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Binge eating (BE) and drug seeking share similar behavioral features, including loss of control over consumption and compulsive seeking of the craved substance. Previous studies in animal models have demonstrated a complex interaction between 'state' BE, produced by intermittent access to a palatable diet, and 'trait' BE, a phenotypical proneness towards overeating. In the present study, we examined the relationship between state and trait BE and cocaine seeking. We used Otsuka Long Evans Tokushima Fatty rats, a genetic model for obesity that demonstrates BE-like behavior, and Long Evans Tokushima Otsuka controls. They received a schedule of limited access to a palatable diet (3 days/week or 5 days/week access to Ensure for a month). Next, they underwent cocaine self-administration training (1 mg/kg, 1 hour/day for 10 days) followed by extinction sessions (7 days). We found that the degree of BE-like behavior and the state and trait BE combination predicted cocaine craving patterns. Lower levels of dopamine D2 receptors in the prefrontal cortex were correlated with increased drug craving. Moreover, restricted access to an attractive diet was found to be a risk factor for heightened cocaine craving, particularly in trait binge eaters, as rats on the 3 days/week access schedule persistently failed to cease cocaine seeking throughout extinction. Hence, we postulate a joint role of state and trait BE as risk factors for heightened cocaine craving.

A major problem in the treatment of addiction is predicting and preventing relapse following a rehabilitation program. Recently, in preclinical rodent studies dehydroepiandrosterone (DHEA) was found to markedly improve the resistance to drug reuse. In a double-blind, placebo-controlled study, we examined the effect of DHEA on relapse rates in adult polydrug users taking part in a detoxification program enriched with intensive psychosocial interventions and aftercare. During treatment, participants (79 percent males, mean age 28) consumed DHEA (100 mg/day) or placebo daily for at least 30 days. Of the 121 initial volunteers, 64 participated for at least 1 month. While in treatment, DHEA reduced negative affect on the Positive and Negative Affect Scale (F = 4.25, P = 0.04). Furthermore, in a 16-month follow-up, we found that reuse rates in the DHEA condition were about a third compared with placebo (12 versus 38 percent; χ(2) = 5.03, P = 0.02). DHEA treatment also resulted in an increase in DHEA sulfate (DHEA-S) 1 month following treatment, and the level of DHEA-S predicted relapse in the follow-up assessment.

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.

b-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of b-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular b-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on b-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 lM) and was blocked by coadministration of SCH-23390 (10 lM). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular b-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in b-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the b-endorphin neurons within the arcuate nucleus‐nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.

In the CNS, nitric oxide (NO) functions as both neuromodulator and neurotoxic agent. In vivo neuronal expression of NO synthase (NOS) has been attributed to constitutive NOS--both the neuronal and the endothelial types. The other class of NOS--the inducible NOS (iNOS)--is known to mediate toxic effects of NO in various tissues. In this study, we show for the first time that direct intracerebellar injection of endotoxin and cytokine (lipopolysaccharide and interferon-gamma) induced in vivo neuronal expression of the iNOS gene, as demonstrated by fluorescent in situ hybridization and immunohistochemical staining analyzed by confocal laser-scanning microscopy. This raises the possibility that neuronal iNOS might contribute significantly to the vulnerability of the brain to various insults.

Depression is associated with significant morbidity, mortality, and expense (both personal and economic). Premature discontinuation of antidepressant medication involves a high risk of relapse, i.e., 30–50% of patients will relapse during the following 4 months. Fast onset and prevention of relapse to drug use by depressive patients are the major goals of the present research. Flinders Sensitive Line (FSL) rats are a novel experimental model for depression. FSL rats exhibit behavioral features characteristic of depression, such as cognitive (learning) difficulties, sleep disturbances, reduced activity, and reduced body weight. Long-term, but not acute, treatment of the FSL rats with antidepressant drugs diminishes, and in some cases abrogates, their behavioral manifestations of depression. We found that the total norepinephrine, dopamine, and serotonin content of the mesolimbic areas of the FSL rats was three- to fivefold higher than those in normal rat counterparts. We also found that long-term treatment of the FSL rats with antidepressant drugs resulted in a return to normal of these norepinephrine, dopamine, and serotonin levels, but did not affect the levels in normal, healthy rats. These rats, therefore, fulfill the diagnostic symptoms of major depression in humans, and show a high face-, construct- and predictive- validity. Recently, we found that FSL rats, treated with clinically used antidepressants (desipramine, fluoxetine, paroxetine, and nefazodone), can be followed for behavior improvements up to 6 months after treatment, albeit with different results related to certain drugs. The onset of action of these drugs also differed between treatments. The results obtained elucidate the potential screen for new antidepressants to provide an earlier onset and long-lasting action than conventional antidepressant treatments. The results also facilitate identification of the pharmacodynamic processes and neuronal circuits involved in response to drugs that effectively treat depressive disorders, both of which are critical to the development of improved psychiatric treatments and prevention strategies. Drug Dev. Res. 50:392–399, 2000. © 2000 Wiley-Liss, Inc.

1. Strychnine, which is known as a potent and selective antagonist of the inhibitory glycine receptor in the central nervous system, inhibits the nicotinic stimulation of catecholamine release from bovine cultured adrenal chromaffin cells in a concentration-dependent (1-100 microM) manner. At 10 microM nicotine, the IC50 value for strychnine is approximately 30 microM. Strychnine also inhibits the nicotine-induced membrane depolarization and increase in intracellular Ca2+ concentration. 2. The inhibitory action of strychnine is reversible and is selective for nicotinic stimulation, with no effect observed on secretion elicited by a high external K+ concentration, histamine or angiotensin II. 3. Strychnine competes with nicotine in its effect, but not modify the apparent positive cooperatively of the nicotine binding sites. In the absence of nicotine, strychnine has no effect on catecholamine release. Glycine does not affect catecholamine release nor the inhibitory action of strychnine on this release. 4. These results suggest that strychnine interacts with the agonist binding site of the nicotinic acetylcholine receptor in chromaffin cells, thus exerting a pharmacological effect independently of the glycine receptor.

1. Glycine is an inhibitory neurotransmitter in the spinal cord and brainstem. The mechanism of this inhibition is via binding of glycine to specific receptors, increasing transmembrane Cl- conductance and hyperpolarizing neurones. Strychnine selectively antagonizes these effects. The role of glycinergic neurones in supraspinal regions is poorly understood. 2. Effects of glycine on release of catecholamines in the striatum were examined by microdialysis in freely-moving rats. Transcription of the genes encoding strychnine-sensitive glycine receptors was assessed in the striatum and substantia nigra, by use of reverse transcription followed by the polymerase chain reaction. 3. Glycine administered via the microdialysis probe dose-dependently increased concentrations of dopamine and its metabolites, dihydroxyphenylacetic acid and homovanillic acid, in the perfusate, indicating increased local release and metabolism of dopamine. Strychnine markedly attenuated these responses. Whereas striatal tissue did not contain mRNA for either the adult or neonatal form of strychnine-sensitive glycine receptor, nigral tissue contained a message for the adult form. 4. The results suggest that dopaminergic cells in the substantia nigra synthesize strychnine-sensitive glycine receptors and transport the receptors to terminals in the striatum. Occupation of the glycine receptors then exerts a net stimulatory effect on striatal dopamine release in vivo.