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.

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.

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.

Brain glucose sensing and counterregulatory response to hypoglycaemia.

An important obstacle to achieve optimal glycaemic control in diabetics on intensive insulin therapy is the frequent occurrence of insulin induced hypoglycaemic events. In healthy subjects and in diabetics without autonomic neuropathy hypoglycaemia activates the sympathetic nervous system, resulting in epinephrine and glucagon release. Both hormones increase hepatic glucose production and this counterregulatory response is of key importance of glucose homeostasis. Recent research shed light on the fact that antecedent hypoglycaemic episodes play pivotal role in hypoglycaemia associated autonomic failure (HAAF). In this condition the sympatho-adrenal response to decreased blood glucose level is blunted. The existence of HAAF clearly indicates that the nervous system contributes to glucose homeostasis in a substantial manner. This review outlines the mechanisms of both peripheral and central neuronal glucose sensing and of neural pathways involved in the counterregulatory response.

Clindamycin release determined by high performance liquid chromatography from a novel low-cost local drug delivery system: a new potential treatment option for chronic osteomyelitis.

Osteomyelitis continues to be a severe problem worldwide, causing plenty of hospital admissions and entailing vast expenses. Previously, we developed a low-cost polymethyl-methacrylate (PMMA)-sorbitol based capsule system for local long-term drug delivery. In the present study we aimed to test the in vitro release of clindamycin capsules by high performance liquid chromatography. By the end of the clinically relevant period (42 days), the capsules released 70-100% of their load. Furthermore, the release kinetics suggested that an effective antimicrobial concentration may be maintained within the target area. Our findings indicate that these newly developed capsules may be a versatile device for local clindamycin delivery by providing efficient release and reducing financial burdens.

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.

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.

Comparative analytical evaluation of thyroid hormone levels in pregnancy and in women taking oral contraceptives: a study from an iodine deficient area.

Increase of serum thyroxine binding globulin (TBG) resulting from estrogen action may lead to problems in thyroid diagnostics. The aim of the present study was to define the most diagnostically reliable thyroid parameters in women exposed to differentially elevated estrogens. Sera of three groups of healthy women were analyzed: women taking no medicine (controls), those taking oral contraceptives and pregnant women (in weeks 16 or 32 of gestation). All women involved in the study lived in a moderately iodine-deficient geographical area. Thyroid stimulating hormone (TSH), TBG, total thyroxine (T4), total tri-iodothyronine (T3) and free T3 were determined and free T4 indices (total T4 x T3 uptake; total T4/thyroxine binding capacity (TBC); total T4/TBG) were calculated. Free T4 was measured simultaneously with a one-step T4-analog enzyme-linked immunosorbent assay (ELISA), a labeled T4 antibody radioimmunoassay (RIA), and a two-step microparticle enzyme immunoassay (MEIA). Estrogen-dependent differences were found in all investigated parameters; however, they remained in the reference interval for TSH, total T4 x T3 uptake, total T4/TBC,free T3 and free T4 MEIA. It was concluded that simultaneous estimations of free T4 and free T3 should follow a primary TSH measurement. The necessity of a distinct reference range has emerged for free thyroid hormones in midterm and late pregnancy as well as in the use of oral contraceptives, especially in iodine-deficient areas.

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.

A method for detection of doxorubicin-induced cardiotoxicity: Flow-mediated vasodilation of the brachial artery.

BACKGROUND: The cardiotoxicity of anthracyclin antibiotics such as doxorubicin (DOX) is a serious side effect in cancer therapy. Reduced antioxidant capacity may be a factor responsible for DOX-induced oxidative damage to the heart. The endothelial dysfunction that results from excessive free radicals can be easily detected by flow-mediated vasodilation (FMD) of the brachial artery. OBJECTIVES: To determine the change in endothelial function after intravenous DOX bolus; to determine the change in biochemical parameters, reflecting increased activity of free radicals or decreased endogenous antioxidant capacity, after intravenous DOX bolus; and to determine the relation between alteration of en-dothelial function after the first DOX bolus and the change in left ventricular function during follow-up. PATIENTS AND METHODS: Twenty-two patients, with either non-Hodgkin's lymphoma (18 patients) or Hodgkin's disease (four patients) were enrolled for the study (seven women and 15 men), with a mean age of 37.3+/-13.7 years. Each patient was treated with a DOX-containing regimen. The actual mean dose of DOX was 33+/-12 mg/m(2). FMD was evaluated before and after DOX administration. In nine patients more frequent measures were taken to determine the time course of change in FMD after DOX administration. FMD was measured 6, 12, 24 and 48 h after DOX. On average each patient was followed up for 18.6+/-8.1 months following the first DOX administration. The mean cumulative DOX dose was 229+/-112 mg/m(2) by the end of the follow-up period. Left ventricular ejection fraction was determined regularly during and at the end of the study. RESULTS: FMD was normal (more than 5%) at baseline in each patient but decreased significantly after DOX bolus (9.9+/-4.4% versus 6.1+/-4.6%, P<0.02). Marked individual differences were found in FMD changes after DOX. Patients who had a more than 5% decrease in FMD after DOX bolus were pretreated with 1000 mg of vitamin C intravenously, just before the next intravenous bolus of DOX was given. The decrease in FMD was prevented. Stepwise multiple regression analysis showed that the decrease in left ventricular ejection fraction during follow-up significantly and independently correlated with the cumulative DOX dose and the value of FMD alteration after the first DOX bolus administration. CONCLUSIONS: FMD in the brachial artery was significantly impaired after the first DOX bolus. The marked individual differences suggest different antioxidant capacities in these patients. The results suggest that alterations in FMD after DOX allows for detection of patients with insufficient antioxidant capacity and patients at a higher risk of DOX-induced cardiotoxicity.

