Neuropeptide-dopamine interactions. II. Cyclo (His-Pro) augmentation of amphetamine- but not apomorphine-induced stereotypic behavior

Histidyl-proline diketopiperazine (cyclo [His-Pro]) not only exists in the basal ganglia of rodents, monkeys, and humans, but also exhibits a variety of biologic activities, some of which appear to be mediated via dopaminergic mechanisms. We investigated the potential modulation by cyclo (His-Pro) of amphetamine- and apomorphine-induced stereotypic behavior, a behavior that is associated with the activation of postsynaptic dopamine receptor. Administration of amphetamine to rats resulted in a dose-dependent increase in stereotypic behavior that was further augmented if animals were pretreated with cyclo (His-Pro). Although apomorphine also led to a dose-related progression in the stereotypic behavior, the apomorphine effects were not modified by cyclo (His-Pro) pretreatment. We conclude that cyclo (His-Pro) either acts indirectly at the presynaptic dopamine site or modulates other neurotransmitters to potentiate actions of amphetamine.     

Neuropeptide-dopamine interactions. I. Dopaminergic mechanisms in cyclo(His-Pro)-mediated hypothermia in rats

Administration of cyclo(His-Pro) to rats produces a dose-dependent hypothermia that is attenuated by dopaminergic antagonists. Chronic treatment with cyclo(His-Pro) potentiates hypothermia induced by apomorphine. These results suggest that cyclo(His-Pro) acts via a dopaminergic mechanism to modulate body temperature.     

Effects of continuous exposure to light on behavioral dopaminergic supersensitivity.

BACKGROUND: This study examines the effects of long-term continuous exposure to light on dopaminergic supersensitivity induced by repeated treatment with haloperidol in rats. METHODS: Spontaneous general activity in an open-field (SGA) and stereotyped behavior induced by apomorphine (SB-APO) or amphetamine (SB-AMP) were used as experimental parameters. Rats were allocated to four groups in each experiment: saline-treated animals kept under a 12-hour light/dark cycle (LD) or 24-hour light/light cycle (LL), and 2 mg/kg haloperidol-treated animals kept under the above cycles. Plasma corticosterone concentration was also measured by radioimmunoassay in saline-treated rats kept under a LD or LL cycle. RESULTS: All the behavioral parameters used showed the development of central dopaminergic supersensitivity in rats kept under both cycles. Continuous exposure to light enhanced SGA and SB-AMP in both saline- and haloperidol-treated rats, but did not modify SB-APO. Animals kept under the LL cycle presented an increased plasma corticosterone concentration. CONCLUSIONS: Our results suggest that continuous exposure to light leads to an increase in dopaminergic function in both normal and "supersensitive" rats. This effect seems to be mediated by a presynaptic mechanism possibly involving corticosterone actions.     

Cyclo(His-Pro) and the development of tolerance to the hypothermic effect of ethanol

Acute intraperitoneal administration of ethanol to rats causes a dose-dependent transient hypothermia. On repeated exposure, however, rats develop tolerance to hypothermic effects of ethanol. Cyclo(His-Pro), an endogenous brain peptide, modifies both acute and chronic themomodulatory effects of alcohol. For example, a) acute pretreatment of rats with increasing amounts of cyclo(His-Pro) produces a progressive decrease in ethanol hypothermia, and b) chronic cyclo(His-Pro) administration augments the development of tolerance to hypothermic effects of alcohol. While the mechanism of cyclo(His-Pro) action is not clear, these data are interpreted to suggest that this peptide may play important roles in ethanol intoxication, preference, tolerance, and/or addiction.     

Effects of two diketopiperazines, cyclo (His-Pro) and Cyclo (Asp-Phe), on striatal dopamine: A microdialysis study

The effects of two diketopiperazines, Cyclo (His-Pro) (CHP) and Cyclo (Asp-Phe) (CAP), on striatal extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were examined using in vivo microdialysis in anaesthetized rats. Treatment with neither CHP (0.1–10 mg/kg IP and 0.3 mg/kg IV) nor CAP (0.1–10 mg/kg IP and 10 mg/kg PO) significantly changed the efflux of DA, DOPAC, HVA, or 5-HIAA when compared to the effects of treatment with saline. Our results suggest that systemic administration of CHP or CAP alone does not modify striatal dopaminergic neurotransmission. The previous findings of enhanced DA release by systemic administration of thyrotropin releasing hormone (TRH) are probably not explained by formation of CHP from TRH.     

