Selective effects on prefrontal cortex serotonin by dopamine D3 receptor agonism: interaction with low-dose haloperidol

1. Negative symptoms of schizophrenia are characterized by amotivation, anhedonia and anergia. These aspects of the symptom profile can be modeled by D3 agonism in animal behavioral models. 2. Serotonergic systems have been implicated in pathophysiologic substrates for this disorder; most notably, in deficit state schizophrenia, as newer 'atypical' neuroleptics which are especially efficacious for treating this syndrome antagonize central 5-HT2 receptors. 3. FC regions may also be important in chronic negative symptoms, as hypofrontality has been associated with these schizophrenic features. 4. The author examined effects of a behaviorally-active dose of the D3 agonist, 7OH, on 5-HT metabolism in FC, and the ability of a low-dose neuroleptic treatment to antagonize this biochemical effect. 5. Acute administration of 7OH induced a selective decrease of 5-HT turnover in the FC without affecting metabolism of this transmitter in more subcortical DA regions. 6. Hal, which has previously been demonstrated to antagonize electrophysiologic, biochemical and behavioral effects of 7OH, was without effect on agonist-induced decreases in 5-HT turnover. 7. The biochemical association between D3 agonism and reductions of FC 5-HT may be significant for pathophysiologic mechanisms of negative symptoms, and antagonism of this effect may differ for neuroleptics with varying efficacy in alleviating these symptoms.     

Brain dopamine and seizure susceptibility in mice

In electroshock test apomorphine appeared without effect, D, L-amphetamine and L-DOPA (in a high dose) elevated the convulsive threshold, while amantadine decreased it. Among investigated dopamine (DA) receptor blockers spiperone, pimozide and fluphenazine lowered the threshold, haloperidol being without effect. The convulsive threshold elevated by L-DOPA was not affected by neuroleptics and phentolamine but on the other hand DA receptor blockers and phentolamine anatagonized the effect of D, L-amphetamine. The effect of amantadine was not influenced by neuroleptics. In pentylenetetrazol (PTZ) test only amantadine and L-DOPA (in high doses) affected the threshold, increasing seizure susceptibility; the above effect was not abolished by pimozide. Our results seem to indicate that the activity of brain DA system seems not to be involved directly in the susceptibility to electrogenic or PTZ-induced seizures in mice.     

B-HT 920, a dopamine D2 agonist, in the treatment of negative symptoms of chronic schizophrenia

A prospective, nonblind 8-week trial of talipexole dihydrochloride (B-HT 920), a dopamine D2 agonist, was conducted in 15 schizophrenic patients with predominantly negative symptoms. B-HT 920 was initiated at 0.15 mg/day and then adjusted at 0.15-2.4 mg/day on the basis of clinical response and side effects. Dosage of concurrent neuroleptics was fixed at least 3 weeks prior to the trial and was unchanged throughout the study period. In addition to clinical assessment, levels of plasma homovanillic acid (pHVA), a potential index of central dopamine turnover, were measured. There was a small but significant (p < 0.01, Wilcoxon test) reduction in total scores of the Scale for the Assessment of Negative Symptoms or in a cluster score of three negative items (Emotional Withdrawal, Blunted Affect, and Psychomotor Retardation) of the Brief Psychiatric Rating Scale (BPRS). No change was observed in cluster scores of positive items of BPRS. There was a weak negative correlation between pHVA levels and the cluster scores of negative items of BPRS both at weeks 0 and 8 of the trial. The clinical results suggest that activation of D2 receptors was related to partial amelioration of the negative symptoms. The clinical and biochemical findings are consistent with a hypothesis that decreased dopaminergic activity may be related to the etiology of negative symptoms of schizophrenia.     

Feeding-related dopamine in the amygdala of freely moving rats

Extracellular levels of dopamine (DA) were measured in the central part (the central and intercalated nuclei) of the amygdala (AMY) using microdialysis at 20 min intervals before, during and after 1 h of feeding in 12 h food-deprived rats. The results were compared with the effects of peripheral injections of glucose or a low dose (200 mU) of insulin in non-deprived animals. Feeding caused a 130% increase in extracellular DA. Glucose resulted in an increase in DA levels (+86%). In contrast, insulin caused a decrease of DA (-50%) and metabolites. The results show that natural feeding is associated with an increase in DA turnover in the amygdala, and that peripheral glucose and insulin can affect DA metabolism in the amygdala presumably in response to changes in glucose utilization.     

