Selective Dopamine Antagonists Research Articles

Mental Illness: Social Dimension, is it Being Systematically Ignored?

For nearly half a century, the predominant focus of research in mental health has been on understanding the biological basis of mental disorders and new drugs. This was a major shift from the first half of the 20th century, when the psychoanalytic model was dominating the scene. Our understanding of the biological basis of many mental disorders has definitely improved in the last few decades with the advances in structural and functional imaging. However, there has not been any major advancement on the therapeutic side, with no significant introductions after the selective serotonin reuptake inhibitors and serotonin dopamine antagonists. Mental disorders have been identified as an important contributor to the global burden of disease, with the burden not shown any fall over the last 3 decades. Thus, there is a need to focus on the social dimension of mental disorders which has been systematically ignored. The strategies may include following a public health approach, dealing with stigma associated with mental disorders, strengthening the mental health services in the community, and improving their accessibility, and promotion of mental health well-being, dealing with disease burden, building resilience, involving families in management, targeting recovery, social prescribing, and using information technology, wherever appropriate.

A study to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors and serotonin dopamine antagonists.

Introduction:Hyponatremia can be a common but often overlooked side effects of psychotropics drugs. Most patients with drug-induced hyponatremia are asymptomatic and diagnosis is made incidentally following routine blood tests.Objectives:The aim of the study was to understand the pattern of hyponatremia in patients using selective serotonin reuptake inhibitors (SSRI) and serotonin dopamine antagonists (SDA).Materials and Methods:All inpatients and outpatients who were diagnosed with International Classification of Diseases-10 psychiatric disorders and undergoing treatment with SSRI, SDA, or combination of both for the same, were included in the study after simple random sampling, subject to inclusion and exclusion criteria.Statistical Analysis Used:Categorical variables were observed as numbers and percentages. Continuous variables were evaluated as mean ± standard deviation. A Chi-square test was done to find the association between categorical variables. SPSS (IBM) version 21 was used for data analysis.Results:In 150 patients, we found hyponatremia in 17 patients (11.33%). About 66–75 age group patients had maximum found cases of hyponatremia (66.66%). About 20.31% of females found hyponatremia. Among SSRIs, 16% of individuals had hyponatremia whereas among SDA it was 6%. Patients who were taking both SSRIs and SDA total prevalence of hyponatremia was 12%.Conclusions:Older age groups and females had higher chances of hyponatremia while taking SSRIs and SDAs. Among SSRIs, escitalopram had maximum percentage of hyponatremia, whereas fluvoxamine had minimum. Among SDAs, risperidone had maximum percentage, whereas quetiapine had minimum percentage of hyponatremia. Patients who were taking both fluoxetine + olanzapine or fluoxetine + risperidone had higher percentage of hyponatremia.

The place and role of domperidone in the practice of a gastroenterologist. Overview of options at the present stage

Diseases of the gastrointestinal tract (GIT) occupy a significant place in the overall structure of somatic diseases worldwide. Apart from functional diseases (the incidence of functional dyspepsia (FD) in population is 20 %), the following inflammatory and destructive diseases are widespread: gastroesophageal reflux disease (GERD) in up to 40 % of the population, chronic gastritis and chronic duodenitis in 45 — 50 % of the population, peptic ulcer of the stomach and duodenum in 14 — 15 % of the population. Each of these diseases has its own features of etiopathogenesis and approaches to treatment. However, a common pathological factor contributing to the development of these nosologies is a violation of motor‑evacuation function. The administration of drugs for the normalization of peristaltic activity is a component of treatment. The range of existing drugs with prokinetic activity against the gastrointestinal tract is quite large.One of the effective and safe prokinetics registered in October 2020 in Ukraine is the domperidone preparation Doprokin (World Medicine). This drug has a proven effectiveness in the treatment of patients with FD, GERD, chronic gastritis, especially in comorbidity with Diabetes mellitus II (diabetic gastroparesis) and gastroparesis of other etiology. This is a selective dopamine antagonist, that blocks D2‑receptors in the central and peripheral nervous systems. It increases the pressure of the lower esophageal sphincter, esophageal clearance, reduces intragastric pressure, activates peristalsis of the esophagus and antrum of the stomach, increases the frequency, amplitude and duration of contractions of the duodenum, reduces the time of passage of food masses through the small intestine. The indications for domperidone administration include relief of symptoms of nausea, vomiting, heartburn, belching, early satiety, bloating. In contrast to metoclopramide, it almost does not cross the blood‑brain barrier and does not cause unwanted central adverse reactions. Doprokin is over the counter preparation. For adults, the recommended dose is 1 tablet (10 mg) 3 times a day (15 — 30 minutes before the meals). The maximal daily dose is 30 mg, maximal treatment duration should not exceed 1 week.

