Paul J. Manberg
University of North Carolina at Chapel Hill
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Brain Research | 1980
Charles B. Nemeroff; Garth Bissette; Paul J. Manberg; Albert J. Osbahr; George R. Breese; Arthur J. Prange
Neurotensin (NT), an endogenous tridecapeptide, produces significant hypothermia after intracisternal (i.c.) or intracerebroventricular (i.c.v.) administration in microgram quantities in a variety of laboratory animals. The present study sought to clarify the mechanism of the hypothermic action by utilizing pharmacological treatments which alter the function of brain neurotransmitter systems. Pretreatment of rats with anti-muscarinic (atropine), anti-noradrenergic (propranolol, a beta-blocker; phenoxybenzamine, an alpha-blocker) or anti-opiate (naloxone) agents did not significantly alter NT-induced hypothermia. Similarly depletion of brain serotonin (5-HT) with parachlorophenylalanine did not affect NT-induced hypothermia. However, depletion of brain catecholamine content with 6-hydroxydopamine resulted in a significant potentiation of NT-induced hypothermia as did pretreatment with haloperidol, a dopamine (DA) receptor antagonist. Furthermore, in rats with selective depletions of brain DA, but not norepinephrine (NE), NT-induced hypothermia was significantly augmented. Thus an interaction between brain DA systems and NT appears likely. These data indicate that NT-induced hypothermia is not dependent on intact functional activity of NE, 5-HT, muscarinic ACh or endogenous opiate systems but suggests interactions between brain DA circuits and NT. In other experiments, NT-induced hypothermia was found to be antagonized significantly by i.c. injection of thyrotropin-releasing hormone (TRH), but not by pretreatment with L-triiodothyronine. Another endogenous tripeptide (Pro--Leu--Gly--NH2, MIF-I) had no effect. Thyroidectomy (THX) significantly potentiated NT-induced hypothermia; NT administered i.c. significantly reduced the high serum TSH levels of THX rats. Thus, NT and TRH, two endogenous peptides, appear to be antagonists in certain systems.
Journal of Neurochemistry | 1982
Paul J. Manberg; William W. Youngblood; Charles B. Nemeroff; Leslie L. Iversen; Arthur J. Prange; John S. Kizer
Abstract: Neurotensin (NT) is an endogenous neuropeptide that is active in many preclinical screening tests for neuroleptic drugs. Using a radioimmunoassay, we have studied the regional distribution of NT in postmortem human brain and in cerebrospinal fluid. Highest levels were present in the hypothalamus, substantia nigra, and limbic areas, whereas much lower amounts were found in the cortex and striatum. The chromatographic properties of hypothalamic immunoreactivity on ion‐exchange and high pressure liquid chromatography were similar to those of the synthetic tridecapeptide. We conclude that NT is present in human brain with a distribution resembling that seen in other species, such as rat and monkey.
Life Sciences | 1978
Garth Bissette; Paul J. Manberg; Charles B. Nemeroff; Arthur J. Prange
Abstract Neurotensin, a tridecapeptide appears to be localized in various parts of the brain and gut. A high affinity binding component of neurotensin to brain membranes, synaptosomes and mast cells has been reported. After peripheral administration the peptide exerts a medley of effects which appear directed mainly to glucose metabolism. In addition, complex vascular effects have also been noted including hypotensin, cyanosis, vasodilation and increased permeability. The peptide may also be associated with inflammatory events. Complex effects upon the secretion of anterior pituitary tropic hormones have been observed. After central administration neurotensin exerts several effects all of which appear to be sufficiently explained by the potent hypothermic action. The resolution of the question of which, if any, of the actions of neurotensin are involved in physiological regulation has not been achieved.
European Journal of Pharmacology | 1979
Albert J. Osbahr; Charles B. Nemeroff; Paul J. Manberg; Arthur J. Prange
Intracisternal (IC) neurotensin (NT) produces muscle relaxation in the Julou-Courvoisier traction test, a screening procedure utilized for assessing neuroleptic drug activity. A dose-response relationship was not observed. IC administration of thyrotropin-releasing hormone (TRH) totally abolished the effects of NT. Two other peptides, substance P and bradykinin, were inactive in the traction test. These data provide further evidence for CNS effects on NT and indicate that this peptide exerts neuroleptic-like activity in a screening test for antipsychotic agents.
Annals of the New York Academy of Sciences | 1982
Paul J. Manberg; Charles B. Nemeroff; Leslie L. Iversen; M. N. Rosser; John S. Kizer; Arthur J. Prange
Numerous biochemical and behavioral effects occur following administration of neurotensin (NT). This suggests that NT may play a physiological role in the regulation of several homeostatic mechanisms, including endocrine function, thermoregulation, reaction to painful stimulation, carbohydrate metabolism, and other aspects of mental function. Interactions between NT and dopaminergic systems, described elsewhere in this volume by Nemeroff et al., are especially provocative in light of current theories concerning the cause of schizophrenia. In fact, the observed similarities between NT and antipsychotic drugs have even led to speculation that NT may be an endogenous neuroleptic (Nemeroff’). However, such a theory requires that the tridecapeptide or a closely related compound be present in areas of human brain critical to the functions that are disordered in that condition. In this report, we will present data that suggest that NT is distributed within the human brain in a pattern similar to that reported in lower species. Furthermore, studies on cerebrospinal fluid and postmortem brain tissue from patients with a diagnosis of schizophrenia or Huntington’s chorea show that NT levels may in fact be altered in these states.