The consequences of depressive affect on functioning in relation to Cluster B personality disorder features.

The authors examined the effects of depressed affect (DA) on functioning measured by behavioral tasks pertaining to abstract reasoning, social functioning, and delay of gratification in relation to Cluster B personality disorder features (PDs) in a clinical sample. Individuals were randomly assigned to either a DA induction or control condition. Consistent with clinical conceptualizations, the authors expected that Cluster B PD symptoms would be related to maladaptive responding (e.g., poorer delay of gratification) when experiencing DA. As hypothesized, many of the relations between the Cluster B PDs and functioning were moderated by DA (e.g., borderline PD was negatively related to abstract reasoning, but only in the DA condition). However, many of the Cluster B PDs symptom counts were related to more adaptive responses in the DA condition (e.g., less aggressive social functioning, better delay of gratification). The authors speculate that individuals with Cluster B PDs may be more likely to respond maladaptively to alternative negative mood states, such as anger and fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine and the structure of personality: Relation of agonist-induced dopamine activity to positive emotionality.

Modern trait theories of personality include a dimension reflecting positive emotionality (PE) based on sensitivity to signals of incentive-reward. In animals, responsivity within an emotional system analog of PE is dependent on brain dopamine (DA) activity. To determine whether human PE trait levels are also associated with central DA, effects of a specific DA D? receptor agonist were assessed in 23 Ss who were widely distributed along the trait dimension of PE. The degree of agonist-induced reactivity in 2 distinct central DA indices was strongly and specifically associated with trait levels of PE, but not with other personality traits. The results suggest that the trait structure of personality may be related to individual differences in brain DA functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dual dopamine/serotonin releasers: Potential treatment agents for stimulant addiction.

"Agonist therapy" for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the "antistimulant" role of 5-HT2C receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of ketamine anaesthesia on the content of monoamines and their metabolites in the rat brain

The effects of ketamine anaesthesia (100 mg/kg i.p.) on the content of brain 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (5HIAA), noradrenaline (NA), dopamine (DA) and homovanillic acid (HVA) were studied in male Wistar rats. Fifteen min after ketamine injection, when the rats were deeply anaesthetized, the 5HT content in many brain regions tended to be increased. An opposite tendency was found in the brain 5HIAA content. In rats treated with probenecid, which markedly lengthened ketamine anaesthesia, the accumulation of 5HIAA was significantly reduced by ketamine. In addition to ketamine anaesthesia, probenecid was found to lengthen thiopental anaesthesia. One hour after the ketamine administration, when the rats were no longer anaesthetized but were excited, the brain NA concentration was increased by 17% (P less than 0.02). The brain DA content was unchanged, but at 15 min and 1 hour after ketamine administration the striatal HVA content was increased by about 55% (P less than 0.05), suggesting an increased turnover of DA. The results suggest that during recovery from ketamine anaesthesia the increased NA content and the increased DA turnover may be associated with the postanaesthetic excitement of the rat, whereas the decreasamine anaesthesia.     

Changes in catecholamine levels and turnover rates in hypothalamic, vocal control, and auditory nuclei in male zebra finches during development

