Patients with difficult-to-treat depression do not exhibit an increased frequency of CYP2D6 allele duplication.

The insufficient response of patients to antidepressant medications may result from several factors, including altered drug metabolism. CYP2D6 genotyping may help assess the possible factors that contribute to difficult-to-treat depression. The aim of our study was to determine the frequency of CYP2D6 allelic variants and the prevalence of predicted CYP2D6 phenotypes in patients who were suffering from difficult-to-treat depression and compare the data with those for the healthy population of Hungary.55 patients who failed to respond to 2 or more adequate trials of different CYP2D6-dependent antidepressants were selected for genotyping.The prevalence of the predicted CYP2D6 phenotypes in the patient population was 1.8% for the UMs, 80.0% for EMs, 3.6% for IMs and 14.5% for PMs compared with 1.9% for UMs, 83.3% for EMs, 6.5% for IMs and 8.3% for PMs in the Hungarian population.The CYP2D6 allele frequencies and the predicted phenotype distributions in patients with difficult-to-treat depression were not significantly different to those found in the healthy population of Hungary. The cumulative frequency of the CYP2D6*1XN, *2XN and *35XN alleles was 0.9% in the patient population -suggesting that CYP2D6 duplication or multiplication does not play a significant role in antidepressant pharmacotherapy failure in this patient sample. The cumulative frequency of the non-functional alleles (33.5%) and the prevalence of the genetically determined PM phenotype (14.5%) were relatively high in the patient group. These figures draw attention to the possibility of unrecognised and non-reported side effects and non-adherence to drug treatment.

Relationship of adipokines and non-esterified fatty acid to the insulin resistance in non-diabetic individuals.

BACKGROUND: Altered secretion of adipokines and non-esterified fatty acid (NEFA) seems to play a pivotal role in the abdominal obesity-related insulin resistance (IR). AIM: To determine semi-quantitatively the impact of serum NEFA, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, and resistin levels on IR measured by homeostasis model assessment (HOMA-IR). MATERIAL/SUBJECTS: Seventy-four Caucasian subjects forming 3 age-, and sex-matched groups were included into the study [Group 1 and 2: non-diabetic obese patients, no.= 25, body mass index (BMI): 28-39.9 kg/m(2), no.=25, BMI≥40 kg/m(2), respectively, and Group 3: 24 healthy, normal weight control subjects]. METHODS: Serum levels of NEFA and adipokines as well as other metabolic variables including HOMA-IR were measured. RESULTS: HOMA-IR was associated positively with BMI, waist circumference, serum NEFA, leptin, IL-6, and TNF-α levels, negatively with adiponectin, with no significant relation to resistin. In multiple regression analyses, of these factors leptin was a strong, IL-6 and adiponectin were weak independent predictors of HOMA-IR, while the others were not significant determinants of HOMA-IR. However, even together, they explained only 35-36% of variance of HOMAIR. CONCLUSIONS: Although IR has associations with many of the investigated parameters, of these, only serum level of leptin, and in lesser degree IL-6 and adiponectin are independent determinants of the severity of IR. Moreover, even together they explain only a minority of variance IR.

Negative association of L-arginine methylation products with oocyte numbers.

BACKGROUND: The aim of this study was to determine the concentrations of L-arginine and methylarginines in follicular fluid obtained from women participating in our IVF program and to find clinical correlates of these biochemical parameters. METHODS: Follicular fluid was obtained from 108 women by ultrasonography guided transvaginal puncture following controlled ovarian hyperstimulation. Follicular fluid L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA) concentrations were determined with liquid chromatography-tandem mass spectrometry. The integrated index of arginine methylation (arg-MI) was calculated according to the formula: arg-MI = (ADMA + SDMA)/MMA. RESULTS: There were significant inverse relationships between IVF embryo number and follicular fluid L-arginine (r = -0.507, P < 0.001), ADMA (r = -0.356, P < 0.024), SDMA (r = -0.347, P < 0.028), MMA (r = -0.449, P < 0.004) and to L-arginine/ADMA ratio (r = -0.328, P < 0.031). By contrast, arg-MI was directly related to IVF embryo number (r = 0.426, P < 0.006). Moreover, the number of IVF oocytes was also inversely related to ADMA (r = -0.202, P < 0.037) and MMA (r = -0.384, P < 0.012) and positively to arg-MI (r = 0.450, P < 0.03). CONCLUSIONS: The elevated levels of follicular fluid l-arginine and methylarginines appear to have an adverse influence on the reproductive processes as reflected by a reduction in the number of oocytes and embryos conceived. In contrast, the integrated methylation index proved to be positively correlated to the above parameters of fertilization.