Dopamine and serotonin antagonists fail to alter the discriminative stimulus properties of ±methylenedioxymethamphetamine

Most studies on discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) have been conducted using a relatively low dose (1.5 mg/kg), and those studies have invariably implicated serotonergic mechanisms. In contrast, dopaminergic mechanisms mediate the discriminative stimulus effects of amphetamine (AMPH). Some studies have suggested that the discriminative stimulus effects of a higher (3.0 mg/kg) dose of MDMA might rely on both serotonergic and dopaminergic mechanisms. This study aimed to determine effects of selective dopamine (DA) and serotonin (5HT) antagonists on the discriminative stimulus properties of AMPH (0.5 mg/kg) and MDMA (3.0 mg/kg). Separate groups of rats were trained to discriminate AMPH (0.5 mg/kg) or MDMA (3.0 mg/kg) from saline using a food-reinforced drug-discrimination procedure. Effects of DA (SCH 23390: 0.003-0.03 mg/kg and eticlopride: 0.03-0.3 mg/kg) or 5HT (ritanserin: 1.0-10.0 mg/kg, WAY-100635: 0.3-1.0 mg/kg and GR129375: 1.0-3.0 mg/kg) antagonists on the discriminative stimulus effects of both drugs were determined. Both DA antagonists dose-dependently decreased the AMPH but not the MDMA discrimination. None of the 5HT antagonists altered the discriminative stimulus effects of either drug. The MDMA (3.0 mg/kg) stimulus comprises both a DAergic and 5HTergic response, and the results suggest that either one is sufficient, but not required, to maintain the stimulus effects.

Importance of D1 and D2 receptor stimulation for the induction and expression of cocaine-induced behavioral sensitization in preweanling rats

The behavioral manifestations of psychostimulant-induced sensitization vary markedly between young and adult rats, suggesting that the neural mechanisms mediating this phenomenon differ across ontogeny. In this project we examined the importance of D1 and D2 receptors for the induction and expression of cocaine-induced behavioral sensitization during the preweanling period. In the behavioral experiments, rats were injected with reversible D1 and/or D2 antagonists (SCH23390 and/or raclopride) or an irreversible receptor antagonist (EEDQ) either before cocaine administration on the pretreatment day (induction) or before cocaine challenge on the test day (expression). In the EEDQ experiments, receptor specificity was assessed by using selective dopamine antagonists to protect D1 and/or D2 receptors from inactivation. Receptor binding assays showed that EEDQ caused substantial reductions in dorsal striatal D1 and D2 binding sites, while SCH23390 and raclopride fully protected D1 and D2 receptors from EEDQ-induced alkylation. Behavioral results showed that neither D1 nor D2 receptor stimulation was necessary for the induction of cocaine sensitization in preweanling rats. EEDQ disrupted the sensitization process, suggesting that another receptor type sensitive to EEDQ alkylation was necessary for the induction process. Expression of the sensitized response was prevented by an acute injection of a D1 receptor antagonist. The pattern of DA antagonist-induced effects described for preweanling rats is, with few exceptions, similar to what is observed when the same drugs are administered to adult rats. Thus, it appears that maturational changes in D1 and D2 receptor systems are not responsible for ontogenetic differences in the behavioral manifestation of cocaine sensitization.

New perspective therapy of breast cancer based on selective dopamine receptor D2 agonist and antagonist effects on MCF-7 cell line.

