Faculty Bibliography

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The hypothalamic-pituitary-adrenal (HPA) axis is regulated by stress-related excitatory inputs, and various inhibitory and negative-feedback controls by glucocorticoids and opioids, including pro-opiomelanocortin (POMC)-derived peptides. The role of POMC-derived peptides of pituitary origin in the modulation of brain POMC mRNA expression and opioid receptor binding was investigated using a line of transgenic mice that express a fusion gene composed of the pituitary expression-specific promoter region of the POMC gene driving the herpes simplex viral-1 thymidine kinase (TK). Male adult mice were treated with the antiherpes agent ganciclovir that selectively ablates cells expressing TK. Following treatment, POMC mRNA levels, measured by quantitative solution hybridization/RNase protection assays, were decreased by 48% in the pituitary of the TK+/+ mice, reflecting an expected loss of the pituitary corticotrope POMC cells. This treatment also significantly lowered pituitary beta-endorphin immunoreactivity content and plasma concentrations of corticosterone. In contrast, POMC mRNA levels were increased by 79% in the hypothalamus of the TK+/+ mice with pituitary POMC cell ablation. Binding of [(3)H]DAMGO to mu opioid receptors, as measured by quantitative autoradiography, was significantly reduced in several brain regions including the central grey, median raphe and superficial grey layer of the superior colliculus. These regions are innervated by hypothalamic POMC neurones. No significant differences in binding to either kappa or delta opioid receptors were found in the brain regions studied. These results suggest that POMC-derived peptides of pituitary origin may exert a tonic negative-feedback effect on hypothalamic POMC neurones. In turn, the downregulation of central mu opioid receptors in this model may be mediated through a mechanism related to hypothalamic POMC overexpression

The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using a selective 5-HT1A receptor agonist, [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), and a 5-HT2A receptor antagonist, [3H]ketanserin, as tritiated ligands in a quantitative autoradiography study. Rats were administered cocaine in a 'binge' pattern, 15 mg/kg/injection, three times a day, at 1-h intervals for 14 days to mimic the pattern often seen in human cocaine addicts. A significant decrease in the binding of [3H]8-OH-DPAT was found in the ventromedial hypothalamus (P < 0.001) and the dorsal dentate gyrus (P < 0.01) in rats administered cocaine as compared with rats injected with saline. No significant difference in the binding of [3H]ketanserin was found in frontal, parietal, agranular insular, and piriform cortices, caudate-putamen, olfactory tubercle, nucleus accumbens, thalamus, septohippocampal nucleus, and claustrum. Several studies have shown that 5-HT1A receptor agonists have antidepressant properties. Other studies, in animal models, have shown that 5-HT1A receptor agonists stimulate the hypothalamic-pituitary-adrenal axis, which is of interest, since chronic activation of this axis has been related to anxiety and depression. Our data show that the 5-HT1A component of the serotonergic system is altered following chronic 'binge' pattern cocaine administration in an animal model and may be related to changes in the HPA axis and behavior

In our previous positron emission tomography studies striatal binding for both [11C]SCH23390 and [11C]N-methylspiperone (NMSP) were decreased in the rat brain on the last day of chronic (14 days) binge cocaine administration. We have found that [11C]SCH23390 binding to dopamine D1 receptors returns to saline control levels within ten days withdrawal from chronic binge cocaine and remains at control levels after 21 days withdrawal. An 18% decrease in [11C]NMSP binding to dopamine D2 receptors was observed after ten days withdrawal. However, importantly, after 21 days withdrawal [11C]NMSP binding was at saline control levels. Changes of in vivo [11C]NMSP binding required a longer abstinence period for normalization than [11C]SCH23390 binding. The apparent recovery of dopamine D2 receptors after prolonged abstinence from chronic cocaine and the different rates of normalization for dopamine D1 versus D2 receptors may be critical information for development of pharmacotherapies for cocaine dependent patients

The aim of the present study was to determine the effect of 'binge' pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain. Male Sprague Dawley rats were injected three times at 1 hr intervals with saline or cocaine (15 mg/kg) each day for 2, 7, or 14 d. The in vivo binding of [11C]SCH23390 (dopamine D1 receptor antagonist) and [11C]N-methylspiperone (NMSP; dopamine D2 receptor antagonist) in the striatal region was measured by a high-resolution positron emission tomography at 1 and 3.5 hr, respectively, after the last cocaine or saline injection. Acute (2 d) binge cocaine administration did not change the in vivo binding potential of [11C]SCH23390 or the binding of [11C]NMSP in the striatum. After 7 d of binge cocaine administration, a significant decrease in the binding potential of [11C]SCH23390 was observed, whereas no change in the binding of [11C]NMSP was found. After 14 d of binge cocaine administration, the in vivo binding was significantly reduced for both [11C]SCH23390 and [11C]NMSP. Separate saturation experiments indicated that the observed alterations of in vivo binding were attributable mainly to apparent alterations in the affinity and not the number of binding sites. These results suggest that both dopamine D1 and D2 receptors may have altered physiologically available binding sites after binge pattern cocaine administration