The catecholamines norepinephrine (NE) and dopamine (DA) have been implicated in the sexual differentiation of brain and behavior and in species-specific learning in several species. To determine if these neurotransmitters might be involved in sexual differentiation of the vocal control system and song learning in male zebra finches, NE and DA levels and turnover rates were quantified in 10 behaviorally relevant brain nuclei [6 vocal control (VCN), 2 auditory (AN), and 2 hypothalamic (HN)] at four critical points during sexual differentiation of the VCN and the period of song learning, 25, 35, 55, and 90 days of age. Some birds were pretreated with alpha-methyl-para-tyrosine (alphaMPT) to allow estimation of NE and DA turnover rates. NE and DA levels in microdissected nuclei were quantified using high-performance liquid chromatography with electrochemical detection. AlphaMPT treatment suppressed catecholamine synthesis just as effectively in juveniles as it does in adults and proved an effective method for estimating NE and DA turnover rates. Patterns of NE and DA function in most VCN and AN over development were quite different from those in HN in which NE and DA function changed gradually and showed no striking peaks. NE turnover rates changed significantly over development in all six VCN [nucleus interfacialis (Nlf), high vocal center (HVC), nucleus robustus of the archistriatum (RA), dorsomedial portion of the intercollicular nucleus (DM), Area X of the parolfactory lobe, and lateral portion of the magnocellular nucleus of the anterior neostriatum (IMAN)]; one AN [nucleus mesencephalicus lateralis pars dorsalis (MLd)], and one HN [preopticus anterior (POA)]. NE levels changed significantly in two VCN (Nlf and Area X). In Nlf, RA, Area X, IMAN, and MLd, NE levels and/or turnover rates showed a striking peak at day 25, which was not seen in HN. Both DA levels and turnover rates changed profoundly over development in 5 of 6 VCN (Nlf, RA, DM, Area X, and IMAN) and both AN (MLd and Field L). These nuclei showed striking peaks in DA levels and turnover rates, primarily on day 35 and/or 55, which then declined profoundly by day 90. This contrasted with the minimal change in DA turnover rates seen in one HN (POA) and the sixth VCN, HVC. In several VCN and AN, NE and DA levels and turnover rates during development reached levels never seen in adult males. Previous research has shown that catecholamine function is heightened in VCN during development compared to surrounding tissues. Our data demonstrate that NE and DA function during development shows pronounced peaks in most VCN not seen in HN. This is interesting because both VCN and HN are hormone sensitive, and both show hormone-modulated NE and DA function in adult males. The timing of these peaks suggests that increased catecholaminergic function may be involved in sexual differentiation of the VCN and song learning in finches.     

Corticosteroids and avascular necrosis of the femoral head in childhood

The time-course of psychopathological symptoms, of extrapyramidal side effects, and of changes in cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were simultaneously studied during Haloperidol treatment of 14 psychotic patients with chronic organic brain damage. After 15 days of treatment significant antipsychotic effect was found, while Parkinsonism scores in clinical and experimental tests increased only slightly. CSF concentration of HVA increased significantly by 150% compared to the baseline value (p less than 0.05) and 5-HIAA remained unchanged. No correlation was found between the clinical and biochemical variables studied. The comparison of these results with those obtained in patients without brain damage suggests that different psychopathological and extrapyramidal responses to neuroleptics are not strictly associated with specific HVA changes in CSF.     

Central dopamine turnover in guinea pig pups during separation from their mothers in a novel environment.

Guinea pig pups that were separated from their mothers and placed into a novel environment for 90 min showed an increase in dopamine (DA) turnover (ratio of metabolites to DA) in the septum compared with undisturbed baseline controls. Pups placed into the novel environment with their mothers exhibited an intermediate level of DA turnover. After 24 hr of separation in the novel environment, pups' DA turnover in the septum had returned to the baseline level. DA turnover in the caudate nucleus was unaffected by these procedures. Also, turnover in both septum and caudate nucleus when pups were not separated was positively correlated with the number of vocalizations emitted during 30 min of separation. These results closely parallel findings in separated monkeys and indicate that the guinea pig represents a useful rodent model for studying such effects. That elevated DA turnover during separation occurred in the septum suggests involvement of the mesolimbic system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopaminergic sensitization: implications for the pathogenesis of schizophrenia

