Faculty Bibliography

Injection of the dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (NPA; 5-40 micrograms) into anterior ventral striatal sites (either lateral (VL) or medial (VM) elicited dose-dependent oral and sniffing stereotypies of rapid onset, long duration and high intensity. In contrast, injection into anterior dorsolateral (DL) or posterior ventral (lateral (PL) or medial (PM] sites produced little oral and moderate sniffing behavior of slower onset, shorter duration and low intensity. Injection into the dorsomedial (DM) striatum produced intermediate effects. Intra-accumbens NPA elicited weak oral activity and moderate sniffing which was similar in onset, duration and intensity to the least sensitive striatal sites (DL, PM and PL). In other experiments, DA receptors were inactivated with the irreversible blocking agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 6 mg/kg) and behavioral recovery was monitored by challenge with 20 micrograms NPA into the VL or the nucleus accumbens (NA) at various times after EEDQ. Sniffing behavior recovered rapidly (normal by day 4 in both regions), whereas oral activity required 8 (NA) and 12 days (VL) to return to control levels. The results are discussed in terms of a possible topographic distribution of behavior in the striatum. Alternatively, heterogeneity of DA receptor density may account for these findings

The present study was undertaken to evaluate the potential usefulness of 11C-buprenorphine (bup) as a ligand for investigating opioid receptors in living primates, including humans, using positron-emission transaxial tomography (PETT). Because PETT studies of receptor function are best carried out under conditions of low receptor occupancy, the pharmacokinetics, uptake into brain, and specific binding to opioid receptors within brain of 3H-bup were examined in rats under conditions in which occupancy of opioid receptors by 3H-bup never exceeded 2% of sites in the brain at any time point examined. Male Sprague Dawley rats (weight range 140-220 grams) were injected s.c. with either naloxone (10 mg/kg) or saline. Five min later, a saline solution containing [15, 16-3H] bup (39 Ci/mmole) was injected into tail veins at a dose of 0.4 microgram/kg body weight. At least 90-95% of radioactivity was cleared from the blood in the first 5 min. In saline pretreated rats, total brain uptake 15 min after injection of 3H-bup was about 0.4% of the administered dose. Ligand specifically bound to receptors may be estimated by comparing the amount of radioactivity in the brain following injection of labeled ligand alone to that obtained when a high concentration of an unlabeled competitor is pre- or co-administered. In the present study, average levels obtained in brain (excluding cerebellum) were higher in saline pretreated rats than in naloxone pretreated rats at all time points and the difference increased with time indicating specific binding to opioid receptors. Specific binding may also be estimated by comparing radioactivity accumulated in brain areas rich in opioid receptors with 'background' levels achieved in areas known to be low in opioid receptors, e.g., the cerebellum in rats. In the present study, ratios of the amount of radioactivity in brain (excluding cerebellum) to the amount in the cerebellum increased with time (to about 4 after 60 min) in saline pretreated rats, but remained close to 1 in naloxone pretreated rats. The effects of biological variation were less when specific binding was estimated by the latter method since each animal served as its own control. Tissue distribution of radioactivity to other tissues (blood, skin, muscle, fat, liver, kidney) was similar in naloxone and saline pretreated rats. The results presented here suggest that 11C-bup or an 18F-labeled fluorinated derivative would be a useful ligand for PETT studies

Lateral ventricular injections of the 'nonspecific' opioid antagonist naloxone (100 micrograms) and the kappa-selective opioid antagonist nor-binaltorphimine (50 micrograms) elevated the electrical brain stimulation frequency threshold for eliciting feeding behavior. Mesopontine aqueductal injections of nor-binaltorphimine, on the other hand, lowered the feeding threshold while naloxone still elevated threshold. These findings suggest the existence of forebrain kappa receptors at which endogenous opioid activity results in a facilitation of feeding while kappa receptors in the brainstem seem to mediate an inhibitory effect

Selective agonists for mu- and kappa-opioid receptor types were infused, bilaterally, into the intralaminar central lateral nucleus of the rat. Subcataleptic doses of the mu-agonist, DAGO (0.25 and 1.0 microgram), elevated tailshock threshold for eliciting pain vocalization and motor responses. The hyperalgesic effect of U50,488 is not likely to be the result of antagonist action at a mu 2-isoreceptor; the general mu-antagonist, naloxone, and its less lipophilic quaternary analogue, both failed to produce a significant reduction in pain thresholds. Paralleling their effects on pain, DAGO and U50,488 elevated and reduced, respectively, lateral hypothalamic electrical stimulation threshold for positive reinforcement. These results suggest that medial thalamic opioid mechanisms are not exclusively involved in pain modulation but may generally regulate the responsiveness of the organism to motivating stimuli. Moreover, mu- and kappa-receptors may mediate opposite behavioral effects of opioid peptides

Highly specific antibodies to dynorphin A(1-13), infused into the lateral ventricle, elevated brain stimulation threshold for eliciting feeding behavior. Antibodies to beta-endorphin had little or no effect. Temporal analysis of the anorectic action indicated a striking similarity to the effect of systemically administered naloxone. These findings suggest that central dynorphin is involved in the control of ingestive behavior and that the anorectic action of naloxone may result from antagonism of dynorphinergic transmission

The cyclic AMP response to catecholamines in the rat cerebral cortex is mediated by both beta- and alpha-adrenoceptors. The beta-receptors cause a direct activation of adenylate cyclase whereas the alpha alpha-receptors play a modulatory role and act by potentiating the response to beta stimulation. The present study investigated whether the functions of these two types of cyclic AMP-linked receptors are regulated differently by various physiological factors known to affect adrenoceptor function. It was found that treatments that affect central noradrenergic neuronal function including repeated administration of desmethylimipramine or lesion of central noradrenergic pathways produced selective changes in the cAMP response to beta-receptor stimulation whereas treatments that affect adrenocortical function including ACTH of corticosterone administration and hypophysectomy or adrenalectomy produced selective changes in the potentiation response to alpha-receptor stimulation. The change in the alpha potentiation effect caused by corticosterone was found to be abolished in the presence of prazosin indicating that the hormone affects alpha 1-adrenoceptor function. The results support the hypothesis that the beta response in the cortex is under the control of the noradrenergic system while the alpha potentiation response is under the control of the adrenocortical system