A major metabolite of arginine vasopressin in the brain is a highly potent neuropeptide.

A peptide that accumulated as the major product during the proteolysis of arginine vasopressin by rat brain synaptic membranes was isolated and its structure was shown to be the hexapeptide pGlu-Asn-Cys(Cys)-Pro-Arg-Gly-NH2. When administered intracerebroventricularly in extremely low doses, this vasopressin fragment and its desglycinamide derivative facilitated memory consolidation in a passive avoidance situation. These vasopressin metabolites, which are devoid of pressor activity, constitute highly potent neuropeptides with selective effects on memory and related processes; they are activated via proteolytic processing of vasopressin by brain peptidases.

European survey on national training activities in clinical research.

BACKGROUND: Investigator-initiated clinical studies (IITs) are crucial to generate reliable evidence that answers questions of day-to-day clinical practice. Many challenges make IITs a complex endeavour, for example, IITs often need to be multinational in order to recruit a sufficient number of patients. Recent studies highlighted that well-trained study personnel are a major factor to conduct such complex IITs successfully. As of today, however, no overview of the European training activities, requirements and career options for clinical study personnel exists. METHODS: To fill this knowledge gap, a survey was performed in all 11 member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardised questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the landscape of academic training opportunities, to facilitate the exchange of expertise and experience among countries and to identify new fields of action. RESULTS: The survey found that training for Good Clinical Practice (GCP) and investigator training is offered in all but one country. A specific training for study nurses or study coordinators is also either provided or planned in ten out of eleven countries. A majority of countries train in monitoring and clinical pharmacovigilance and offer specific training for principal investigators but only few countries also train operators of clinical research organisations (CRO) or provide training for methodology and quality management systems (QMS). Minimal requirements for study-specific functions cover GCP in ten countries. Only three countries issued no requirements or recommendations regarding the continuous training of study personnel. Yet, only four countries developed a national strategy for training in clinical research and the career options for clinical researchers are still limited in the majority of countries. CONCLUSIONS: There is a substantial and impressive investment in training and education of clinical research in the individual ECRIN countries. But so far, a systematic approach for (top-down) strategic and overarching considerations and cross-network exchange is missing. Exchange of available curricula and sets of core competencies between countries could be a starting point for improving the situation.

Minor disturbances in central nervous system function in familial neurohypophysial diabetes insipidus.

Familial neurohypophysial diabetes insipidus (FNDI) is caused by a defect in vasopressin synthesis and release as a result of a heterozygous mutation in the gene for the vasopressin prohormone. The predominant characteristic of FNDI is excessive thirst and urine production. However, vasopressin not only has peripheral endocrine effects, but also regulates numerous brain functions. We investigated whether central functions are affected in FNDI, by studying neuropsychological functioning of 23 affected members (15 males, 8 females) of a large family carrying a T/G transition mutation at nucleotide 2110 (codon 116) of the vasopressin prohormone gene (Cys116Gly). The relatively large number of family members with FNDI made it possible to compare cognitive and other CNS effects in these subjects with those of family members without FNDI. Thirty-seven adult volunteers (20 males, 17 females) from the same family and 11 non-family members (2 males, 9 females) from northern part of The Netherlands were tested. The mean age of the subjects was 35+/-12 years. Of the 63 quantified neuropsychological parameters few were statistically different between the subjects with FDNI and control subjects. Memory retrieval processes and sustained attention were worse in the subjects with FDNI. Moreover, these individuals reported significantly fewer symptoms of agoraphobia and miscellaneous symptoms, and had significantly lower scores on a scale measuring anger. The performance of FNDI subjects on an auditory verbal learning test (the 15-word test learning trial) was worse, but not significantly so, than that of the subjects without FDNI. There were subjective complaints of forgetfulness and slow recalls and those were observed in daily life by non-affected family members. These moderate differences in neuropsychological performance indicate that in human FNDI parvocellular vasopressin systems that supply the brain may be less affected or give no such serious disabilities, than the magnocellular hypothalamo-neurohypophysial system that provides vasopressin for endocrine regulation of water homeostasis.

