Weak Dopamine Research Articles

Fentanyl dose-sparing in polyarthritic rats requires full agonism at 5-HT1A receptors: Comparison between NLX-112, (±)8-OH-DPAT, and buspirone.

NLX-112 (a.k.a. F13640, befiradol) is a highly selective and fully efficacious agonist at 5-hydroxytryptamine (5-HT1A) receptors. It has been shown to be robustly and potently active in nociceptive, neuropathic and traumatic pain models in rats and mice. In particular, NLX-112 decreases oral fentanyl self-administration (FSA) in polyarthritic rats, ie, it has opioid dose-sparing effects. To examine if the dose-sparing effects of NLX-112 in polyarthritic rats are shared by other 5-HT1A ligands: the prototypical 5-HT1A receptor agonist 8-HYDROXY-2-(DI-n-PROPYLAMINO)TETRALIN ((±)8-OH-DPAT), and the 5-HT1A receptor partial agonist and weak dopamine D2 receptor blocker, -buspirone. Polyarthritis was induced by inoculating rats with heat-killed Mycobacterium butyricum. They then had access to either a fentanyl (0.008 mg/mL) or a sweetened solution in their home cage. NLX-112, (±)8-OH-DPAT, or buspirone was administered via an osmotic minipump (5 µL/h) during a 2-week infusion period from day 14 to day 28 post-inoculation with Mycobacterium butyricum. Control infusions consisted of sterile 0.9 percent NaCl. NLX-112 (0.63 mg/day) significantly decreased FSA by 47 percent and increased total fluid consumption (TFC) by 7 percent (vehicle-loaded minipumps as controls). Both (±)8-OH-DPAT and buspirone (0.63 and 2.5 mg/day, respectively) failed to reduce FSA; (±)8-OH-DPAT did not modify TFC, while buspirone significantly decreased it by 17 percent. These results suggest that oral FSA dose-sparing effect, in this rat polyarthritis pain model, requires high efficacy activation of 5-HT1A receptors, such as that afforded by NLX-112. By contrast, the agonist efficacy of (±)8-OH-DPAT and buspirone seems insufficient for FSA dose-sparing.

Quetiapine Fumarate: A Review of Analytical Methods.

Atypical antipsychotics are newer second-generation antipsychotics with weak dopamine type 2 blocking but potent 5-HT2 antagonistic activity. They are considered first-line treatments for schizophrenia and gradually replace typical antipsychotics. Extrapyramidal side effects are minimal, and they tend to improve impaired cognitive function in psychotics. Quetiapine fumarate is an atypical antipsychotic drug used to treat schizophrenia, mania and depression in people with bipolar disorder combined with other drugs or alone. Quetiapine was developed in 1985 and approved for medical use in the USA in 1997. Thorough computer-aided literature, surveys revealed that numerous analytical methods were reported over the years. The present study reviews analytical methods with their validation parameters published during the last 22years (1999-2021) either as a single entity or combination in dosage form, and determination from biological samples. Novel strategies for increasing separation quality, such as QbD analysis and green spectroscopy, were discovered during the evaluation, and this review can be utilized for further research reference.

Leki przeciwdepresyne typu SNRI — medycyna oparta na faktach i doświadczeniu

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants are drugs registered for the treatment of depression and anxiety disorders. These drugs affect the reuptake of both serotonin and noradrenaline. There are two such drugs available in Poland: venlafaxine and duloxetine. The mechanism of venlafaxine’s antidepressant effect in humans is believed to be related to increased neurotransmitter activity in the central nervous system (CNS). Preclinical studies have shown that venlafaxine and its major metabolite (O-demethylenlafaxine, ODV) are serotonin and norepinephrine reuptake inhibitors. Venlafaxine is also a weak dopamine reuptake inhibitor. Venlafaxine acts by blocking neurotransmitter transport and reuptake proteins and acts through postsynaptic terminals, ultimately enhancing postsynaptic stimulation. Duloxetine is an inhibitor of serotonin (5-HT) and norepinephrine (NA) reuptake. It weakly inhibits dopamine reuptake (e.g. in frontal regions), and has no significant affinity for histamine, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular serotonin and norepinephrine concentrations in different brain areas in animals. In this paper we will discuss the most important literature data concerning the above mentioned drugs, as well as define a patient profile that could most benefit from individually selected treatment.

