Faculty Bibliography

Chronic food restriction and weight loss were previously shown to produce a naltrexone-reversible facilitation of perifornical lateral hypothalamic self-stimulation. In the present study, high affinity receptor-selective antagonists were used to determine the particular opioid receptor type(s) that mediates the facilitation of reward by food restriction. Separate groups of food-restricted and ad libitum fed rats were used to conduct i.c.v. dose-response studies with TCTAP (mu), norbinaltorphimine (kappa), and naltrindole (delta). The highest dose of naltrindole (50.0 nmol) raised self-stimulation threshold independently of feeding condition. This suggests that delta opioid activity is involved in self-stimulation under basal conditions and may explain previous findings that high systemic doses of naloxone or naltrexone reduce self-stimulation. The highest doses of TCTAP and norbinaltorphimine (5.0 and 50.0 nmol, respectively) reversed the lowering of self-stimulation threshold produced by food restriction while having no effect on thresholds of ad libitum fed rats. These results suggest that state-dependent mu and kappa opioid activity facilitate reward. Since food restriction is known to increase the rewarding effect of food and drugs of abuse, the opioid mechanism identified in the present study may mediate adaptive behavior and, under some circumstances, pathological behavior. The possible relation of state-dependent opioid activity to Anorexia Nervosa, binge eating, and the high comorbidity of eating disorders and substance abuse is discussed

Feeding induced by lateral hypothalamic electrical stimulation is sensitive to opioid antagonism and has previously been blocked by naloxone and antibodies to dynorphin A fragments. In the present study, high affinity receptor-selective antagonists were used to determine the particular opioid receptor type(s) that mediates stimulation-induced feeding (SIF). Separate groups of rats were used to conduct i.c.v. dose-response studies with TCTAP (mu), naltrindole (delta) and norbinaltorphimine (kappa). TCTAP, at the highest dose tested (i.e. 5.0 nmol) and norbinaltorphimine, at doses of 10.0 and 50.0 nmol, increased the brain stimulation frequency threshold for eliciting SIF. Naltrindole, at doses up to 50.0 nmol, had no effect. Results of another study, recently conducted in this laboratory, indicate that the present doses of TCTAP and norbinaltorphimine have no effect on thresholds for lateral hypothalamic self-stimulation. This suggests that mu and kappa opioid activity are associated with feeding, rather than the eliciting brain stimulation, and excludes non-specific performance deficits as an explanation of elevated SIF thresholds. In the SIF test, where 5 determinations of threshold are obtained in serial order, naloxone characteristically increases thresholds toward the end of a test while conventional appetite suppressants increase thresholds uniformly throughout a test. TCTAP and norbinaltorphimine produced a 'naloxone-like' pattern of threshold elevation, suggesting that mu and kappa receptors are involved in the process whereby endogenous opioid activity sustains feeding once initiated

A previous in vivo autoradiographic study demonstrated reduced 3H-diprenorphine binding in anterior cingulate cortex of rats that were injected (i.v.) with the radiolabeled opiate during lateral hypothalamic stimulation-induced feeding (SIF). This suggests that an opioid peptide is released in cingulate cortex during feeding and excludes binding of the tracer. The aim of the present study was to determine whether opioid activity in cingulate cortex contributes to the expression of SIF. Agonists and antagonists for multiple opioid receptors were microinjected into cingulate cortex and effects on stimulation frequency threshold for SIF were determined. Although the universal opioid antagonist naloxone (20.0 micrograms) increased threshold, high doses of selective antagonists for mu, delta, and kappa receptors--D-Tic-CTAP, natrindole and norbinaltorphimine, respectively--had no effect. The unique efficacy of naloxone may be due to this lipophilic compound's rapid diffusion throughout an extensive volume of anterior cingulate tissue. While high doses of the kappa agonist U50,488 and the delta agonist DPDPE had no effect, the mu agonist, DAGO (1.0 microgram), decreased the SIF threshold. Moreover, the threshold-lowering effect of DAGO was blocked by pretreatment with the irreversible mu antagonist beta-FNA. These results suggest that mu opioid activity in cingulate cortex can facilitate SIF but that under basal conditions endogenous opioid activity in this brain region makes only a small positive contribution, if any, to the expression of SIF

Many peptide hormone and neuropeptide precursors undergo post-translational processing at mono- and/or dibasic residues. An enzymatic activity capable of processing prodynorphin at a monobasic processing site designated 'dynorphin converting enzyme' has been previously reported in rat rain and bovine pituitary. In this study the distribution of dynorphin converting enzyme activity in ten regions of rat brain has been compared with the distribution of subtilisin-like processing enzymes and with the immuno-reactive dynorphin peptides. The distribution of dynorphin converting enzyme activity generally matches the distribution of immuno-reactive dynorphin B-13 in most but not all brain regions. The regions that are known to have a relatively large number of immuno-reactive dynorphin-neurons also contain high levels of dynorphin converting enzyme activity. The distribution of dynorphin converting enzyme activity does not match the distribution of subtilisin-like processing enzyme or carboxypeptidase E activities. Taken together the data support the possibility that the dynorphin converting enzyme is involved in the maturation of dynorphin, as well as other neuropeptides, and peptide hormones

The purpose of this study was to evaluate the hypothesis that neuroleptic non-response in the face of 'adequate' DA post-synaptic receptor blockade reflects failure of regulatory mechanisms to decrease DA pre-synaptic activity. Eight chronic schizophrenics, meeting rigorous criteria for neuroleptic non-response, were treated for four weeks with alpha-methylparatyrosine as an adjunct to their previously stable neuroleptic dose. Treatment with AMPT produced a prompt decrease in plasma HVA that was, on average, 72% lower at the end of the study. While there was also strong clinical evidence of reduction in central dopaminergic activity (both a significant reduction in dyskinetic movements and increase in extrapyramidal symptoms), there was virtually no change in severity of psychotic symptoms. Thus, in this group of non-responders, psychotic symptoms persisted despite both extensive dopamine post-synaptic receptor blockade and marked reduction of presynaptic activity. These symptoms may not be directly DA dependent

We measured serum phospholipase A2 (PLA2) activity in 39 schizophrenics, 26 psychiatric controls, and 26 normal controls using a radioenzymatic assay with phosphatidylcholine as precursor. Serum PLA2 activity was significantly higher in schizophrenics (p = 0.002) and other psychiatric (including substance abusing) patients (p = 0.032) than in normal controls. Enzyme activity did not differ between the schizophrenic patients and psychiatric controls. Fifty-one percent of the schizophrenics and 46% of psychiatric controls had PLA2 values above the highest value for normal controls. In the psychiatric control group higher than normal PLA2 activities were observed in all diagnostic categories, including major depression, bipolar disorder, posttraumatic stress disorder (PTSD), and substance abuse. In the context of others' findings of increased circulating PLA2 in infectious and inflammatory conditions, these increases must be viewed as disease nonspecific. The significance of these changes and their relationship to other acute-phase protein changes needs to be clarified in future research