Biomedical subjects
D de Wied
Publications and source records attributed to D de Wied.
Structure activity relationship studies with C-terminal fragments of vasopressin and oxytocin on avoidance behaviors of rats.
The potency of various C-terminal fragments of the neurohypophyseal hormone [Arg8]vasopressin [AVP-(1-9)] was determined using different avoidance behavioral test procedures in rats. Passive avoidance behavior was facilitated by these peptides. The fragments [Cyt6]AVP-(5-8) and [Cyt6]AVP-(5-9) were the most potent peptides tested after postlearning injection (consolidation) and preretention treatment (retrieval), respectively, after s.c. treatment. Comparable results were found when the peptides were injected into the lateral brain ventricle, but after this route of administration the peptides were about 3 to 4 order of magnitude more potent as compared to the s.c. route. Pentylenetetrazol-induced retrograde amnesia was reversed by AVP-(1-9) and various C-terminal fragments. In this respect [Cyt6] AVP-(5-9) and [pGlu4,Cyt6]-AVP-(4-9) appeared to be the most potent peptides. Injection of AVP-(1-9) and various C-terminal fragments after the acquisition of pole-jumping avoidance behavior induced resistance to extinction of the behavior. The fragment [pGlu4,Cyt6]AVP-(4-8) was the most potent peptide for this effect. Passive avoidance behavior was attenuated by s.c. administered oxytocin [OXT-(1-9)] and various C-terminal fragments. [pGlu4,Cyt6]-OXT-(4-9), [pGlu4,Cyt6]OXT-(4-8) and [Cyt6]OXT-(5-8) were the most potent of the peptides tested after postlearning administration, whereas [Cyt6]OXT-(5-9) was the most potent sequence after preretention injection. In all experiments the effects of the peptides were dose-dependent and of a long term nature. The results show that C-terminal fragments of the neurohypophyseal hormones potently modulate various aspects of memory processes, as assessed with different avoidance behaviors.(ABSTRACT TRUNCATED AT 250 WORDS)
Continuous measurement of cerebral blood volume in rats with the photoelectric technique: effect of morphine and naloxone.
The validity of a photoelectric method for continuous cerebral blood volume (CBV) measurement was tested and modified for the rat's brain. A new way of introducing a miniature light source between the two hemispheres and fixing a light sensitive silicone blue cell to the outer surface of the parietal bone was developed. Light extinction factor of the rat's blood was determined experimentally (Eb rat = 1.38 +/- 0.15) in order to calculate absolute CBV value in this species, resulting in a 4.77 +/- 0.13 vol % absolute CBV value. Data obtained in anesthetized, artificially ventilated rats by simultaneous recording of CBV and local cerebral blood flow (H2-gas clearance technique) show that local hypothalamic blood flow decreased significantly after morphine (1.0 mg/kg s.c.), while total CBV remained unchanged. Opiate receptor blockade with naloxone (1.0 mg/kg s.c.) on the contrary, as well as naloxone and morphine administration, caused no change in local hypothalamic blood flow, but resulted in a significant increase of total cerebral blood volume.
gamma-Endorphin and schizophrenia: amino acid composition of gamma-endorphin and nucleotide sequence of gamma-endorphin cDNA from pituitary glands of schizophrenic patients.
The possibility has been mentioned that a change in the structure is responsible for the deviant behavioral activity of gamma-endorphin in extracts of postmortem brain and pituitary gland samples of schizophrenic patients. This paper describes the investigation of this possibility by means of: amino acid composition analysis of alpha- and gamma-endorphin isolated from a pituitary gland of a schizophrenic patient; and nucleotide sequence analysis of the gamma-endorphin coding region of pro-opiomelanocortin (POMC) mRNA from two other pituitary glands, using the primer extension method. Both methods require no more than a single pituitary to obtain reliable results. alpha- and gamma-endorphin were isolated from an acid extract by gel filtration and two subsequent HPLC steps. In addition, the gamma-endorphin region of beta-endorphin was analyzed by enzymatic cleavage of beta-endorphin and isolation of the resulting fragment. Single-stranded gamma-endorphin cDNA was synthesized by reverse transcriptase using total cellular pituitary RNA and a 5' 32P-labeled oligodeoxyribonucleotide primer (20-mer) hybridizing close to the gamma-endorphin coding region of POMC mRNA. Single-stranded cDNA was digested with restriction enzyme HaeIII which generated a 148 nucleotides long radioactive cDNA fragment containing the gamma-endorphin cDNA sequence. The sequence of the 148 nucleotides fragment was determined. Neither the amino acid composition analysis nor the amino acid sequence derived from the cDNA nucleotide sequence revealed differences between schizophrenics and controls. Thus, no evidence was found for changes in the amino acid sequence of pituitary gamma-endorphin in these analyses, which include 3 cases of schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)
[Centralized animal experimentation policy as harmful to biomedical research].
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The interaction between gamma-type endorphins and HLA class I antigens.