Urinary 3-Methoxytyramine Is a Biomarker for MYC Activity in Patients With Neuroblastoma.

PURPOSEElevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis.METHODSUrinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine β-hydroxylase proteins was performed on primary tumors.RESULTSElevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P < .0001). Finally, a strong MYCN and weak dopamine β-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels.CONCLUSIONElevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk.

Quetiapine Abuse Fourteen Years Later: Where Are We Now? A Systematic Review

Background: Quetiapine, an atypical antipsychotic endowed with weak dopamine antagonist, potent 5-HT2A-blocking, partial 5-HT1A-agonist, anti-H1 histamine, adrenolytic, and sigma1 receptor agonist activities, since an original 2004 report is increasingly misused. Although some of its pharmacodynamics might explain some motives for voluptuary use, most of its actions are directed at setting-off those motives. Hence, it is possible that its popularity in special populations is due to the fact that the unpleasant or unwanted effects of addiction substances are somehow soothed by quetiapine. Currently, quetiapine is tested in substance use disorders, showing some promise, but it is likely to be misused in certain contexts. Objectives: To review the evidence for the use of quetiapine as addiction substance and investigate the characteristics of populations involved in such addiction. Methods: A systematic review of literature on various databases retrieved on September 7, 2018 87 records to comment. Results. We reviewed the evidence for quetiapine’s addictive potential in the light of its pharmacodynamics properties and presented two cases of recreational quetiapine use, by a 35-year old male patient with past addictive behavior and by a 50-year-old woman with major depressive disorder and conversion disorder. We found quetiapine to be abused mainly by addict populations and people with law involvement. Conclusions/Importance: There is no reason to include quetiapine among regulated substances, but monitoring of its use in selected populations is warranted. Psychiatrists and physicians working in the penitentiary system should be aware of the addictive potential of quetiapine and adopt measures restricting its use.

Mice deficient in protein tyrosine phosphatase receptor type Z (PTPRZ) show reduced responsivity to methamphetamine despite an enhanced response to novelty.

Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.

In Vitro Neurochemical Assessment of Methylphenidate and Its "Legal High" Analogs 3,4-CTMP and Ethylphenidate in Rat Nucleus Accumbens and Bed Nucleus of the Stria Terminalis.

3,4-dichloromethylphenidate (3,4-CTMP) and ethylphenidate are new psychoactive substances and analogs of the attention deficit medication methylphenidate. Both drugs have been reported on online user fora to induce effects similar to cocaine. In the UK, 3,4-CTMP appeared on the drug market in 2013 and ethylphenidate has been sold since 2010. We aimed to explore the neurochemical effects of these drugs on brain dopamine and noradrenaline efflux. 3,4-CTMP and ethylphenidate, purchased from online vendors, were analyzed using gas chromatography and mass spectroscopy to confirm their identity. Drugs were then tested in adolescent male rat brain slices of the nucleus accumbens and stria terminalis for effects on dopamine and noradrenaline efflux respectively. Fast cyclic voltammetry was used to measure transmitter release. Methylphenidate (10 μM) increased evoked dopamine and noradrenaline efflux by 4- and 2-fold, respectively. 3,4-CTMP (0.1 and 1 μM) increased evoked dopamine and noradrenaline efflux by ~6-fold and 2-fold, respectively. Ethylphenidate (1 μM) doubled evoked dopamine and noradrenaline efflux in both cases. 3,4-CTMP's effect on dopamine efflux was greater than that of methylphenidate, but ethylphenidate appears to be a weaker dopamine transporter inhibitor. Experiments using the dopamine D2 antagonist haloperidol, the noradrenaline α2 receptor antagonist yohimbine, the dopamine transporter inhibitor GBR12909 and the noradrenaline transporter inhibitor desipramine confirmed that we were measuring dopamine in the accumbens and noradrenaline in the ventral BNST. All three psychostimulant drugs, through their effects on dopamine efflux, may have addictive liability although the effect of 3,4-CTMP on dopamine suggests that it might be most addictive and ethylphenidate least addictive.