1. Which transmitters are primarily or secondarily involved in the pathogenesis of schizophrenia has been extensively studied during the last years. This review concentrates on the two systems, that most constantly have been found dysfunctioning in patients; that are the dopaminergic and glutamatergic systems. 2. Numerous neuropathological defects have been found in schizophrenia, but it is as yet unknown which changes are causative and which reflect maladaptive reactions. 3. All findings, however, involve the cortico-striato-thalamo-cortical circuits, which are central for attention and information processing. 4. The article focuses on the consequence of transmitter dysfunction for perception and for the ability of the individual to adapt to a constantly changing environment. Both clinical and experimental studies point to a primary/early cortical defect involving the glutamatergic system, and to a later developed intermittent hyperactivity of the dopaminergic system superimposed on a basal hypodopaminergic state. 5. The authors have previously demonstrated, how it is possible to potentiate mesolimbic dopaminergic activity by intermittent electrical stimulations of the cells in the ventral tegmental area, and that influence on the central mesolimbic dopamine cells is essential for the strengthened neuroplastic response. A changed neuroplastic response to environmental stimulation due to dopaminergic sensitization can explain how an episodic, subcortical hyperactivity can act on a basic glutamatergic and dopaminergic hypofunction to produce psychotic symptoms. Based on our own and others clinical and experimental findings, the "filter" hypothesis for schizophrenia and the state-dependence of schizophrenic symptoms, the authors present a hypothesis for spontaneous mesolimbic dopaminergic sensitization and progressive evolution of psychosis.     

Acute dystonic reaction with low-dose pimozide

It is essential to recognize individual susceptibility to neuroleptic-induced side effects for treatment guidelines. This paper reports on a 6.9-year-old autistic male who developed repeated episodes of acute dystonic reactions associated with pimozide administration at the doses of 0.096 mg/kg/day and 0.032 mg/kg/day and 32 hours following pimozide withdrawal, as well as during subsequent thioridazine administration. It draws the clinician's attention to unusual susceptibility to extrapyramidal side effects and suggests that if a child shows this type of susceptibility to one neuroleptic, he/she may react similarly to other neuroleptics as well.     

Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat.

Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats.

Opiate withdrawal has been correlated with decreased extracellular dopamine (DA) levels in the nucleus accumbens (NAC) of morphine-dependent rats. The authors tested the hypothesis that DA transmission plays a critical role in the induction of motivational and somatic withdrawal symptoms. First, the authors used a 6-hydroxydopamine-induced lesion of the NAC to chronically disrupt mesolimbic DA transmission. Second, global DA neurotransmission was acutely stimulated by the nonselective DA agonist (apomorphine) or inhibited by nonselective DA antagonists (droperidol or flupentixol). Morphine-dependent rats bearing 6-hydroxydopamine-induced lesions displayed naloxone-precipitated motivational and somatic withdrawal symptoms similar to those of sham-lesioned rats. Administration of apomorphine did not reduce naloxone-induced opiate withdrawal. Moreover, in total absence of naloxone, DA antagonists did not precipitate either conditioned place aversion or somatic abstinence signs in dependent rats. Taken together, these findings suggested that DA transmission is not critical for the induction of opiate withdrawal syndrome. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral and neurochemical alterations following intracerebroventricular administration of anti-serotonin antibodies in adult Balb/c mice

The effects of intracerebroventricular injections of serotonin (5-HT) antibodies were studied for changes in 5-HT, dopamine (DA), their metabolites and norepinephrine (NE) as well as 5-HT mediated behavior in adult mice. While nociceptive thresholds (tail-flick latency) were inhibited in antibody treated animals, tremor response to 5-methoxy-N,N-dimethyl tryptamine administration was increased. 5-HT and DA in the nucleus raphe dorsalis (NRD), substantia nigra (SN), nucleus caudatus putamen (NCP) and in the substantia grisea centralis, and NE in the former two nuclei were significantly decreased in these animals. 5-Hydroxyindoleacetic acid was unaffected in all nuclei except NRD, where it was inhibited. Homovanillic acid and 3,4-dihydroxyphenylacetic acid were inhibited in all nuclei except in NCP. The brunt of insult was more evident in NRD and SN where all neurotransmitters were inhibited for a longer period. 5-HT turnover was increased in all the nuclei, however only SN showed increased DA turnover. It may be assumed that the observed neurochemical and behavioral changes were the consequence of the antibodies binding to 5-HT, which in turn influenced the anatomically and functionally connected neurotransmitters. While the study contributes to the existing understanding of central neurotransmitter control on behavior, it fails to delineate the underlying mechanism. The possibility of developing a useful, drug-free 5-HT deficient animal model for studying clinical disorders, as well as for solving some of the basic questions related to the physiological functions of 5-HT in adult animals are envisaged from the study.     