Examination of the interaction of different lighting conditions and chronic mild stress in animal model.

We examined the effects of different shift work schedules and chronic mild stress (CMS) on mood using animal model. The most common international shift work schedules in nursing were applied by three groups of Wistar-rats and a control group with normal light-dark cycle. One subgroup from each group was subjected to CMS. Levels of anxiety and emotional life were evaluated in light-dark box. Differences between the groups according to independent and dependent variables were examined with one- and two-way analysis of variance, with a significance level defined at p < 0.05. Interaction of lighting regimen and CMS was proved to be significant according to time spent in the light compartment and the average number of changes between the light and dark compartments. Results of our examination confirm that the changes of lighting conditions evocate anxiety more prominently than CMS. No significant differences were found between the results of the low rotating group and the control group, supposing that this schedule is the least harmful to health. Our results on the association between the use of lighting regimens and the level of CMS provide evidence that the fast rotating shift work schedule puts the heaviest load on the organism of animals.

Sites of behavioral and neurochemical action of ACTH-like peptides and neurohypophyseal hormones.

In order to localize the site of action of neuropeptides in relation to their effects on behavior and memory various approaches have been used. As a result of studies using rats bearing lesions in different areas of the limbic system as well as of studies in which neuropeptides were locally applied into various areas of the brain it appeared that the limbic system (amygdala, hippocampus, septum and some thalamic areas) plays an essential role in the effect of vasopressin and ACTH and their derivatives on behavior and memory. Neurochemical studies generally indicate that changes occur in catecholamine utilization in these various limbic regions upon administration of these neuropeptides. It can be concluded that the effects of vasopressin in the terminal regions of the coeruleo-telencephalic noradrenalin system correlate with its effects on consolidation of memory. It is likely that the effects of vasopressin on other transmitter systems (e.g. dopamine in the amygdala and serotonin in the hippocampus) correspond with the effect of this neuropeptide on retrieval processes. In addition, regional differences in biotransformation of the neurohypophyseal hormones suggest that different patterns of behaviorally active fragments of these peptides may be present locally in the brain.

Natriuretic peptides in alcohol withdrawal: central and peripheral mechanisms.

Abrupt cessation of long-term alcohol consumption produces well-defined symptoms called alcohol withdrawal (AW). The exact pathophysiological mechanisms involved in the appearance of AW symptoms and particularly those related to the precipitation of delirium tremens (DT), still await clarification in spite of the fact that the prediction of complicated AW is essential to guarantee that appropriate therapies may be planned in advance. Changes in central nervous system (CNS) glutamate- and GABA-transmission and a role of voltage-operated calcium channels are equally important elements of neuroadaptation to the chronic presence of alcohol. In addition to the CNS regulation, however, changes in peripheral fluid and electrolyte homeostasis may accompany, and are expected to modify the clinical symptoms of AW. In an early phase of acute withdrawal, plasma levels of atrial natriuretic peptide (ANP), plasma renin activity and aldosterone are high. In patients with DT, elevated levels of ANP were observed days before the actual onset of DT. It is concluded that the altered plasma ANP secretion might be associated with, and therefore used as an indicator of the onset of DT. However, ANP is present in and produced by the brain and thus it can be regarded as a neuropeptide. The role of CNS ANP was studied in mice, rendered tolerant to and physically dependent on alcohol. Intracerebroventricular injections of ANP attenuated, whereas those of an antiserum against ANP intensified hyperexcitability during AW. ANP in the brain - the content of which undergoes sensitive changes in the hippocampus during AW appears to interact primarily with glutamate transmission through the NMDA-receptors. This brain structure is of utmost importance for the generation of withdrawal-related hyperexcitability. It is concluded that peripheral secretion of ANP might be a diagnostics indicator, whereas ANP in the CNS might be a modulator of AW.

Selective attenuation of passive avoidance behaviour by microinjection of beta-LPH62-77 and beta-LPH66-77 into the nucleus accumbens in rats.