Attitudes towards neuroleptic treatment: reliability and validity of the attitudes towards neuroleptic treatment (ANT) questionnaire

Non-compliance problems may rise to 50% among patients undergoing neuroleptic treatment. There are no direct measures available to predict compliance, if previous non-compliance is not taken into account. Attitudes towards neuroleptic treatment and insight into psychotic symptoms may vary during the course of the treatment process. It would be relevant to evaluate these items before taking any clinical action and later reassess the degree of change. The instrument thus far available has been the Drug Attitude Inventory. It has limitations for use with first-episode-patients and their follow-up. Its statements are dichotomous, which makes it difficult to determine the variation of attitudes e.g. during maintenance treatment, and most of the items concentrate on the subjective state of the patient, leaving attitudes as a minority in the scale.In this study, we report the new Attitudes towards Neuroleptic Treatment (ANT) questionnaire for the quantitative assessment of attitudes. We developed 10 statements for attitudes and two items for insight in the Visual Analogue Scale form (0-100 points). These were compared with the Drug Attitude Inventory 10 Questionnaire (DAI-10) (Hogan, T. P., Awad, A.G., Eastwood, R., 1983. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol. Med. 13, 177-183.) among 106 subjects receiving neuroleptic medication.The 12 Visual Analogue Scales showed a high inter-item consistency and fair test-retest validity. The results were in accordance with the DAI-10. The scales comprised three factors: general attitudes, subjective feeling and expectations and insight.Attitudes towards neuroleptic treatment and insight into psychotic symptoms are different dimensions and can be measured quantitatively. The Attitudes towards Neuroleptic Treatment scale is useful in assessing the state of attitudes before starting medication and for follow-up among patients receiving neuroleptic medication.     

The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity — Inhibition of apomorphine-induced climbing

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.     

Effects of TRH, cyclo-(His-Pro) and (3-Me-His)TRH on identified septohippocampal neurons in the rat

Neurons located in the medial septum-nucleus of the diagonal band of Broca (vertical limb) and antidromically activated by electrical stimulation of the fimbria were recorded in urethane anesthetized rats. Forty-three percent of these septohippocampal neurons (SHNs) were excited by the iontophoretic application of thyrotropin-releasing hormone (TRH). Rhythmically bursting SHNs were more often excited (63%) by TRH than the non-bursting SHNs (35%). The majority of the TRH-sensitive SHNs could also be excited by cholinergic agonists. TRH-induced excitations were not abolished by the simultaneous application of atropine. Potentiation by TRH of acetylcholine, carbachol or glutamate-induced excitations of SHNs were rarely observed. Cyclo (His-Pro) and (3-Me-His²)-TRH were observed to have similar, although less dramatic, effects. These results demonstrate that the SHNs, which are the neurons of origin of the septohippocampal pathway, are readily excited by TRH.     

Comparison of chlormethiazole (Heminevrin) and chlordiazepoxide (Librium) in the treatment of acute alcohol withdrawal

This study was carried out to compare the efficacy of chlormethiazole and chlordiazepoxide in the treatment of acute alcohol withdrawal syndrome in 40 patients. Repeated biochemical, clinical, and psychophysiological measurements were obtained in a randomized, double-blind design in which one group of patients received chlormethiazole and a second group received chlordiazepoxide over a period of 7 days. Analysis indicated both drugs to be of equivalent potency and were equally well tolerated by patients. The more severe aspects of withdrawal were brought under control within the first 4 days of treatment. However, even at 7 days, there still persisted some symptoms attributable to the withdrawal from alcohol.     

Effect of neuroleptic treatment on involuntary movements and motor performances in Huntington''s disease.

Eighteen patients with Huntington's chorea were examined before and after neuroleptic treatment (haloperidol, pimozide, tiapride) to study the effect of such treatment on hyperkinesia and motor performance. Pimozide and haloperidol improved hyperkinesia; none of the drugs significantly affected motor performance. No correlation was found between the severity of hyperkinesia and motor performance scores, or between hyperkinesia and intelligence score, before and after therapy.     

The effects of acute levodopa withdrawal on motor performance and dopaminergic receptor sensitivity in patients with Parkinson''s disease.