Different studies have shown the role of neurotransmitters (e.g., dopamine) in the progression of cancers via their various types of receptors. The aim of this study was to determine the pattern of dopamine receptors gene expression on MCF-7 cells and to evaluate the selective dopamine receptors agonist and antagonist effects on them. In addition, some other discoveries which are patented for the treatment of breast cancer are reviewed in this article. To determine the pattern of dopamine receptors gene expression in human breast cancer cells (MCF-7), RT-PCR was performed. Then, MCF-7 cells were treated by different doses of bromocriptine and remoxipride for 48 hours. Cell viability was evaluated by MTT assay. Thus, nuclear morphology of cells was analyzed by mixed dye florescent staining. Real time PCR technique was performed to determine the decreasing rate of proliferating cell nuclear antigen (PCNA) gene expression in treated MCF-7 cells. Finally, quantification of apoptosis and its difference with necrosis at the single cell level were assessed by Flowcytometery technique. This study revealed that, unlike remoxipride, bromocriptine suppressed proliferation of the MCF-7 cells (54.3% at 12.5µM bromocriptine concentration), but remoxipride could suppress the effect of bromocriptine. Bromocriptine has inhibitory effects on MCF- 7 cells by induction of apoptosis via D2-like receptors. Therefore, in future studies, bromocriptine can be used as a new choice for the treatment of tumoral breast cancer cells.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

Nicotine is a psychomotor stimulant with ‘reinforcement enhancing’ effects — the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by nicotine and they implicate dopaminergic systems both in conditioned approach as well as the incentive-promoting effects of nicotine.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

Amisulpride-Induced Macrocytic Anemia

Back to table of contents Previous article Next article LettersFull AccessAmisulpride-Induced Macrocytic AnemiaSujit Sarkhel, M.B.B.S., M.D., D.P.M., Samir Kumar Praharaj, M.B.B.S., M.D., D.P.M., and Sayeed Akhtar, M.B.B.S., M.D., D.N.B.Sujit SarkhelSearch for more papers by this author, M.B.B.S., M.D., D.P.M., Samir Kumar PraharajSearch for more papers by this author, M.B.B.S., M.D., D.P.M., and Sayeed AkhtarSearch for more papers by this author, M.B.B.S., M.D., D.N.B.Published Online:1 Jan 2013https://doi.org/10.1176/appi.neuropsych.12010001AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Amisulpride, an atypical antipsychotic used in treatment of both positive and negative symptoms of schizophrenia, has a benign adverse-effect profile.1 Commonly reported adverse effects include dose-related extrapyramidal syndromes, gastrointestinal, and sexual problems.2 A summary of product characteristics3 for amisulpride does not report any hematological toxicity. A PubMed search did not reveal any such association. We report a case of macrocytic anemia induced by amisulpride that reversed after discontinuation of the drug.Case ReportThe patient, a 29-year-old man, diagnosed with paranoid schizophrenia 10 years ago, presented with wandering behavior, suspiciousness, and unprovoked violence. Mental status revealed guarded attitude and constricted affect with grandiose and persecutory delusions. His mother had paranoid schizophrenia. His baseline investigations including complete hemogram; liver and renal function tests were normal. The patient responded to a combination of depot zuclopenthixol injection 200 mg every 3 weeks and olanzapine 7.5 mg/day without any emergent adverse effect. However, because of prominent negative symptoms, olanzapine was discontinued and tablet amisulpride 100 mg/day was added. After 2 months, he reported fatigability and, on examination, pallor was noted. Complete hemogram revealed macrocytic anemia (Hb 4.6 gm/dl; PCV 14.9%; MCV 119.2 fl; MCH 39.2 pg; MCHC 32.9%). There was no history of alcohol abuse, and nutritional status was adequate. His liver and renal function tests were within normal range. A possibility of amisulpride-induced macrocytic anemia was considered and the drug was discontinued, after which the affected hematological parameters normalized. A Naranjo ADR probability scale score of 4 suggested a possible association.4DiscussionIn our case, macrocytic anemia appeared within a few weeks of exposure to amisulpride, which improved after discontinuation of the suspected offending agent. Before initiation of amisulpride, baseline hematological indices were normal. There was no change in dietary intake during this period. Also, no folate or vitamin supplement was prescribed. Therefore, it is possible that amisulpride was the offending agent in our case.Macrocytic anemia is commonly associated with folate and vitamin B12 deficiency, among others. Besides alcohol, drug-induced causes of macrocytic anemia include sulphasalazine, methotrexate, hydantoins, valproate, and oral contraceptives.5–8 Although the exact mechanism is not known, folate deficiency, either by inhibition of absorption or interference with metabolism, has been commonly hypothesized.8 A similar mechanism is likely to have caused macrocytic anemia in our case.The recent edition of Meyler’s Side Effects of Psychiatric Drugs9 does not list any hematological adverse effects with amisulpride. Thus, our case study exemplifies that rare adverse effects, not previously reported in pre-marketing trials or post-marketing efficacy and safety studies, may occur during clinical use.Institute of Psychiatry, Institute of Postgraduate Medical Education and Research (IPGMER), Kolkata, IndiaDept. of Psychiatry, Kasturba Medical College, Manipal, Karnataka, IndiaCentral Institute of Psychiatry, Kanke, Ranchi, Jharkhand, IndiaCorrespondence: Samir Kumar Praharaj, M.B.B.S., M.D., D.P.M.; e-mail: [email protected]co.inReferences1 Leucht S: Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 2004; 7(Suppl 1):S15–S20Crossref, Medline, Google Scholar2 Coulouvrat C, Dondey-Nouvel L: Safety of amisulpride (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol 1999; 14:209–218Crossref, Medline, Google Scholar3 Solian SPC: (Date of revision March 2008); available at http://www.sanofi-aventis.co.uk/products/Solian_SPC.pdf; accessed on July 29, 2011Google Scholar4 Naranjo CA, Busto U, Sellers EM, et al.: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239–245Crossref, Medline, Google Scholar5 Stebbins R, Bertino JR: Megaloblastic anaemia produced by drugs. Clin Haematol 1976; 5:619–630Medline, Google Scholar6 Grieco A, Caputo S, Bertoli A, et al.: Megaloblastic anaemia due to sulphasalazine responding to drug withdrawal alone. Postgrad Med J 1986; 62:307–308Crossref, Medline, Google Scholar7 Kornberg A, Segal R, Theitler J, et al.: Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives. Isr J Med Sci 1989; 25:142–145Medline, Google Scholar8 Greer JP, Foerster J, Rodgers GM, et al.: Wintrobe’s Clinical Hematology, 12th Edition. Philadelphia, PA, Lippincott, Williams & Wilkins, 2009Google Scholar9 Aronson JK: Meyler’s Side Effects of Psychiatric Drugs. Oxford, UK, Elsevier, 2009Google Scholar FiguresReferencesCited byDetailsCited byAntipsychotic Drugs Volume 25Issue 1 Winter 2013Pages E10-E11 Metrics PDF download History Published online 1 January 2013 Published in print 1 January 2013

