Testosterone reinforcement: intravenous and intracerebroventricular self-administration in male rats and hamsters.

RATIONALE: Anabolic steroids are drugs of abuse. However, the potential for addiction remains unclear. Testosterone induces conditioned place preference in rats and oral self-administration in hamsters. OBJECTIVES: To determine if male rats and hamsters consume testosterone by intravenous (IV) or intracerebroventricular (ICV) self-administration. METHODS: With each nose-poke in the active hole during daily 4-h tests in an operant conditioning chamber, gonad-intact adult rats and hamsters received 50 microg testosterone in an aqueous solution of beta-cyclodextrin via jugular cannula. The inactive nose-poke hole served as a control. Additional hamsters received vehicle infusions. RESULTS: Rats ( n=7) expressed a significant preference for the active nose-poke hole (10.0+/-2.8 responses/4 h) over the inactive hole (4.7+/-1.2 responses/4 h). Similarly, during 16 days of testosterone self-administration IV, hamsters ( n=9) averaged 11.7+/-2.9 responses/4 h and 6.3+/-1.1 responses/4 h in the active and inactive nose-poke holes, respectively. By contrast, vehicle controls ( n=8) failed to develop a preference for the active nose-poke hole (6.5+/-0.5 and 6.4+/-0.3 responses/4 h). Hamsters ( n=8) also self-administered 1 microg testosterone ICV (active hole:39.8+/-6.0 nose-pokes/4 h; inactive hole: 22.6+/-7.1 nose-pokes/4 h). When testosterone was replaced with vehicle, nose-poking in the active hole declined from 31.1+/-7.6 to 11.9+/-3.2 responses/4 h within 6 days. Likewise, reversing active and inactive holes increased nose-poking in the previously inactive hole from 9.1+/-1.9 to 25.6+/-5.4 responses/4 h. However, reducing the testosterone dose from 1 microg to 0.2 microg per 1 microl injection did not change nose-poking. CONCLUSIONS: Compared with other drugs of abuse, testosterone reinforcement is modest. Nonetheless, these data support the hypothesis that testosterone is reinforcing.

Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.

Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.

NAALADase (GCP II) inhibition prevents cocaine-kindled seizures.

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutamate, would produce antiepileptogenic effects against cocaine was tested. Cocaine kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling.

Endogenous opioids in dopaminergic cell body regions modulate amphetamine-induced increases in extracellular dopamine levels in the terminal regions.

Opioid antagonists attenuate behavioral effects of amphetamine and amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and striatum of rats but do not alter those effects of cocaine. This study was performed to determine 1) if the effect of opioid antagonists on the dopamine response to amphetamine is mediated in either the terminal or cell body region of the nigrostriatal and mesolimbic pathways, and 2) if the enkephalinase inhibitor thiorphan, which slows degradation of endogenous opioid peptides, increases the dopamine response to amphetamine but not to cocaine. Microdialysis probes were placed either into a dopaminergic terminal region or into both a terminal and cell body region of rats. Naloxone methiodide (1.0 microM), a lipophobic opioid antagonist, was administered into either the terminal or cell body region by reverse dialysis, whereas extracellular dopamine was collected in the terminal region. Increases in extracellular dopamine in nucleus accumbens and striatum caused by amphetamine (0.1-6.4 mg/kg, s.c.) were reduced significantly (28-39%) by naloxone methiodide administered into either substantia nigra or ventral tegmentum but not into terminal regions. Thiorphan (10 microM) administered into substantia nigra increased significantly the dopamine response to amphetamine in the ipsilateral striatum by as much as 42% but did not affect the dopamine response to cocaine (3.0-56 mg/kg, i.p.). These results suggest that amphetamine promotes release of endogenous opioids, which, through actions in the ventral tegmentum and substantia nigra, contribute to amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and striatum.