Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADASE).

In this study we examined the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and GPI 5693, selective inhibitors of the enzyme N-Acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21), which cleaves glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG), on the conditioned place preference (CPP) response to cocaine in male rats. The i.p. administration of 15 mg/kg of cocaine produced a significant CPP response. The acquisition and expression of the CPP response to cocaine was blocked by the i.p. administration of 100 mg/kg of 2-PMPA and the p.o. administration of 30 mg/kg of GPI 5693. In contrast, neither 2-PMPA nor GPI 5693 produced a CPP or conditioned place aversion response when administered alone. Furthermore, neither 2-PMPA or GPI 5693 altered the expression of the CPP response to food. These results indicate that NAALADase inhibitors block the incentive motivational value of cocaine, suggesting that such agents may be of use in treating cue-induced craving in cocaine addicts.

Extinction training regulates tyrosine hydroxylase during withdrawal from cocaine self-administration.

Chronic exposure to drugs of abuse is known to modulate tyrosine hydroxylase (TH) levels in the mesolimbic dopamine system. In this study, 12 d of cocaine self-administration in rats (4 hr/d) reduced TH immunoreactivity by 29% in the nucleus accumbens (NAc) shell, but not core, after a 1 week withdrawal period. In contrast, TH immunoreactivity in the NAc was completely restored in animals that experienced extinction training (4 hr/d) during the same withdrawal period. Extinction training also increased TH levels in the ventral tegmental area (VTA) by 45%, whereas TH was not altered in the VTA by cocaine withdrawal alone. Thus, extinction-induced normalization of NAc TH levels could involve increased TH synthesis, stability, and/or transport from the VTA to the NAc. A similar extinction training regimen failed to alter TH levels in the NAc or VTA of rats trained to self-administer sucrose pellets, indicating that TH regulation in cocaine-trained animals is not a generalized effect of extinction learning per se. Rather, these data suggest that neuroadaptative responses during cocaine withdrawal ultimately are determined by a complex interaction between chronic drug exposure and drug-seeking experience. The ability of extinction training to restore NAc TH levels is hypothesized to accelerate recovery from dopamine depletion and anhedonia during cocaine withdrawal.

Opiates inhibit neurogenesis in the adult rat hippocampus.

Recent work implicates regulation of neurogenesis as a form of plasticity in the adult rat hippocampus. Given the known effects of opiates such as morphine and heroin on hippocampal function, we examined opiate regulation of neurogenesis in this brain region. Chronic administration of morphine decreased neurogenesis by 42% in the adult rat hippocampal granule cell layer. A similar effect was seen in rats after chronic self-administration of heroin. Opiate regulation of neurogenesis was not mediated by changes in circulating levels of glucocorticoids, because similar effects were seen in rats that received adrenalectomy and corticosterone replacement. These findings suggest that opiate regulation of neurogenesis in the adult rat hippocampus may be one mechanism by which drug exposure influences hippocampal function.

Naloxone does not alter amphetamine-induced rotational behavior or striatal dopamine levels of nigrally-lesioned rats.

Previous studies on rats have shown that the opioid antagonist naloxone attenuates amphetamine-induced stimulation of locomotor activity and increases in extracellular dopamine in the brain. However, in this study, naloxone did not attenuate amphetamine-induced rotational behavior or increases of extracellular dopamine in the intact striatum of nigrally-lesioned rats. These results suggests differences in the way in which endogenous opioids contribute to the behavioral and neurochemical effects of amphetamine in nigrally-lesioned compared to intact rats.

Differential effects of delta- and mu-opioid receptor antagonists on the amphetamine-induced increase in extracellular dopamine in striatum and nucleus accumbens.