Bulbocapnine is not a selective DA1 receptor antagonist.

Antagonist activity of bulbocapnine on DA1 versus DA2 dopamine receptors was studied simultaneously in a dog under pentobarbitone anaesthesia and without phenoxybenzamine pretreatment. Fenoldopam (SK&F 82526) injected into the renal artery was the DA1 agonist and dipropyl dopamine or piribedil injected into the femoral artery were the DA2 agonists. Both at 0.5 and 1 mg kg-1 doses intravenous bulbocapnine caused nearly equal inhibition of DA1 and DA2 dopamine receptor-mediated responses. Our results show that under these experimental conditions bulbocapnine is not a selective DA1 dopamine antagonist.

Dopamine D1 Receptors Participate in Cocaine-Induced Place Preference via Regulation of Ryanodine Receptor Expression

Ryanodine receptors (RyRs) with three different isoforms in the brain play a role to facilitate Ca(2+) release from the intracellular Ca(2+) pool. Although cocaine is a strongly addictive psychostimulant that dramatically affects the central nervous system function, the role of RyRs and regulation of their expression by cocaine-induced place preference have not yet been defined well. The present study investigated the regulation of RyR expression in mice under intermittent cocaine treatment using the place preference procedure. The cocaine-induced place preference was inhibited by intracerebroventricular pretreatment with dantrolene, a RyRs antagonist, in a dose-dependent manner. The levels of RyR-1 and -2 in the limbic forebrain and frontal cortex significantly increased in the cocaine-conditioned mice, whereas that of RyR-3 in these two brain regions showed no changes. Although the up-regulation of RyRs was not affected by blockade of L-type voltage-gated calcium channels, the increase of RyR-1 and -2 in the limbic forebrain and frontal cortex was completely abolished by SCH23390, a selective antagonist of dopamine D(1) receptors, but not by sulpiride, a selective antagonist of dopamine D(2) receptors. These findings indicate that RyRs play a critical role in the development of cocaine-induced place preference and that the up-regulation of RyRs in the brain of a mouse showing cocaine-induced place preference is regulated by dopamine D(1) receptors.

