PubMed · 5165643
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M B Wallach, S Gershon. 1971. Sensitization to amphetamines.. https://pubmed.ncbi.nlm.nih.gov/5165643/
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RATIONALE: MDMA is a serotonergic neurotoxin but few pre-clinical studies have found long-term behavioural consequences. As human users of MDMA are polydrug users, it is important to investigate whether the behavioural effects of other drugs are modulated by prior exposure to MDMA. OBJECTIVE: . This study investigated whether pretreatment with a multiple high dose regimen of MDMA altered the rewarding effects of other drugs of abuse. METHODS: Adult male Lister Hooded rats ( n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle IP every 2 h for 6 h. Fourteen days later, conditioned place preference (CPP) to d-amphetamine (3 mg/kg), cocaine (20 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) was assessed. RESULTS: In general, MDMA pretreatment had no effect on drug reward or habituation to the place conditioning apparatus. However, in contrast to saline pretreated rats, those animals receiving MDMA failed to show CPP after ethanol. CONCLUSION: MDMA pretreatment reduced the rewarding properties of ethanol. This finding may represent a functional consequence of MDMA-induced neurotoxicity. By extrapolation, human users of MDMA may be exposed to an increase in risks associated with alcohol abuse.
Changes in the firing pattern of midbrain dopamine neurons are thought to encode information for certain types of reward-related learning. In particular, the burst pattern of firing is predicted to result in more efficient dopamine release at target loci, which could underlie changes in synaptic plasticity. In this study, the effects of dopamine on the firing patterns of dopaminergic neurons in vivo and their electrophysiological characteristics in vitro were examined by using a genetic dopamine-deficient (DD) mouse model. Extracellular recordings in vivo showed that, although the firing pattern of dopamine neurons in normal mice included bursting activity, DD mice recordings showed only a single-spike pattern of activity with no bursts. Bursting was restored in DD mice after systemic administration of the dopamine precursor, L-3,4-dihydroxyphenylalanine (L-dopa). Whole-cell recordings in vitro demonstrated that the basic electrophysiology and pharmacology of dopamine neurons were identical between DD and control mice, except that amphetamine did not elicit a hyperpolarizing current in slices from DD mice. These data suggest that endogenously released dopamine plays a critical role in the afferent control of dopamine neuron bursting activity and that this control is exerted via a network feedback mechanism.
Although recent data has shown that 5-HT(6) receptor antagonists' can enhance basal cholinergic and glutamatergic neurotransmission in the cortex and hippocampus, the distribution of this receptor within terminal regions of the dopaminergic system suggests a possible role for this receptor in the modulation of dopamine (DA). Therefore, the role of the 5-HT(6) receptor was examined in the rat striatum in the presence and absence of the DA transport inhibitor/releaser, amphetamine. Amphetamine (0.3mg/kg s.c.) induced a selective increase in extracellular DA reaching a maximum of 311.3+/-73.5% of preinjection levels. Administration of SB-271046 (1 and 10mg/kg s.c.) followed by amphetamine produced an augmentation of amphetamine-induced changes in both DA and 5-hydroxytryptamine (5-HT), reaching maximum levels of 510.1+/-110.5% and 271+/-93.4% of preinjection values, respectively. Similarly, local infusion of amphetamine (100 nM) resulted in an increase in striatal DA levels reaching a maximum of 365.7+/-73.3% of preinfusion values. However, combination treatment with SB-271046 (1mg/kg s.c.) and amphetamine produced no augmentation of amphetamine-induced increases in extracellular levels of DA or in any other neurotransmitter measured. Taken together these data indicate that the 5-HT(6) receptor is not playing a role in the tonic modulation of NA, DA, 5-HT or glutamate neurotransmission in the striatum. However, when dopaminergic neurotransmission is enhanced the 5-HT(6) receptor appears to have a modulatory influence on not only DA but also 5-HT systems. This is the first direct neurochemical evidence that the 5-HT(6) receptor may have modulatory influences on both DA and 5-HT systems in the rat striatum.