Buprenophine functions as a weak dopamine releaser in the absence of heroin but blocks the dopamine releasing effects of heroin in its presence

With the rise in opioid use and opioid‐related death in modern society, it is imperative to understand how these drugs affect neural circuits, particularly those implicated in drug‐seeking and motivated behavior. Generally, all drugs of abuse are thought to increase mesolimbic dopamine concentrations through various mechanisms, and it is widely believed these fluctuations in dopamine concentrations (and subsequent hypodopaminergic states) are implicated in the acquisition, persistence, and maintenance of addiction. Here we sought to identify increases in phasic dopamine in the nucleus accumbens of rats after intravenous diacetylmorphine (heroin) administration. Then, we sought to identify the effects on phasic dopamine after buprenorphine administration, followed by subsequent heroin administration. Utilizing fast‐scan cyclic voltammetry in awake behaving animals, we administered cumulative animal‐equivalent doses based on clinical investigations that correlated subjective measures of the drug's effect to dosage in human subjects. Either heroin or buprenorphine administered alone causes large increases in dopamine transient amplitude and frequency, whereas heroin administration after buprenorphine causes a decrease in the amplitude and frequency of transients. These data suggest a modulatory effect of buprenorphine on opioid receptors in the presence of exogenous opiates.Support or Funding InformationFunding for the project was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBO and an institutional UROP to KJP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

New Trends in the Treatment of Schizophrenia.

This article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments. Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine- type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects are becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia are emerging but have not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed. The heterogeneity of the pathophysiology of the various domains of schizophrenia requires a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.

Mining the Potential of Label-Free Biosensors for In Vitro Antipsychotic Drug Screening.

The pharmaceutical industry is facing enormous challenges due to high drug attribution rates. For the past decades, novel methods have been developed for safety and efficacy testing, as well as for improving early development stages. In vitro screening methods for drug-receptor binding are considered to be good alternatives for decreasing costs in the identification of drug candidates. However, these methods require lengthy and troublesome labeling steps. Biosensors hold great promise due to the fact that label-free detection schemes can be designed in an easy and low-cost manner. In this paper, for the first time in the literature, we aimed to compare the potential of label-free optical and impedimetric electrochemical biosensors for the screening of antipsychotic drugs (APDs) based on their binding properties to dopamine receptors. Particularly, we have chosen a currently-used atypical antipsychotic drug (Buspirone) for investigating its dopamine D3 receptor (D3R) binding properties using an impedimetric biosensor and a nanoplasmonic biosensor. Both biosensors have been specifically functionalized and characterized for achieving a highly-sensitive and reliable analysis of drug-D3R binding. Our biosensor strategies allow for comparing different affinities against the D3R, which facilitates the identification of strong or weak dopamine antagonists via in vitro assays. This work demonstrates the unique potential of label-free biosensors for the implementation of cost-efficient and simpler analytical tools for the screening of antipsychotic drugs.

Unique Effects of Clozapine: A Pharmacological Perspective.

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

BackgroundSchizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.MethodA systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).ResultsNineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.ConclusionsTentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.

An open-label pilot study of quetiapine plus mirtazapine for heavy drinkers with alcohol use disorder.

Animal research suggests that medications that produce a weak dopamine D2 receptor blockade and potentiate noradrenergic activity may decrease alcohol drinking. In an open-label pilot study of subjects with alcohol dependence, we tested whether the combination of quetiapine, a weak dopamine D2 receptor antagonist, whose primary metabolite, desalkylquetiapine, is a norepinephrine reuptake inhibitor, and mirtazapine, a potent α2 norepinephrine receptor antagonist, would decrease alcohol drinking and craving. Twenty very heavy drinkers with alcohol dependence entered a trial of 8 weeks of treatment with quetiapine followed by 8 weeks of treatment with a combination of quetiapine plus mirtazapine. Alcohol use was assessed weekly with a Timeline Follow-Back interview and craving with the Penn Alcohol Craving Scale. Among the 11 completers, subjects reported improved outcomes in the quetiapine plus mirtazapine period compared to the quetiapine alone period: fewer very heavy drinking days per week (1.3 [SD=2.4] vs. 2.1 [SD=2.8]; t=2.3, df=10, p=0.04); fewer total number of drinks per week (39.7 [SD=61.6] vs. 53.4 [SD=65.0]; t=2.8, df=10, p=0.02); and lower craving scores (2.5 [SD=1.4] vs. 3.2 [SD=1.2]; t=2.4, df=10, p=0.04). All subjects reported at least one adverse event; 72.7% reported somnolence. In this open-label pilot study, treatment with quetiapine plus mirtazapine was associated with a decrease in alcohol drinking and craving. These findings are consistent with our previous work in animal models of alcohol use disorders and suggest that further study of medications or combinations of medications with this pharmacologic profile is warranted.