Various fragments of beta-lipotropin were micro-injected into the nucleus accumbens of free-moving rats and the effects on one-trial passive avoidance behaviour were studied. The following peptides were used: beta-endorphin (beta-LPH61-91), met-enkephalin (beta-LPH61-65), des-tyrosine-gamma-endorphin (DT gamma E, beta-LPH62-77), des-enkephalin-gamma-endorphin (DE gamma E, beta-LPH66-77), des-tyrosine-alpha-endorphin (DT alpha E, beta-LPH 62-76) and beta-LPH47-53(ACTH4-10). The gamma-type endorphins (DT gamma E and DE gamma E) were the only peptides which significantly attenuated passive avoidance behaviour when given in a 20 pg dose 1 hr before the 24-hr retention test. All the other peptides were ineffective. Microinjection of DT gamma E into the dentate gyrus of the dorsal hippocampus, on the other hand, was without effect on passive avoidance. The accumbens nucleus, therefore, is a preferential highly sensitive brain site for gamma-type endorphins. The attenuation of passive avoidance behaviour following systemic administration of these peptides might be the result of an interaction with this mesolimbic structure.

Effects of haloperidol on morphine-induced antinociception morphine tolerance and withdrawal in hyperprolactinaemic rats.

Male rats with hyperprolactinaemia, induced by adenohypophyseal homografts under the kidney capsule, were injected with haloperidol for 3 days and then subjected to treatment with morphine, administered twice in a day at increasing doses for 12 days. At the first treatment, morphine induced an antinociceptive effect that was more prolonged in homografted rats than in sham-operated controls. The pretreatment with haloperidol did not change the prolongation of morphine-induced antinociception in homografted rats. After 12 days of treatment with morphine, all animals were tested for the development of tolerance to the antinociceptive effect of morphine. Pituitary homografts resulted in an inhibition of the development of tolerance, while this effect was absent in homografted rats pretreated with haloperidol. At the end of the treatment with morphine, the naloxone-precipitated abstinence syndrome was studied. Homografted rats shown an attenuation of the withdrawal syndrome and pretreatment with haloperidol did not change this response. These results suggest an involvement of dopaminergic transmission in prolactin-induced changes in the development of tolerance to morphine, but not in the antinociceptive effect following an acute injection of morphine and in naloxone-precipitated withdrawal syndrome of the rat.

Oxytocin and a C-terminal derivative (Z-prolyl-D-leucine) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain.

The effects of oxytocin (OXT) and of dipeptides derived from the C-terminal portion of oxytocin (Z-prolyl-leucine and Z-prolyl-D-leucine) on the development of acute and chronic tolerance to, and dependence on morphine were tested in the mouse. Oxytocin and the dipeptides attenuated the development of acute and chronic tolerance to the antinociceptive effect of morphine and delayed the onset of the naloxone-precipitated withdrawal syndrome. Both oxytocin and Z-prolyl-D-leucine affected drug-induced behavioural responses related to dopamine (DA) in the brain. Thus, oxytocin potentiated the hypermotility induced by a large dose of apomorphine and decreased the supersensitivity of the DA receptors. Small doses of Z-prolyl-D-leucine inhibited the hypomotility elicited by a small dose of apomorphine and potentiated the hyperactivity induced by amphetamine. The data indicate that both oxytocin and Z-prolyl-D-leucine affect tolerance to and dependence on morphine. While oxytocin interacts mainly with postsynaptic DA-ergic neuronal elements, the dipeptide primarily affects DA-ergic neurotransmission at the presynaptic level.

The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity.

Cocaine is a widely used drug of abuse. One of the characteristic effects of this stimulant drug in the CNS of mice is the induction of motor hyperactivity. It was demonstrated that cocaine-induced motor hyperactivity could be blocked by pimozide, a dopamine receptor blocker, suggesting that dopamine was involved in cocaine-induced hyperactivity. Oxytocin, a neurohypophyseal neuropeptide, also partially antagonized cocaine-induced motor hyperactivity. Moreover, oxytocin antagonized the increased utilization of dopamine, elicited by cocaine in the nucleus accumbens. The data suggest that oxytocin may influence the behavioural effects of cocaine by affecting dopaminergic neurotransmission in some regions of the brain.

Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats.

