-taking for both the cocaine- and MDMA-trained rats. In a separate group of cocaine-trained rats that received repeated exposure to 10.0 mg/kg MDMA, the initial exposure to MDMA (10.0 mg/kg, i.p.) failed to reinstate extinguished responding but MDMA became an effective prime for reinstatement of extinguished cocaine-taking behavior with repeated exposure. Effects of MDMA in MDMA-trained rats was greater than the effect in cocaine-trained rats suggesting that extensive experience with MDMA self-administration might have sensitized rats to this effect. These findings show that extinguished MDMA self-administration, like self-administration of other drugs of abuse, can be reinstated by exposure to psychostimulants thereby precipitating relapse.

MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding.

3,4-Methylenedioxymethamphetamine (MDMA) self-administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug-naïve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self-administration was measured during daily 6-h sessions. Dose-effect data were obtained for MDMA (0.25-1.0 mg/kg/infusion) self-administration under a progressive ratio (PR) schedule of reinforcement. The effect of experimenter- or self-administered MDMA on [3H] paroxetine binding in several brain regions was measured. Acquisition of MDMA self-administration was highly variable and not different for 0.25 or 1.0 mg/kg/infusion progressed with approximately 60% of the rats acquiring reliable self-administration during the 15-day test period. The percentage of rats that acquired MDMA self-administration was lower than the percentage of rats that acquired cocaine (0.5 mg/kg/infusion) self-administration, and cocaine self-administration was acquired with a shorter latency. Responding maintained by MDMA was dose dependent, and breakpoints under a PR schedule increased with dose. Radioligand binding and autoradiography demonstrated lower densities of serotonin transporter sites (SERT) in MDMA self-administering rats as compared with controls across brain regions. The reduction in SERT densities was comparable in magnitude to rats treated with experimenter-administered doses of MDMA. These data support the idea that MDMA is a drug with high abuse liability, and long-term self-administration may lead to long-lasting deficits in serotonin neurotransmission.

N-benzylpiperazine has characteristics of a drug of abuse.

The ability of benzylpiperazine (BZP) to substitute for cocaine and to initiate self-administration in drug-naive subjects was assessed to determine whether BZP has abuse liability. Further, the effects of a pretreatment with dopamine D1-like receptor antagonist (SCH23390) were examined to elucidate the mechanisms associated with BZP reward. First, the ability for BZP (0.125, 0.25 and 0.5 mg/kg/infusion) to substitute for cocaine self-administration was assessed, and the acquisition of BZP (0.5 mg/kg/infusion) self-administration by drug-naive and untrained rats was determined during a 15-day period. Subsequently, dose-effect curves for cocaine (0.06, 0.125, 0.25 or 0.5 mg/kg/infusion) and BZP self-administration (0.125, 0.25, 0.5 or 1.0 mg/kg/infusion) and the effect of SCH23390 (0.00 or 0.02 mg/kg) on BZP and cocaine self-administration were examined. BZP substituted for cocaine, and drug-naive rats rapidly acquired BZP self-administration. BZP self-administration was maintained by a more restricted range of doses than was cocaine self-administration, and responding maintained by BZP was sensitive to dopamine antagonism. The present findings indicate that BZP self-administration, like cocaine self-administration, is readily acquired and mediated by dopaminergic mechanisms.

The effect of Parkinson's disease on time estimation as a function of stimulus duration range and modality.

The present research sought to investigate the role of the basal ganglia in timing of sub- and supra-second intervals via an examination of the ability of people with Parkinson's disease (PD) to make temporal judgments in two ranges, 100-500 ms, and 1-5 s. Eighteen non-demented medicated patients with PD were compared with 14 matched controls on a duration-bisection task in which participants were required to discriminate auditory and visual signal durations within each time range. Results showed that patients with PD exhibited more variable duration judgments across both signal modality and duration range than controls, although closer analyses confirmed a timing deficit in the longer duration range only. The findings presented here suggest the bisection procedure may be a useful tool in identifying timing impairments in PD and, more generally, reaffirm the hypothesised role of the basal ganglia in temporal perception at the level of the attentionally mediated internal clock as well as memory retrieval and/or decision-making processes.

Conditioning following repeated exposure to MDMA in rats: role in the maintenance of MDMA self-administration.

There has been some controversy in the literature concerning the ability of +/-3,4 methylenedioxymethamphetamine (MDMA) to reinforce operant responding in rats. In the present study, operant responding maintained by intravenous MDMA infusions increased when the fixed ratio schedule was increased from 1 to 5, decreased when saline was substituted for MDMA, and increased again when MDMA was reintroduced. During self-administration training, each infusion of MDMA was paired with the illumination of a light stimulus. The role of the continued presentation of this drug-associated stimulus in operant responding was measured in groups of rats that had received comparable exposure (average 19 daily test sessions) to MDMA during training. When either the light stimulus or the drug infusion was omitted, operant responding decreased gradually over the 15-day test period following training. When both the light stimulus and the MDMA infusion were omitted, there was a dramatic decrease in operant responding that persisted for the entire 15-day test period. These findings suggest that cues associated with MDMA develop conditioned properties that might contribute to drug taking.

Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats.

RATIONALE: +/-3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") use is increasing around the globe but there is a paucity of studies examining the abuse liability of this drug. OBJECTIVES: The ability of drugs to reinforce operant responding in laboratory animals is a valid and reliable predictor of abuse potential. MDMA is self-administered by humans, but there have been few reports of reliable self-administration by drug-naive laboratory animals. The present study sought to examine the acquisition and maintenance of MDMA self-administration by laboratory rats. The influence of prior training with cocaine self-administration on the acquisition of MDMA self-administration was also examined. METHODS: MDMA self-administration (0.25-2.0 mg/kg per infusion) was examined in rats that were first trained to self-administer cocaine as well as by those that were drug-naive. The dose-dependency of MDMA self-administration and the temporal pattern of responding maintained by various doses of MDMA were examined. In some rats, self-administration of MDMA during a 24-h session was also examined. RESULTS: MDMA was self-administered by laboratory rats that were experienced with self-administration of cocaine as well as by rats that were initially drug naive. For drug naive rats, the acquisition of MDMA self-administration (1.0 mg/kg per infusion) developed gradually during daily test sessions. The latency to acquisition of self-administration was shorter in cocaine-trained rats. Self-administration was dose-dependent, extinguished when saline was substituted for MDMA and, was reinstated when MDMA was reintroduced. During a 24-h self-administration session, a high rate of responding was produced during the first hour of the test session followed by a steady and lower rate of two to four responses per hour during subsequent hours of the test. CONCLUSIONS: These results suggest that prior experience with cocaine self-administration facilitates the acquisition of MDMA self-administration. The results also suggest that MDMA has abuse liability and that increased use of the drug should raise concern of a growing and widespread potential for chronic abuse.