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.
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.
<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>
<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>
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