The clinical response of schizophrenic patients to treatment with gamma-type endorphins was found to be associated with certain HLA class I antigens (Bw22, B15, B13). Moreover, pretreatment of lymphocytes from healthy donors with des-Tyr1-gamma-endorphin (DT gamma E) inhibits the complement-dependent cytotoxicity between alloantisera and those HLA antigens, of which the frequency was increased among schizophrenic patients, who respond well to the gamma-endorphin therapy. Also for the opiate antagonist, naloxon interactions with HLA class I antigens could be demonstrated. Using the inhibition assay with DT gamma E it was possible to detect a subtype of HLA-A2, which, until now, was only defined by cytotoxic T lymphocytes and biochemistry. These data suggest an interaction between the HLA class I antigens and the receptor(s) for DT gamma E and naloxon, which may support the hypothesis that HLA class I antigens play a role in many recognition processes. Their role in immunological recognition would then be only a specialized form of a more general function.
Melanocortins, neural plasticity and aging.
Peptides derived from ACHT and alpha-MSH are known to exert trophic influences on peripheral and central nervous structures. Age-related brain diseases may in part be related to loss of neural plasticity. Melanocortins improve adaptional abilities of the nervous system. Chronic treatment with melanocortins may counteract age-related brain pathology.
Antipsychotic action of gamma-type endorphins: animal and human studies.
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Intracerebroventricular injection of anti-prolactin serum suppresses excessive grooming of pituitary homografted rats.
Rats with endogenous hyperprolactinaemia, as induced by pituitary homografts under the kidney capsule, displayed increased grooming behavior as compared to that of sham-operated animals. Twelve days after surgery, intracerebroventricular injection of anti-prolactin serum (dilution 1:100, 1 microliter) suppressed the excessive grooming of homografted rats. These observations suggest that prolactin from a peripheral source may reach the central nervous system to affect brain mechanisms involved in grooming behavior.
Characterization and quantitation of vasopressin metabolites in the rat brain by specific radioimmunoassay and high-pressure liquid chromatography.
The content of endogenous vasopressin (AVP1-9) and its metabolites in rat's various brain areas and pituitary gland was investigated by the combination techniques of high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). In addition to the AVP1-9, several compounds with C-terminal AVP immunoreactivity were detected in hypothalamus, hippocampus, amygdala, medulla oblongata and septum. The C-terminal AVP1-9 metabolites were virtually absent in the pituitary gland. In view of the highly potent and selective effects on memory processes of AVP metabolites, some endogenous AVP metabolites in the brain may play an important role in the central nervous system (CNS) function.
The effect of gamma-type endorphins on alpha-MSH release in the rat.
Neuroleptic drugs increase the level of alpha-melanotropin (alpha-MSH) in the blood of the rat. We have investigated whether neuroleptic-like peptides, the gamma-type endorphins, also affect alpha-MSH release. A structure-activity study revealed that (des-enkephalin)-gamma-endorphin (DE gamma E, beta-LPH-(66-77), beta-endorphin-(6-17)) is able to increase plasma alpha-MSH levels after intracerebroventricular injection, while the longer gamma-type endorphins, i.e. gamma E (beta-LPH-(61-77)), beta-endorphin-(1-17)), and DT gamma E (beta-LPH-(62-77), beta-endorphin-(2-17)) were without effect in the dosage used. A dose-response study revealed a more or less bell-shaped relationship for the effect of DE gamma E on plasma alpha-MSH levels. The effect of DE gamma E could not be counteracted by apomorphine or naloxone. The observations indicate that DE gamma E increases plasma alpha-MSH levels in a way distinct from that of haloperidol and the opiate peptide beta-endorphin. On the other hand, a time-course of plasma alpha-MSH levels after DE gamma E administration resembled the one which has been seen after haloperidol injection. From experiments performed on pituitary neurointermediate lobes incubated in vitro, it seems not likely that DE gamma E acts directly on the dopamine receptors of the pituitary in affecting alpha-MSH release. In conclusion, it appears that DE gamma E affects alpha-MSH levels in plasma in a way distinct from that of the neuroleptic drug haloperidol and of the opiate-peptide beta-endorphin.
N alpha-Acetyl-gamma-endorphin is an endogenous non-opioid neuropeptide with biological activity.
N alpha-acetyl-gamma-endorphin (Ac gamma E) was identified in the rat neurointermediate pituitary, based on its immunological properties, comigration with synthetic Ac gamma E on HPLC and resistance to aminopeptidase-M degradation. The peptide appeared to be the main form of gamma-endorphin (gamma E) in this tissue and in brain areas remote from the hypothalamus (hippocampus, septum, amygdala). The anterior pituitary, the hypothalamus and the thalamus contained almost exclusively the non-acetylated form of gamma E. In contrast to gamma E, Ac gamma E was completely devoid of specific affinity for brain opiate binding sites. Yet, the peptide mimicked gamma E in that it potently attenuated passive avoidance behaviour in rats, when injected topically into the nucleus accumbens. It is concluded that Ac gamma E is an endogenous neuropeptide with non-opioid biological activity. N alpha-acetylation may not merely represent a mechanism for the inactivation of opioid activities of endorphins, but rather allow the organism to select specific sets of biological activities that reside in the endorphin structure.