BLOCKADE OF TACHYKININ NK-3 RECEPTOR REVERSES HYPERTENSION THROUGH A DOPAMINERGIC MECHANISM IN THE VENTRAL TEGMENTAL AREA OF SPONTANEOUSLY HYPERTENSIVE RATS: PP.29.161

Intracerebroventricularly (i.c.v.) injected tachykinin NK-3 receptor (R) antagonists normalized mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR). This study was pursued to define the role played by NK-3R located on dopamine (DA) neurons of the ventral tegmental area (VTA) in the regulation of MAP in SHR. SHR (16 weeks) were implanted permanently with i.c.v. and/or VTA guide cannula. Experiments were conducted 24 h after catheterization of the abdominal aorta to measure MAP and heart rate (HR) in freely behaving rats. Cardiovascular responses to i.c.v. or VTA injected NK-3R agonist (senktide) and antagonists (SB222200 and R-820) were measured before and after systemic administration of selective DA antagonists for D-1R (SCH23390), D-2R (raclopride) or non-selective D-2R (haloperidol) and after destruction of the VTA with ibotenic acid. Senktide (10, 25, 65 and 100 pmol) elicited more prominent increases of MAP and HR when injected in the VTA than i.c.v. and this cardiovascular response was blocked by R-820, SCH23390 and haloperidol. I.c.v. or VTA injected SB222200 and R-820 (500 pmol) evoked anti-hypertension, which was blocked by raclopride. Destruction of the VTA prevented the pressor response to i.c.v. senktide and the anti-hypertension to i.c.v. R-820. VTA injected SB222200 prevented the pressor response to i.c.v. senktide, and vice versa, i.c.v. senktide prevented the anti-hypertension to VTA SB222200. Repeated i.c.v. injection of R-820, once a day for 5 days, caused a sustained anti-hypertensive effect in SHR. Tachykinin NK-3R in the VTA is implicated in the maintenance of hypertension by increasing midbrain DA transmission in SHR. Hence, these receptors may represent a therapeutic target in the treatment of arterial hypertension.

Dopamine Receptor Ligands. Part 18: Modification of the Structural Skeleton of Indolobenzazecine-Type Dopamine Receptor Antagonists

On the basis of the D(1/5)-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca(2+) assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200–250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5–2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5–2 mg/kg, s.c.), a selective antagonist of dopamine D 2 receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5–10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5–10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5–2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5–2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D 2 receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.

Rotation and immediate-early gene expression in rats treated with the atypical D1 dopamine agonist SKF 83822

Classical agonists of the dopamine D1 receptor activate both adenylyl cyclase and phospholipase C (PLC) signaling pathways. As a result, the extent to which these two pathways are essentially involved in various effects produced by D1 receptor agonists is currently uncertain. In the present report we examined the effects of SKF 83822, a dopamine D1 agonist which has been reported to activate adenylyl cyclase, but not PLC, on behavior and immediate early gene (IEG) expression in rats with unilateral 6-hydroxydopamine lesions. SKF 83822 (25–100 μg/kg) induced dose dependent contralateral rotation in these subjects, and, additionally, stimulated strong expression of the IEG products c-Fos, Fra2, Zif/268 and Arc in the deinnervated striatum. All of these effects could be antagonized by pretreatment with the selective D1 dopamine antagonist SCH 23390 (0.5 mg/kg). Although PLC may be involved in many effects mediated through dopamine D1 receptors, these results suggest that direct activation of PLC is not necessary for the induction of either rotation or IEG expression in dopamine depleted rats.