The effects of acute levodopa withdrawal were studied in nine patients with levodopa related on-off oscillations. One patient withdrew from the study due to off period confusion and hallucinations. A marked deterioration in motor disability occurred in all patients following overnight withdrawal of levodopa and a further mild delayed deterioration was present over a mean withdrawal period of 44 hours. Patients with more severe disease were able to tolerate levodopa withdrawal for a shorter period of time than those with milder disease severity. The minimum therapeutic dose of subcutaneous apomorphine needed to produce a similar improvement in patients' mobility, before and after several days of drug withdrawal, did not differ, thus providing no clinical evidence for alterations in striatal dopamine receptor sensitivity after acute levodopa withdrawal.     

Young Investigators in Biological child and adolescent psychiatry (YIBcap)--insights after one year of networking

Biological determinants of mental illness in children and adolescents, such as genetic predisposition, gene x environment interactions, structural or functional brain abnormalities, and endocrine dysfunction are poorly understood. We report here on the foundation of and first achievements by a network of young professionals in the area of child and adolescent psychiatry that fosters biological research. YIBcap--Young Investigators in Biological child and adolescent psychiatry was founded in December 2005 and currently comprises 33 scientists from more than ten different German university hospitals, and seven internationally renowned senior advisors. Peer-to-peer support is provided by means of web-based communication software, regular meetings, workshops on research methods and fundraising, special symposia at scientific conferences, research collaborations, and career coaching. First multi-centre studies are planned. Increasingly positive results within the first year let us hope to be able to establish a forum that can contribute to improving scientific output and to encouraging young investigators in child and adolescent psychiatry.     

用药态度对精神分裂症患者治疗依从性和症状影响的1年随访研究

目的探讨精神分裂症整合治疗(心理社会干预合并药物治疗)的疗效,分析不同干预方式中用药态度对治疗依从性和精神症状的影响,探讨整合治疗疗效机制。方法 2012年至2015年间纳入170例精神分裂症患者,随机分为整合治疗组(86例)和常规药物治疗组(84例),整合治疗组给予常规药物治疗合并心理社会干预,常规药物治疗组仅给予常规药物治疗,入组3个月、6个月和12个月随访,分别采用用药态度量表(drug attitude inventory,DAI)、自知力问卷(self-awareness inventor,SAI)—治疗依从性量表、阳性和阴性症状量表(positive and negative syndrome scale,PANSS)评估用药态度、治疗依从性、临床精神病性症状。结果随访12月时,整合治疗组PANSS阳性症状和一般精神症状量表减分、DAI和SAI治疗依从性增分均高于药物治疗组(均P0.05),整合治疗组药物依从率高于药物治疗组(72.1%vs.45.2%,P0.01)。常规药物治疗组PANSS总分减分与DAI的增分呈正关联(β=0.31,P=0.02),且治疗依从性的改善中介二者之间的关系(β=0.18,P=0.18);而整合治疗组患者中,未发现DAI增分与PANSS总分减分之间的相关关系(P0.05),SAI—治疗依从性的增分与PANSS量表的阳性症状量表减分(r=0.31,P=0.01)和一般精神症状量表的减分(r=0.36,P0.01)呈正相关。结论本研究表明常规药物治疗组中,用药态度通过提高治疗依从性来改善精神性症状,整合治疗症状改善与治疗依从性改善有关,与用药态度可能无关。     

The effect of withdrawal of dopaminergic medication on simple and choice reaction time and the use of advance information in Parkinson''s disease.

Eight patients with Parkinson's disease performed simple reaction time (SRT), uncued, partially and fully cued four choice (CRT) tasks. They were tested on two occasions; on their normal dose of dopaminergic medication and following withdrawal of such medication for an average of 14.4 hours. Disability as rated on the Webster scale was greater in the drug reduced state. Although RTs were generally slower when tested in the drug reduced state than when on medication, few differences emerged. Withdrawal of dopaminergic medication had no effect on unwarned SRT and unwarned and uncued CRT performance. Both on and off medication, the patients benefited from a warning signal presented before the imperative stimulus. In both medication states, the speeding up of RT was greatest with a warning signal presented 200 ms before S2. When the imperative stimulus was unwarned, the temporal predictability of its occurrence speeded RT more when on medication than when off. Advance movement parameter information was used by patients to pre-programme responses both on and off medication. In both medication states, the fully cued CRT was the same as SRT only with the 3200 ms S1-S2 interval. Medication state had no effect on movement time or the number of errors. It is suggested that slowness in motor readiness and motor programming may not be specific to striatal dopamine deficiency but rather a nonspecific concomitant of brain damage.     