Behavioural adaptation to and the effects of the neurohypophyseal peptide, oxytocin, on repeated treatment with cocaine were investigated in rats. The content of immunoreactive oxytocin in the plasma, hypothalamus and different limbic structures in the brain were also studied after treatment with cocaine, identical to that used in the behavioural experiment. Repeated administration of cocaine (7.5 mg/kg, s.c.) produced a behavioural tolerance to the stereotyped sniffing-inducing effect of the challenge doses (1.875, 3.75 and 7.5 mg/kg, s.c.) of cocaine on the fifth day, which was demonstrated by parallel shifting of the dose-response and time-effect curves of the test doses of cocaine. The development of tolerance was inhibited by pretreatment with oxytocin (0.05 micrograms, (s.c.), administered before each daily injection of cocaine. A smaller dose of oxytocin (0.005 micrograms, s.c.) had no effect in this model. A decreased amount of immunoreactive oxytocin was detected in the plasma, in the hypothalamus and in the hippocampus, after repeated treatment with cocaine. Replacement of oxytocin by local injection (100 pg) into the ventral hippocampus, before each daily administration of cocaine, prevented the development of tolerance to cocaine. These results suggest that endogenous oxytocin, localized in limbic-forebrain areas, may have an important regulatory role in the development of behavioural changes induced by the repeated administration of cocaine.

Role of oxytocin in the neuroadaptation to drugs of abuse.

Oxytocin (OXT), a neurohypophyseal hormone, has a wide range of behavioral effects outside its classic peripheral endocrine functions. OXT involvement in adaptive central nervous system processes has been demonstrated as an inhibitory, amnestic action on learning and memory in different paradigms. Because adaptation and learning are likely to be involved in the neural events leading to drug tolerance and dependence, the question logically arose whether OXT is able to influence the development of tolerance of and dependence on abused drugs. In this review, we summarize our results on the effects of OXT on opiate (including morphine, heroin, and the endogenous opiates beta-endorphin and enkephalin) tolerance and dependence, heroin self-administration, psychostimulant-induced behavioral changes, and behavioral tolerance and sensitization. The sites and mechanisms of action and the possible physiological role of OXT are also discussed. In the first part of this review the effects of exogenously administered OXT on both the acute and chronic behavioral effects of opiates and psychostimulants have been summarized. OXT inhibited the development of tolerance to morphine, heroin, beta-endorphin, and enkephalin, OXT also inhibited the development of cross-tolerance between the predominantly mu-agonist heroin and the predominantly delta-agonist enkephalin in mice. Naloxone-precipitated morphine withdrawal syndrome was also attenuated by OXT. Heroin self-administration was decreased by OXT administration in heroin-tolerant rats. OXT inhibited cocaine-induced exploratory activity, locomotor hyperactivity, and stereotyped behavior in rats and in mice. Behavioral tolerance to cocaine was also attenuated by OXT. On the contrary, OXT stimulated the development of behavioral sensitization to cocaine. OXT did not alter the stereotyped behavior induced by amphetamine. In the second series of experiments, the sites of action of OXT on drug-related behavior were investigated. Intracerebro-ventricular (ICV) and intracerebral (IC) administration of an OXT-receptor antagonist inhibited the effects of peripherally administered OXT on morphine tolerance, heroin self-administration, and cocaine-induced sniffing behavior. This suggests the central, intracerebral location of OXT target sites. Local IC microinjection of OXT in physiological doses into the posterior olfactory nucleus, tuberculum olfactorium, nucleus accumbens, central amygdaloid nucleus, and the hippocampus inhibited the development of tolerance to and dependence on morphine as well as cocaine-induced sniffing behavior and tolerance to cocaine. The physiological role of endogenous OXT in acute morphine tolerance has also been demonstrated, since OXT antiserum (ICV) and OXT-receptor antagonist (injected into the basal forebrain structures) potentiated the development of morphine tolerance. Finally, we investigated the possible mechanisms of action of OXT on drug related behavior. Both morphine tolerance and dependence, and cocaine administration, increased dopamine utilization in the mesencephalon and in the nucleus accumbens, respectively. OXT treatment decreased the alpha-methylparatyrosine-induced dopamine utilization in the mesencephalon and in the nucleus accumbens-septal complex. Chronic OXT treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum. In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine. This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction.

Effects of beta-endorphin and its fragments on inhibitory avoidance behavior in rats.