Autoradiographic localization of binding sites for the arginine-vasopressin (VP) metabolite, VP4-9, in rat brain.
A discrete neuro-anatomical pattern of binding sites was observed for a principal metabolite of arginine-vasopressin (VP4-9) after incubation of tissue sections with [35S]VP4-9 and autoradiography. [35S]VP4-9-labeled binding sites were highly concentrated in the pineal gland, the nucleus tractus solitarii (nts), the arcuate nucleus region (an) and the organum vasculosum lamina terminalis (ovlt). The distribution of these sites is distinctly different from the putative VP and oxytocin receptor systems in rat brain. It is possible that the VP4-9 binding sites are also involved in memory processes and/or that the VP metabolite exerts additional effects on the brain.
Disrupting circadian rhythms in rats induces retrograde amnesia.
Disrupting circadian organization in rats by phase-shifting the illumination cycle or by exposure to a reversed day/night cycle or to continuous light, resulted in retrograde amnesia for passive avoidance behavior. This retrograde amnesia induced by phase-shifting lasted at least 2 days, and gradually diminished the longer the rats were exposed to the new illumination cycle. Retention performance was not impaired when rats were exposed to phase-shifting for 3-5 days before the learning trial. The retrograde amnesia due to changing the illumination cycle is probably due to retrieval disturbances. Extinction of active avoidance behavior was facilitated in rats exposed to a phase-shifted illumination cycle, but social and explorative behavior of rats tested in dyadic encounters were not affected by changing the normal illumination cycle. It is concluded that phase-shifting may result in amnesia for newly learned behavioral responses, but not for more innate behavioral patterns.
Further evidence for a dissociation of peripheral and central effects of vasopressin.
The influence of AVP on open field behavior was studied at 15 and 60 min after s.c. injection. AVP injected 15 min before the session modified all patterns of behavior in the open field. Locomotion and rearing along the wall were significantly decreased, while locomotion in the center was increased. AVP also reduced grooming and defecation. Injection 60 min prior to the session did not affect the open field behavior. AVP increased resistance to extinction of pole-jumping avoidance behavior independent of whether the first acquisition session was given at 20 min after injection at the height of the behavioral depression or at 65 min when these effects had disappeared. However, the rats trained at 20 min after AVP administration made significantly more avoidances on the second day of acquisition training than did the controls. The vasopressin fragment DGAVP, which exhibits almost no peripheral effects, did not cause gross behavioral changes in the open field as did AVP, but it did increase resistance to extinction of the avoidance response comparable to that of AVP. These findings indicate that, although peripheral effects may contribute to the effects of AVP on modulation of memory processes, such effects are not essential.
Behavioral effects of non-opioid fragments of beta-endorphin.
The opioid peptide beta-endorphin (beta E) is converted by brain enzymes to a variety of non-opioid peptide molecules. Several of these peptides specifically affect brain processes in a different manner as assessed in behavioral test procedures. The peptide beta E-(2-9) exhibits behavioral effects resembling psychostimulant drugs in certain aspects and potentiates apomorphine-induced stereotypy following peripheral and intrastriatal treatment. The peptide beta E-(10-16), like serotonin and antidepressant drugs antagonizes the behavioral effects of intra-accumbens injected melatonin. The peptide beta E-(6-17) induces several effects which resemble those of neuroleptic drugs, including an antipsychotic action, and may control the activity of specific dopaminergic systems present in the nucleus accumbens. Thus, non-opioid fragments of beta-endorphin may be involved in the modulation of neurotransmitter systems and consequently in brain homeostasis and possibly in psychopathological syndromes.
Levels of arginine-vasopressin in cerebrospinal fluid during passive avoidance behavior in rats.
The concentration of immunoreactive arginine-vasopressin (IR-AVP) was measured in the cerebrospinal fluid (CSF) during acquisition and retention of passive avoidance behavior. IR-AVP level in CSF of male Wistar rats immediately after the learning trial was increased; the rate of which was related to the intensity of the electric footshock during the learning trial and the avoidance latency as measured 1 day after the learning trial. Immediately after the 24 h retention test IR-AVP levels were significantly increased in rats subjected to the low (0.25 mA) shock intensity during the learning trial, but IR-AVP levels of rats exposed to the high shock (1.0 mA) were under the limit of detection. If the retention test was postponed till 5 days after the learning trial, the increase of IR-AVP level in the CSF was related to avoidance latencies which reflect the intensity of aversive stimulation (electric footshock). The results suggest an association between central AVP release and passive avoidance behavior and may be indicative of the role of this peptide in neuronal mechanisms underlying learning and memory processes.
Influence of substance P and fragments on passive avoidance behavior.
N-terminal and C-terminal fragments of substance P (SP) have been shown to exert opposite effects on antinociception, grooming and fighting in mice. The present experiments explored whether these findings could be generalized to passive avoidance behavior. Substance P (SP-(1-11] and the C-terminal fragment pyroglutamyl-SP-(7-11) attenuated passive avoidance behavior when picogram amounts were injected into the nucleus accumbens. In contrast, the N-terminal fragment SP-(1-7) had an opposite effect and facilitated passive avoidance behavior.