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Background: The cystine-glutamate exchanger is downregulated after chronic cocaine, resulting in reduced extracellular levels of nucleus accumbens glutamate. The importance of cocaine-induced loss of glutamate homeostasis is revealed by N-acetylcysteine restoring cystine-glutamate exchange and attenuating reinstatement to cocaine seeking. Another regulator of extracellular glutamate is the glial glutamate transporter GLT-1. We hypothesized that cocaine self-administration reduces GLT-1 and that GLT-1 upregulation inhibits cocaine seeking., Methods: We measured [(3)H] glutamate uptake and protein expression of GLT-1 and xCT, the catalytic subunit of the cystine-glutamate exchanger, following cocaine self-administration and 3 weeks of extinction training. We also examined the affect of ceftriaxone (previously shown to increase GLT-1) and N-acetylcysteine treatment on the expression of GLT-1 and xCT. Ceftriaxone was also tested for the capacity to inhibit cue- and cocaine-induced relapse., Results: Cocaine self-administration reduced glutamate uptake and the expression of both GLT-1 and xCT. Ceftriaxone restored GLT-1 and xCT levels and prevented cue- and cocaine-induced reinstatement of drug seeking. N-acetylcysteine also restored GLT-1 and xCT levels., Conclusions: These results indicate that glutamate transport and cystine-glutamate exchange may be coregulated and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.

Sufficient evidence exists for the inclusion of the ventral pallidum (VP) into the category of a dopaminoceptive brain region. The effects of inhibiting dopamine D(1)- or D(2)-like receptors in the VP on (a) ethanol intake and (b) extracellular levels of dopamine, were investigated in the alcohol-preferring (P) rat. The D(1)-like antagonist, SCH-23390, and the D(2)-like antagonist, sulpiride (0.25-2 microg/0.5 microl) were bilaterally injected into the VP and ethanol (15%, v/v) intake was assessed in a 1 h limited access paradigm. The results indicate that microinjections of sulpiride significantly increased ethanol consumption (65% increase at the 2.0 microg dose). Whereas the D(1) antagonists SCH-23390 tended to decrease ethanol intake, the effect was not statistically significant. In a separate group of rats, reverse microdialysis of sulpiride and SCH-23390 (10-200 microM) were conducted in the VP of P rats. Local perfusion of only the 200 microM sulpiride dose significantly increased the extracellular levels of dopamine (maximal increase: 250% of baseline). On the other hand, local perfusion of SCH-23390 (10-200 microM) dose dependently increased the extracellular levels of dopamine 180-640% of baseline. Overall, the results of this study suggest that (a) tonic activation of D(2) postsynaptic receptors in VP imposes a limit on ethanol intake in the P rat; (b) there are few D(2) autoreceptors functioning in the VP; (c) there is tonic D(1)-like receptor mediated inhibitory feedback regulation of VP-dopamine release.

Acetaldehyde (ACD), the first metabolite of ethanol, is a biologically active compound, which may mediate some of the reinforcing, behavioral and neurotoxic effects of ethanol. The objective of this study was to test the hypothesis that ACD is reinforcing within the mesolimbic system. The intracranial self-administration (ICSA) technique was employed to determine whether ACD was reinforcing in the posterior ventral tegmental area (VTA), a site that supports the reinforcing actions of ethanol. Adult female alcohol-preferring (P) rats were implanted with guide cannulae aimed at the posterior VTA. Subjects were placed in two-lever operant chambers 7-10 days after surgery. Responding on the "active lever" on a fixed ratio 1 (FR1) schedule of reinforcement caused the delivery of 100 nl of infusate, whereas responses on the "inactive lever" were without consequences. Rats were assigned to one of five groups that self-administered either artificial cerebrospinal fluid (aCSF) throughout all eight sessions (4 h in duration) or 3- and 6-, 11- and 23-, 45- and 90- or 180- and 360-microM ACD for the eight sessions, with the lower concentration of ACD given for the initial four sessions and the higher concentration of ACD given for the last four sessions. A second experiment examined the acquisition (first four sessions), extinction (aCSF in sessions 5 and 6) and reinstatement using 90-microM ACD. A third experiment examined the effects of extending the time-out period (from 5 to 55 s) on the number and pattern of infusions of 23-microM ACD. Adult P rats readily self-administered 6-90-microM ACD and discriminated between the active and inactive levers. Furthermore, rats self-administering 90-microM ACD also demonstrated extinction behavior when aCSF was substituted for ACD and gradually reinstated active lever responding when ACD was reintroduced. P rats maintained similar numbers of infusions and infusion patterns under both time-out schedules. Overall, the data indicate that ACD is a potent reinforcer within the posterior VTA of the P rat.