Effects of iloperidone, combined with desipramine, on alcohol drinking in the Syrian golden hamster

Alcohol use disorder in patients with schizophrenia dramatically worsens their clinical course, and few treatment options are available. Clozapine appears to reduce alcohol use in these patients, but its toxicity limits its use. To create a safer clozapine-like drug, we tested whether the antipsychotic iloperidone, a drug that combines a weak dopamine D2 receptor blockade and a potent norepinephrine alpha-2 receptor blockade would reduce alcohol drinking, and whether its effect on alcohol drinking could be increased if combined with an agent to facilitate norepinephrine activity. Syrian golden hamsters (useful animal model for screening drugs that reduce alcohol drinking in patients with schizophrenia) were given free access to water and alcohol (15% v/v) until stable drinking was established. Animals (n = 6–7/group), matched according to alcohol intake, were treated daily with each drug (iloperidone; clozapine; haloperidol; desipramine [norepinephrine reuptake inhibitor]; with idazoxan [norepinephrine alpha-2 receptor antagonist]) or with a two-drug (iloperidone + desipramine; iloperidone + idazoxan) combination for 14 days. Moderate doses of iloperidone (1–5 mg/kg) significantly reduced alcohol drinking (p < 0.05) in the hamster, whereas higher doses (10–20 mg/kg) did not. In addition, 5 mg/kg of iloperidone reduced alcohol drinking to the same extent as clozapine (8 mg/kg), whereas haloperidol (0.2 mg/kg) did not. Moreover, iloperidone's effects were enhanced via the addition of desipramine (3 mg/kg), but not idazoxan (1.5/3 mg/kg). In this animal model, iloperidone decreases alcohol drinking as effectively as clozapine, and desipramine appears to amplify this effect. The data suggest that iloperidone, alone or in combination with desipramine, should be tested in patients with schizophrenia and alcohol use disorder.

Naltrexone ER/bupropion ER in obesity management: a guide to its use

Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave®, Mysimba™) is an effective adjunct to reduced-calorie diet and increased physical activity for chronic bodyweight management in adults who are either obese, or overweight with at least one bodyweight-related co-morbidity. It provides combination treatment with an opioid antagonist (naltrexone) and a weak dopamine and norepinephrine reuptake inhibitor (bupropion), which synergistically interact in the CNS to control appetite and food intake. In clinical trials in obese adults or overweight adults with controlled hypertension and/or dyslipidaemia (± type 2 diabetes), naltrexone ER/bupropion ER improved bodyweight-related outcomes to a significantly greater extent than placebo, and was generally well tolerated.

Desipramine enhances the ability of paliperidone to decrease alcohol drinking

Alcohol use disorder commonly occurs in patients with schizophrenia and dramatically worsens their course. The atypical antipsychotic clozapine has been associated with reduced drinking in these patients, but its toxicity reduces its use. We have attempted to create a clozapine-like drug by combining agents that capture components of clozapine's pharmacologic action, including its weak dopamine D2 blockade and noradrenergic modulation. The current study assessed whether paliperidone, a dopamine D2 receptor and adrenergic alpha-2 receptor antagonist like clozapine, would attenuate alcohol drinking in the alcohol-preferring P rat and the Syrian golden hamster, and whether desipramine, a norepinephrine reuptake inhibitor, would potentiate the ability of paliperidone to attenuate alcohol drinking in the P rat and the Syrian golden hamster. Daily subcutaneous injections of paliperidone (5 mg/kg for the rat; 1 mg/kg for the hamster) over 20 days slightly and transiently attenuated initiation of alcohol consumption in both animals. Desipramine (3 mg/kg) or lower doses of paliperidone alone did not affect alcohol drinking. However, the combination of desipramine (3 mg/kg) and paliperidone essentially prevented initiation of alcohol drinking and acquisition of alcohol preference in the P rat (2.5 or 5 mg/kg), and almost as dramatically suppressed chronic alcohol intake and alcohol preference in the hamster (2.5 mg/kg). Taken together, the current data suggest that (1) the desipramine and paliperidone combination attenuates alcohol drinking in a synergistic manner, and (2) desipramine and paliperidone may serve as an effective new treatment for alcohol use disorder in patients with schizophrenia.

