We used the autoradiographic 2-deoxy-D-[1-14C]glucose (14C-DG) method of Sokoloff to identify brain areas with altered rates of local cerebral glucose utilization (LCGU) in vivo in response to peripheral I-nicotine administration (0.1, 0.3, 1.0, and 1.75 mg/kg, s.c.). Nicotine stimulated LCGU primarily in areas reported to contain nicotine binding sites, indicating that the sites are true receptors. Increases in LCGU of 100% or more over control were obtained in the medial habenula, fasciculus retroflexus, superior colliculus, and median eminence. Substantial stimulation (50-100% increases) also was obtained in the cerebellar vermis, interpeduncular nucleus, and anteroventral and interanteromedial thalamic nuclei. Moderate increases (20-50%) were observed in the reticular nucleus of the medulla, paramedian lobule, nucleus of the spinal tract of the trigeminal nerve, presubiculum, subiculum, red nucleus, ventral tegmental area, substantia nigra, nucleus ambiguus, nucleus tractus solitarius, dorsal lateral geniculate nucleus, mammillothalamic tract, and fornix. The greatest stimulation in most affected areas was obtained with 0.3 mg/kg nicotine administered at 2 min, but not longer, before 14C-DG. Effects of nicotine on LCGU were antagonized by mecamylamine. The findings indicate that the interaction of nicotine with specific binding sites is coupled to cerebral energy metabolism. The distribution of in vivo cerebral metabolic effects of nicotine implicates various brain regions in the behavioral and physiological effects of nicotine.

The hypothermic effect of capsaicin, the reduced responsiveness towards the hypothermic effect of the drug as well as the impairment of thermoregulation in the warm environment subsequent to the administration of different doses of capsaicin have been studies in rats. The mortality after capsaicin treatment has also been established. 1. Capsaicin given subcutaneously in doses of 1-10 mg/kg induced a dose-dependent fall in body temperature lasting for 2-5 h. A single dose of 10 mg/kg caused the most pronounced hypothermic effect reaching its maximum (3,4 degrees C) after 107 min. After higher doses (20-50 mg/kg) the fall in body temperature was less, being similar to that observed after the administration of 1-2 mg/kg. 2. A decreased sensitivity towards the hypothermic effect of a test dose of 2 mg/kg capsaicin, as well as an impaired tolerance to high ambient temperature have been found in rats 2 weeks after the pretreatment either with a single dose of 20-50 mg/kg or fractionated administration of 50 mg/kg capsaicin. The fractionated administration of a dose of 50 mg/kg capsaicin proved to be beneficial in decreasing mortality without affecting the desensitizing effect of capsaicin pretreatment. 3. After single doses of capsaicin the hypothermic period was followed by a dose-dependent hyperthermia which lasted for at least 2 days. A close correlation between the prolonged hyperthermic action and the desensitizing effect of capsaicin administration has also been established. The possible relationship between the desensitizing and hyperthermia inducing effect of capsaicin is briefly discussed.

Prolonged exposure to opioid agonists can induce adaptive changes resulting in tolerance and dependence. Here, rats were rendered tolerant by subcutaneous injections of increasing doses of morphine from 10 to 60 mg/kg for 3, 5, or 10 consecutive days. -ol]-enkephalin). Although the density of surface -sites did not change after the 5-day morphine treatment, up-regulation of synaptic plasma membrane binding was detected after the 10-day drug administration. In contrast, the number of -binding sites in a light vesicle or microsomal fraction (MI) was elevated by 68 and 30% after 5 and 10 days of morphine exposure, respectively. The up-regulated MI -sites displayed enhanced coupling to G proteins compared with those detected in saline-treated controls. Pertussis toxin catalyzed ADP ribosylation, and Western blotting with specific antisera was used to quantitate chronic morphine-induced changes in levels of various G protein ␣-subunits. Morphine treatment of 5 days and longer induced significant increases in levels of G␣ o , G␣ i1 , and G␣ i2 in MI fractions that are part of an adaptation process. Up-regulation of intracellular -sites may be the result of post-translational changes and in part de novo synthesis. The results provide the first evidence that distinct regulation of intracellular -opioid receptor G protein coupling and G protein levels may accompany the development of morphine tolerance.

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