The specific opioid receptor antagonist naloxone attenuates the behavioral and neurochemical effects of amphetamine. Furthermore, the amphetamine-induced increase in locomotor activity is attenuated by intracisternally administered naltrindole, a selective delta-opioid receptor antagonist, but not by the irreversible mu-opioid receptor antagonist beta-funaltrexamine. Therefore, this research was designed to determine if naltrindole would attenuate the neurochemical response to amphetamine as it did the behavioral response. In vivo microdialysis was used to monitor the change in extracellular concentrations of dopamine in awake rats. Naltrindole (3.0, 10, or 30 micrograms) or vehicle was given 15 min before and beta-funaltrexamine (10 micrograms) or vehicle 24 h before the start of cumulative dosing, intracisternally in a 10-microliters volume, while the rats were lightly anesthetized with methoxyflurane. Cumulative doses of subcutaneous d-amphetamine (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) followed pretreatment injections at 30-min intervals. Dialysate samples were collected every 10 min from either the striatum or nucleus accumbens and analyzed for dopamine content by HPLC. Amphetamine dose-dependently increased dopamine content in both the striatum and nucleus accumbens, as reported previously. Naltrindole (3.0, 10, and 30 micrograms) significantly reduced the dopamine response to amphetamine in the striatum. In contrast, 30 micrograms of naltrindole did not modify the dopamine response to amphetamine in the nucleus accumbens. On the other hand, beta-funaltrexamine (10 micrograms) had no effect in the striatum but significantly attenuated the amphetamine-induced increase in extracellular dopamine content in the nucleus accumbens. These data suggest that delta-opioid receptors play a relatively larger role than mu-opioid receptors in mediating the amphetamine-induced increase in extracellular dopamine content in the striatum, whereas mu-opioid receptors play a larger role in mediating these effects in the nucleus accumbens.

Naloxone reduces the neurochemical and behavioral effects of amphetamine but not those of cocaine.

The specific opioid receptor antagonist naloxone modifies the effects of amphetamine in a wide variety of behavioral paradigms. Naloxone also attenuates the amphetamine-induced increase in extracellular dopamine in the brain of rats. Therefore, these experiments were designed to replicate the neurochemical and behavioral interactions between naloxone and amphetamine, and to extend these observations to interactions between naloxone and cocaine. Microdialysis was performed on adult male rats of Sprague-Dawley descent. Rats were pretreated with a subcutaneous injection of 5.0 mg/kg naloxone or vehicle, which was followed 30 min later by cumulative doses of subcutaneous d-amphetamine (0.0, 0.1, 0.4, 1.6, 6.4 mg/kg) or intraperitoneal cocaine (0, 3, 10, 30, 56 mg/kg) at 30 min intervals. The microdialysis probes were perfused at a flow rate of 0.6 microliter/min with artificial cerebrospinal fluid. Dialysate samples were collected every 10 min from either the nucleus accumbens or striatum and analyzed for dopamine content by high-performance liquid chromatography (HPLC). Locomotor activity (photobeam breaks) was monitored simultaneously with the collection of dialysate samples. Amphetamine and cocaine dose-dependently increased extracellular dopamine in both the nucleus accumbens and striatum. Naloxone pretreatment significantly reduced the amphetamine-induced increase in extracellular dopamine in both brain regions and also attenuated the increase in locomotor activity elicited by amphetamine. Naloxone pretreatment had no effect, however, on the cocaine-induced increase in extracellular dopamine or locomotor activity. These findings suggest that endogenous opioid systems play a role in mediating the neurochemical and behavioral effects of amphetamine, but not those of cocaine.

Co-administration of the D2 antagonist pimozide inhibits up-regulation of dopamine release and uptake induced by repeated cocaine.

To investigate the hypothesis that the D2 dopamine (DA) receptor regulates DA uptake, as well as release, in the nucleus accumbens (N ACC), rats were pretreated for 10 days with either the selective D2 antagonist pimozide (1.0 mg/kg, i.p.) or vehicle, followed 3 h later by either cocaine (20 mg/kg, i.p.) or saline. On day 11, a microdialysis method was performed in which various DA concentrations (0, 10, and 20 nM DA) were perfused through the dialysis probe to characterize the diffusion of DA through tissue to and from the microdialysis probe (recovery). This diffusion of DA has been shown to be sensitive to changes in release and uptake. Pimozide pretreatment was shown to attenuate significantly a cocaine-induced increase in the in vivo recovery of DA (p < 0.01). The in vivo recovery for the vehicle/cocaine group was 47 +/- 4%, whereas the in vivo recovery for the pimozide/cocaine group was 31 +/- 3%. There was no difference between the pimozide/cocaine and control groups (pimozide/saline, 26 +/- 2%; vehicle/saline, 26 +/- 3%). In vitro probe calibrations indicated no significant difference in probe efficiencies between groups. These data suggest that the D2 receptor is capable of modulating uptake as well as release of DA in the N ACC of the rat.