The role of atrial natriuretic peptide in alcohol withdrawal: a peripheral indicator and central modulator?

Changes in fluid and electrolyte homeostasis may accompany and are likely to modify the clinical symptoms of alcohol-withdrawal reactions. It was of obvious theoretical and practical interest therefore to investigate the changes in the secretion of hormones, which regulate the fluid and electrolyte homeostasis (atrial natriuretic peptide, aldosterone and plasma renin activity) during alcohol withdrawal in chronic alcoholic patients. In a phase of severe withdrawal, there were increased plasma renin activity and aldosterone levels observed. In a phase of partial recovery, on the other hand, the elevated plasma renin activity and aldosterone levels were back to the normal range. In 60% of the patients, delirium tremens was gradually developing during the observation period. In these patients, an elevated level of atrial natriuretic peptide was observed at the time of hospital admission, i.e. days before the actual onset of delirium tremens. It is concluded that the disturbed volume homeostasis and the consequently altered plasma atrial natriuretic peptide secretion might be associated with, and therefore used as an indicator of the onset of delirium tremens. To study the role of central nervous atrial natriuretic peptide, mice were rendered tolerant to and dependent on alcohol with an alcohol-liquid diet for 14 days. Five hours after withdrawal from alcohol, withdrawal hyperexcitability symptoms were analyzed. Intracerebroventricular (i.c.v.) injection of atrial natriuretic peptide attenuated, whereas that of an antiserum against atrial natriuretic peptide intensified the severity of handling-induced convulsions. N-methyl-D-aspartate induced behavioral seizures in a dose-dependent manner, whose effect was more intensive during the alcohol-withdrawal period than in alcohol-naive animals. I.c.v. injections of atrial natriuretic peptide dose-dependently inhibited, whereas that of antiserum against atrial natriuretic peptide potentiated the seizure-inducing effect of N-methyl-D-aspartate in alcohol-dependent mice. Although tentatively, it is concluded that peripheral secretion of atrial natriuretic peptide may be an indicator, whereas central nervous atrial natriuretic peptide a neuropeptide modulator of alcohol-withdrawal symptomatology.

Atrial natriuretic peptide modulates N-methyl-D-aspartate-induced hyperexcitability in ethanol-dependent mice.

The role of central nervous atrial natriuretic peptide was investigated for behavioral hyperexcitability in alcohol-dependent mice. Mice were made tolerant to and dependent on ethanol with an ethanol-liquid diet for 14 days. Five hours after withdrawal from ethanol, withdrawal symptoms were analyzed by scoring handling-induced convulsions. N-methyl-D-aspartate (NMDA) induced behavioral seizures in a dose-dependent manner, an effect which was more intensive during the ethanol withdrawal period than in alcohol-naive animals. Intracerebroventricular (i.c.v.) injections of alpha-atrial natriuretic peptide (atrial natriuretic peptide) dose-dependently inhibited, whereas injection of an antiserum against atrial natriuretic peptide potentiated, the seizure-inducing effect of NMDA in ethanol-dependent mice. The main conclusion is that central nervous atrial natriuretic peptide plays a modulatory role in behavioral hyperexcitability during alcohol withdrawal.

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 blocks the development of heroin-fentanyl cross-tolerance in mice.

The development of cross-tolerance to an analgesic effect was observed between two mu-receptor agonists, heroin and fentanyl. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to fentanyl on day 5. The fentanyl dose-response line shifted to the right, and was considered to be a sign of the development of cross-tolerance. Peripheral treatment with oxytocin did not block the development of heroin-fentanyl cross-tolerance. However, intracerebroventricular administration of oxytocin blocked the development of tolerance, causing a leftward shift in the dose-response curve and supporting the assumption that oxytocin blocks the development of heroin-fentanyl cross-tolerance via CNS mechanisms.

Barrel rotation induced by central arginine8-vasopressin treatment: involvement of neurohypophyseal peptide receptors.

Two series of experiments were done to investigate the mechanism underlying arginine8-vasopressin (AVP)-induced barrel rotation in rats. In the first series, the effect of intracerebroventricular (ICV) administration of various neurohypophyseal hormone antagonists on AVP-induced barrel rotation was studied. The more vasopressin was given, the more the rats exhibited barrel rotation. ICV pretreatment with a V1 vasopressin receptor antagonist, d(CH2)5[Tyr(Me)2]AVP, prevented barrel rotation, while similar treatment with a V2-antagonist, d(CH2)5[dIle2Ile4]AVP, did not affect vasopressin-induced barrel rotation. However, Des-Gly,NH2d(CH2)5[Tyr)Me2)Thr4Orn8]-vasotocin, a specific oxytocin antagonist, potentiated the effect of AVP on barrel rotation. The second experiment was performed in rats equipped with a telemetry system to measure heart rate (HR), core temperature (CT), and gross locomotor activity. Also, in this experiment the incidence of AVP-induced barrel rotation was dose-dependent, as was the number of rats that died. Barrel rotation was accompanied by a significant decrease in CT and HR, while rats that did not develop hypothermia did not show barrel rotation. These results suggest that a V1 receptor is involved in barrel rotation. Since AVP-induced hypothermia is also mediated by a V1 receptor, it is postulated that hypothermia is a prerequisite for barrel rotation to occur. Further experiments are needed to substantiate this hypothesis.

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.