The effects on retrieval of a one-trial learning inhibitory avoidance response of beta-endorphin, alpha-endorphin, and gamma-endorphin, given prior to test have been studied in rats. beta-Endorphin (beta-LPH 61-91) in a relatively low dose (1.56 micrograms sc. or 50 ng icv.) facilitated inhibitory avoidance behavior, while a higher dose (10 micrograms sc. or 100 ng icv.) caused bimodal changes (facilitation in 50% of the animals and attenuation in another 40%. Peripheral injection of gamma-endorphin attenuated inhibitory avoidance behaviour in a dose-dependent manner. The C-terminus of beta-endorphin (beta-LPH 78-91) was ineffective. alpha-Endorphin facilitated inhibitory avoidance behavior in a dose dependent manner. Naltrexone pretreatment antagonized the bimodal effect of beta-endorphin: following pretreatment with the opiate antagonist the low latency component disappeared, but the facilitatory effect of the neuropeptide remained the same. It is suggested that beta-endorphin carries more than one bit of behavioral information. Inherent activities either related or unrelated to naltrexone-sensitive opiate as well as biotransformation into alpha- and gamma-endorphin may contribute to the multiple behavioral effects of this neuropeptide.

Oxytocin and addiction: a review.

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.

Oxytocin diminishes heroin tolerance in mice.

Tolerance was induced in mice to the antinociceptive effect of heroin by repeated subcutaneous injections of this narcotic analgesic for 3 days. Pretreatment of mice with daily doses of oxytocin (2-200 micrograms/kg body wt.) resulted in an attenuation of heroin tolerance. A single oxytocin injection prior to the first challenge with heroin was as active in attenuating heroin tolerance as daily treatments with the neuropeptide. A single injection of oxytocin prior to the least heroin challenge also attenuated the expression of tolerance. The neuropeptide failed to modify the acute antinociceptive effect of heroin. It is concluded, therefore, that oxytocin interferes with mechanisms involved in the development and expression of tolerance to heroin.

Peripheral oxytocin treatment modulates central dopamine transmission in the mouse limbic structures.

The effects of subcutaneous (s.c.) oxytocin treatment have been investigated on various parameters of dopaminergic neurotransmission in basal forebrain structures (nucleus olfactorius posterior + nucleus accumbens + septum) of the mouse. Acute oxytocin treatment failed to influence dopamine utilization in the basal forebrain. Following chronic injections of oxytocin (0.2 mg/kg) for 8 8 days, the neuropeptide decreased dopamine utilization. Neither in vivo nor in vitro oxytocin treatment was capable of influencing the in vitro uptake of [(3)H]dopamine in basal forebrain slices. The spontaneous release of [(3)H]dopamine (in the presence of 4.2 mM K(+)) from basal forebrain tissue slices was not affected by in vitro or acute or chronic in vivo oxytocin treatment. The stimulated release of [(3)H]dopamine (in the presence of 30 mM K(+)) was significantly inhibited by chronic in vivo oxytocin administration. Chronic oxytocin treatment decreased the B(max) value of [(3)H]spiroperidol binding in the basal forebrain. The dissociation constant (K(d)) of [(3)H]spiroperidol binding was not influenced by oxytocin. The data indicate that peripheral oxytocin treatment is capable of modifying dopaminergic neurotransmission in mouse basal forebrain regions.

Dose-related effect of the oxytocin fragment (prolyl-leucyl-glycinamide) on ?-MPT-induced catecholamine disappearance and serotonin level in rat brain.

Graded doses of Pro-Leu-Gly-NH(2) (3.5 x 10(?12), 3.5 x 10(?11), 3.5 x 10(?10) or 3.5 x 10(?9) mol) were administered into the lateral cerebral ventricle of rats. The noradrenaline level of the dorsal hippocampus was increased 30 min after a dose of 3.5 x 10(?10) mol Pro-Leu-Gly-NH(2). The dopamine level was increased in the dorsal hippocampus and in the striatum. The serotonin level was increased in the hypothalamus, in the striatum and decreased in the dorsal hippocampus. The catecholamine disappearance following 350 mg/kg of ?-methyl-p-tyrosine indicated an accelerated dopamine disappearance in the striatum for each dose studied, while the hypothalamic noradrenaline disappearance was inhibited by a dose of 3.5 x 10(?11) mol of Pro-Leu-Gly-NH(2). The data indicate that Pro-Leu-Gly-NH(2) induces dose and region-dependent changes in the cerebral monoamine metabolism. The striatal dopamine and hypothalamic serotonin metabolism appeared to be the most sensitive for intraventricular Pro-Leu-Gly-NH(2).