PVLV: The Primary Value and Learned Value Pavlovian Learning Algorithm.

The authors present their primary value learned value (PVLV) model for understanding the reward-predictive firing properties of dopamine (DA) neurons as an alternative to the temporal-differences (TD) algorithm. PVLV is more directly related to underlying biology and is also more robust to variability in the environment. The primary value (PV) system controls performance and learning during primary rewards, whereas the learned value (LV) system learns about conditioned stimuli. The PV system is essentially the Rescorla-Wagner/delta-rule and comprises the neurons in the ventral striatum/nucleus accumbens that inhibit DA cells. The LV system comprises the neurons in the central nucleus of the amygdala that excite DA cells. The authors show that the PVLV model can account for critical aspects of the DA firing data, making a number of clear predictions about lesion effects, several of which are consistent with existing data. For example, first- and second-order conditioning can be anatomically dissociated, which is consistent with PVLV and not TD. Overall, the model provides a biologically plausible framework for understanding the neural basis of reward learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sulpiride: the best known atypical, safe neuroleptic drug. Review of literature

This is a review of literature data on a neuroleptic drug--sulpiride. Sulpiride, a benzamide derivative displays selective affinity for mesolimbic and mesocortical dopamine receptors. For this reason it is classified as an atypical antipsychotic drug. In clinical use, it causes undesirable side effects (particularly extrapyramidal, cholinolytical) less often than classical neuroleptics, does not cause sedation, and has activating and antidepressive properties. These characteristics caused that it is considered a drug of first choice in delusional psychoses with inhibition, depression, lowered activity, intensified negative or deterioration symptoms. The most serious drawback of the drug is the risk of symptoms caused by increased prolactine excretion, and increase in body weight.     

Turnover of catecholamines in some regions of the rat brain during prolonged vasopressin administration and after its withdrawal

Turnover of noradrenaline (NA) and dopamine (DA) in some regions of the rat brain was determined after 1 and 3 weeks of daily injections of lysine vasopressin (LVP) and 2 weeks after the termination of 28-day LVP injections. Disappearance of 3H-DA was estimated in the hemispheres, brain stem and striatum and of 3H-NA in the hemispheres and brain stem after intraventricular injection of 3H-tyrosine. A significant acceleration of 3H-NA disappearance from the hemispheres was found in all the experimental animals and from the brain stem 3 weeks after LVP adminstration and 2 weeks after its withdrawal. No marked changes in dopamine turnover in the examined regions of the rat brain were found. Since prolonged vasopressin administration produces hypertension in the rat it seems likely that central NA, but not DA, plays a role in the vasopressin-induced hypertension.     

Recent advances in the pharmacotherapy of schizophrenia

The limitations of standard antipsychotics have spurred a search for novel agents that are effective against both positive and negative symptoms of schizophrenia but do not produce the extrapyramidal side effects frequently associated with the older medications. Such agents might more effectively prevent relapse, because of enhanced efficacy for the full spectrum of schizophrenic symptoms and improved tolerability--and hence greater medication compliance. Findings concerning the new antipsychotics currently available, clozapine and risperidone, are reviewed, and clozapine's usefulness as a first-line treatment is evaluated. Although serious side effects and the need for weekly blood monitoring may limit clozapine's use as a first-line treatment, risperidone appears promising in this role. Preclinical and clinical studies of new antipsychotic medications recently submitted for approval (olanzapine and sertindole) or in phase III development (quetiapine and ziprasidone) are also reviewed. The findings are encouraging, and researchers hope that some of these new agents may prove valuable as first-line treatments for schizophrenia. Pharmacoeconomic studies comparing clozapine and risperidone to the standard neuroleptics indicate that these newer drugs appear likely to lower the overall cost of treatment for schizophrenia, primarily by reducing rates of relapse and rehospitalization.