Influence of acute, subchronic and chronic treatment with neuroleptic (haloperidol) on enkephalins and their precursors in the striatum of rat brain

We examined the effects of chronic, subchronic and acute treatment with haloperidol on the ME, the MERGL and enkephalin precursor concentrations in rat brain. The changes affected primarily the striatum. The ME content was greatly increased by the treatment, the precursor level was decreased by the haloperidol treatment. The specific mRNA for proenkephalin A increased. For these reasons, we conclude that the effect of haloperidol increase both the biosynthesis and the processing of precursors of enkephalins in the striatum.     

Effects of chronic lithium treatment on dopamine receptors in the rat corpus striatum. I. Locomotor activity and behavioral supersensitivity

Spontaneous locomotor activity and dopaminergic responsivity were assessed after long-term dietary treatment with the anti-manic drug lithium. Chronic dietary Li administration was not accompanied by the toxicities often reported with other modes of administration. In addition, the diet reliably yields serum and brain Li levels in the prophylactic range for manic-depressive illness. After 4 weeks exposure to Li, spontaneous locomotor activity was reduced as compared to subjects on the control diet whether or not food intake was restricted. The depression of locomotor activity following an injection of the dopamine agonist, apomorphine, was less severe in animals that ingested Li compared to those with free access to the control diet. Finally, in confirmation of the findings of Pert et al., chronic Li administration led to a partial attenuation of apomorphine-evoked stereotyped behaviors in subjects rendered supersensitive to the drug by daily injections of haloperidol (HAL) for 3 weeks. The findings suggest that the commonly reported suppressant action of Li on spontaneous behavior is not attributable to overt toxicity or to diminished growth rate. Similarly, these health factors do not account for the ability of chronic Li treatment to suppress the behavioral manifestation of dopaminergic supersensitivity associated with long-term HAL exposure.     

Effects of withdrawal from long-term diphenylhydantoin treatment on audiogenic and maximal electroshock-induced seizures in rats

Rats withdrawal from long-term diphenylhydantoin treatment (DPH) were tested for their sensibility to convulsant stimuli. Animals were more sensitive to convulsions elicited by maximal electroshock and sound, respectively, at 48 and 72 h after drug removal. These results suggest that long-term DPH treatment might develop a central nervous system supersensitivity state.     

Effects of clonidine on opiate withdrawal symptoms. Results - biochemical mechanisms (author's transl)

Clonidine was administered to nineteen patients in an inpatient setting after abrupt discontinuation of chronic opiate addiction (morphine, héroin, dextromoramide). Clonidine produces a decrease sometimes very rapid in opiate withdrawal signs but does not suppress the whole affects associated with. These data support the hypothesis that clonidine has antiwithdrawal effect by replacing opiate-mediated inhibition with alpha 2 mediated inhibition of brain noradrenergic activity.     

The continuous performance test, identical pairs version (CPT-IP): III. Brain functioning during performance of numbers and shapes subtasks

The numbers and shapes subtasks of the CPT-IP are difficulty-matched measures of independent aspects of attentional skill that have been used to differentiate the impairments of schizophrenics and major depressives. Previous studies suggest that they tap into lateralized aspects of attentional performance. To investigate this hypothesis, seven subjects free of psychiatric illness were presented with these CPT-IP subtasks during a SPECT procedure. Subtasks--4-digit number strings and nonsense shapes--were administered on successive weeks, in counterbalanced order, simultaneous with administration of 10 mCi 99mTc HMPAO. Scanning took place after 10 min of test performance. Quantitative data were extracted from each scan via a semi-automated region of interest (ROI) analysis which defined eight cortical and four subcortical ROI on each of five transverse slices. Data for each ROI were normalized and compared between task conditions. Results indicate that the two tasks produce different patterns of functioning within two general areas of the brain. First, during Numbers task performance, left-sided activity was increased on multiple transverse slices in an anterior subcortical region that incorporated the anterior cingulate, frontal white matter, and much of the basal ganglia. Left-sided activity was also increased in a posterior subcortical region including the left side of the thalamus. Lateralization of function, defined as relative activity on the left and right sides, changed within these regions across tasks, but primarily as a result of the contribution of increased or decreased activity on the left side alone. Second, relative perfusion to occipital regions, bilaterally, was more extensive during the Shapes task. These results suggest that subtle alterations in stimulus parameters can affect activation patterns in regions that are critically associated with task performance. They also suggest that the Numbers task may provide more robust activation of anterior attention systems, that may better discriminate the functioning of these systems in normal and psychopathological groups.