Progress in Neuro-psychopharmacology | 1979
Paul J. Manberg; Charles B. Nemeroff; Arthur J. Prange
1. The pharmacological effects of TRH are compared to those produced by d-amphetamine in an attempt to elucidate the mechanisms underlying the activity of this endogenous peptide. 2. Although numerous amphetamine-like actions have been attributed to TRH, several differences have been noted between these compounds and are discussed. 3. At present, it is impossible to propose a single mechanism of action to explain the behavioral effects of TRH.
Progress in Neuro-psychopharmacology & Biological Psychiatry | 1985
Paul J. Manberg; Charles B. Nemeroff; Garth Bissette; Eric Widerlov; William W. Youngblood; John S. Kizer; Arthur J. Prange
Studies describing the CNS distribution of neuropeptides can provide important new insights concerning their possible physiological functions. The rational for studying human post-mortem tissue, as well as some methodological constraints, are reviewed. The localization of NT in normal human brain is presented. Concentrations of NT, TRH, and SRIF were determined in brain tissue from normal controls and patients with schizophrenia or Huntingtons chorea. Specific alterations in the levels of these neuropeptides were found in each disease. Appreciable quantities of NT immunoreactivity are present in human CSF. Sub-normal CSF-NT levels were found in a sub-group of unmedicated schizophrenics but were elevated back to normal concentrations following neuroleptic treatment. Although the pathophysiological significance of these findings is unclear, they nevertheless indicate that neuropeptides are important brain constituents which deserve further study.
Annals of the New York Academy of Sciences | 1982
Erik Widerlöv; Leif Lindström; Gunilla Besev; Paul J. Manberg; Charles B. Nemeroff; George R. Breese; John S. Kizer; Arthur J. Prange
Neurotensin (NT) is a tridecapeptide heterogeneously distributed in the central nervous system and the gastrointestinal tract of various mammals, including man. The peptide has been shown to possess many pharmacological properties that are similar to those of neuroleptic drugs: induces hypothermia and muscle relaxation, reduces spontaneous and amphetamine-induced locomotion, and potentiates ethanol and barbiturate sedation.’ Like neuroleptics, centrally administered NT also increases the synthesis of brain dopamine and elevates the concentration of the principal dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).‘ In the present study, cerebrospinal fluid (CSF) levels of immunoreactive NT:’ in 12 physically and mentally healthy volunteers (20-42 yr; median 26.5 yr) were compared with the CSF levels of NT from 21 age-matched schizophrenic patients (20-40 yr; median 26 yr). The CSF from most of the patients (n = 15) were drawn during both drug-free and neuroleptic-treated phases. The patients were hospitalized and had suffered from schizophrenia for 3-14 yr (median 5 yr). Diagnoses were assessed according to the Research Diagnostic Criteria. The CSF levels of NT for the healthy volunteers were 240.4 f 30.5 pg/ml (mean f SEM; TABLE 1). In contrast to the healthy volunteers, the schizophrenics showed a bimodal distribution of NT during the drug-free phase (p < 0.005). A subgroup of nine patients had markedly lower NT levels (46.7 _t 6.5 pg/ml) compared to the remainder of the schizophrenics (n = 12), who had CSF levels of NT in the same range as the healthy volunteers (249 f 29.2 pg/ml). Of particular interest was the finding that during neuroleptic treatment, the CSF levels increased in the schizophrenic group with low drug-free values to the same concentrations as for the group with the normal drug-free NT levels (278 f 37.9 and 282.8 f 93.6 pg/ml, respectively; TABLE 1). Observed and reported schizophrenic symptoms were scored according to the Comprehensive Psychopathological Rating Scale (CPRS).4 The schizophrenics with low NT levels in CSF had significantly higher scores of psychomotor retardation than the schizophrenics with normal drug-free NT levels in CSF (p < 0.02). Also, the three patients with a catatonic form of schizophrenia all belonged to the group with the low drug-free NT levels in CSF. The concept that the pathogenesis of major mental disorders is primarily due to alterations in monoaminergic neu-
Brain Research | 1982
Paul J. Manberg; William W. Youngblood; John S. Kizer
Pro-Leu-Gly-NH2 (PLG), which is the C-terminal tripeptide tail of oxytocin, has been reported to possess melanocyte-stimulating hormone (MSH)-release-inhibiting activity. Although it has been isolated from bovine hypothalamus, little is known about the CNS distribution of this peptide in other species. In this report, we describe the development of a radioimmunoassay which can be used to measure both PLG and oxytocin following chromatographic separation by high pressure liquid chromatography (HPLC). Using this method, we are unable to demonstrate the presence of any endogenous PLG in rat hypothalamus, preoptic area, pituitary, or eye tissue. However, synthetic PLG, which is added to tissue homogenates as an internal standard, is consistently recovered from all areas. We conclude that the PLG tripeptide is not present in the rat brain and thus cannot be the physiological regulator of MSH secretion.
Science | 1983
Charles B. Nemeroff; William W. Youngblood; Paul J. Manberg; Arthur J. Prange; John S. Kizer