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

BackgroundAlcohol use disorder commonly occurs in patients with schizophrenia. Most antipsychotic drugs do not lessen alcohol use; although the atypical antipsychotic clozapine has been shown to reduce alcohol use in patients with schizophrenia, its toxicity severely limits its use in patients. With an eye toward creation of a safer clozapine-like drug, we have investigated the pharmacological basis of the clozapine's effects on alcohol drinking in the Syrian golden hamster. In this animal, as in patients with schizophrenia, clozapine reduces alcohol drinking while the typical antipsychotic haloperidol does not. We have suggested that clozapine decreases alcohol drinking due to its weak dopamine D2 receptor blockade, its potent norepinephrine α-2 receptor antagonism, as well as its ability to elevate plasma norepinephrine. MethodsWe recreated a clozapine-like drug to reduce alcohol drinking in the Syrian golden hamster by combining low dose haloperidol with a norepinephrine α-2 receptor antagonist, idazoxan, and a norepinephrine reuptake inhibitor, desipramine. Hamsters were given free access to water and alcohol (15% v/v) and were treated daily with each drug or with the three-drug combination for 23 days. ResultsThe drug combination reduced alcohol drinking and preference significantly as compared to vehicle or to haloperidol, idazoxan or desipramine, while not altering food-intake or body-weight. ConclusionThese findings suggest that that haloperidol, which does not reduce alcohol drinking in patients with schizophrenia or the hamster, if combined with idazoxan and desipramine (producing a drug combination that mimics aspects of clozapine's pharmacology) is able to reduce alcohol drinking in the hamster.

Discriminative stimulus properties of N-desmethylclozapine, the major active metabolite of the atypical antipsychotic clozapine, in C57BL/6 mice

N-desmethylclozapine (NDMC) is the major active metabolite of the atypical antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D2 and cholinergic muscarinic M1/M4 agonist, whereas clozapine is a weak dopamine D2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the typical antipsychotic drug haloperidol (dopamine D2 antagonist) and the atypical antipsychotic drug aripiprazole (D2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile.

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl

Raclopride lessens the ability of clozapine to suppress alcohol drinking in Syrian golden hamsters

Emerging evidence suggests that the atypical antipsychotic clozapine decreases alcohol consumption in patients with schizophrenia, while typical antipsychotics, all of which are potent dopamine (DA) D2 receptor antagonists, do not. We have proposed that clozapine, through its weak DA D2 receptor blocking action, coupled with its ability to potentiate noradrenergic and serotonergic activity, may ameliorate a dysfunction in the mesocorticolimbic DA reward circuitry that underlies alcohol use disorder in patients with schizophrenia. In prior studies, we have demonstrated that clozapine also decreases alcohol drinking in the Syrian golden hamster, but haloperidol does not. The purposes of the current study were: (1) to further assess the effect of clozapine (2 or 4 mg/kg/day, s.c.) on alcohol consumption in hamsters, using a continuous access, 2-bottle choice paradigm; and (2) to examine whether clozapine’s effect on alcohol drinking is affected by increasing its DA D2 blockade through adjunctive use of the potent DA D2 receptor antagonist raclopride (2, 4, or 6 mg/kg/day, s.c.). The major findings were: (1) clozapine suppressed both initiation and maintenance of alcohol drinking in hamsters; and (2) these effects of clozapine were lessened when raclopride was given adjunctively with clozapine. These data suggest that clozapine may limit alcohol drinking in the golden hamster (and possibly in patients with schizophrenia) in part because of its weak blockade of the DA D2 receptor.