Activation of D2‐like receptors induces sympathetic climactic‐like responses in male and female anaesthetised rats

In anaesthetised male rats an intravenous (i.v.) injection of p-chloroamphetamine (PCA) produced a specific patterned bursting response in the sympathetic vas deferens nerve (VDN) that corresponds to ejaculation. In the present, study selective dopamine agonists and antagonists were used to investigate whether dopaminergic mechanisms influence the generation of this ejaculatory-related response. Administration of a mixed D(1/2) receptor agonist (0.1-1.0 mg kg(-1) apomorphine i.v.) also evoked the characteristic bursting pattern responses in the VDN. Similar, but fewer, burst pattern responses could also be evoked by a selective D(2/3) receptor agonist (0.1-2.0 mg kg(-1) piribedil). Responses to 1.0 mg kg(-1) apomorphine were blocked by pretreatments with either 0.5 mg kg(-1) remoxipride (D(2) receptor antagonist) or 0.5 mg kg(-1) nafadotride (D(3) receptor antagonist), suggesting that D(2)-like receptors were involved. Responses could not be evoked by i.v. injections of apomorphine (1.0 mg kg(-1)) in anaesthetised male rats with a midthoracic spinal section, indicating that activation of D(2)-like receptors at supraspinal sites leads to an increase in the excitability of the lumbosacral pattern generator for ejaculation. In anaesthetised female rats a similar patterned bursting response occurred in the uterine nerve (UN) in response to apomorphine (0.5-2.0 mg kg(-1) i.v.). Thus a common neural mechanism may regulate sexual climactic reflexes in both sexes.

Classification of dopamine antagonists using functional feature hypothesis and topological descriptors

The designing of selective dopamine antagonists for their own subreceptors can be useful in individual therapy of various neuropsychiatric disorders. Three-dimensional pharmacophore hypothesis and two-dimensional topological descriptors were used to investigate and compare different classes of dopamine antagonists. The structurally diverse D 3 and D 4 antagonists above preclinical trials were selected to map common structural features of highly selective and efficacious antagonists. The generated pharmacophore hypotheses were successfully employed as discriminative probe for database screening. To filter out the false positive from screening hits, the classification models by two-dimensional topological descriptors were built. Molconn-Z and BCUT topological descriptors were employed to develop a classification model for 1328 dopamine antagonists from MDDR database. The soft independent modeling of class analogy and artificial neural network, two supervised classification techniques, successfully classified D 1, D 3, and D 4 antagonists at the average of 80% rates into their own active classes. The mean classification rates for D 2 antagonists were obtained to 60% due to insufficient selective D 2 antagonists. In this paper, we report the validity of our models generated using functional feature hypotheses and topological descriptors. The combining both of classification using functional feature hypotheses and topological descriptors would be a useful tool to predict selective antagonists.

Treatment with medications affecting dopaminergic and serotonergic mechanisms: Effects on fluency and anxiety in persons who stutter

Medications with dopamine antagonist properties, such as haloperidol, and those with serotonin reuptake inhibitor properties, such as clomipramine, have been shown to improve fluency. To examine the degree to which each of these two pharmacological mechanisms might independently affect fluency, a selective serotonin reuptake inhibitor, paroxetine, and a selective dopamine (D-2) antagonist, pimozide, were evaluated. Both types of medications also affect mood and anxiety, factors that could influence fluency levels. Therefore, we also evaluated the medications’ effects on generalized and speech-related anxiety and the relationships between changes in anxiety and changes in fluency in 11 subjects with a history of developmental stuttering. The randomized, double blind, placebo-controlled crossover study that was designed had to be terminated prior to completion due to severe side effects following withdrawal from paroxetine. Even with a reduced sample size ( n = 6), significant improvement in percent fluent speaking time ( p = 0.02) was found using a telephone task between baseline and pimozide ( n = 6), with average duration of dysfluencies significantly shorter ( p = 0.04) but no significant difference in the estimated number of dysfluencies per minute. This significant improvement was associated with non-significant increases in generalized anxiety, but non-significant decreases in speech-related anxiety. No significant differences were found in fluency between baseline and paroxetine ( n = 5). These preliminary results suggest that fluency improvement is more likely to be mediated by dopaminergic rather than serotonergic mechanisms. Due to its side effects, however, pimozide may be considered a risk for treatment of stuttering. Educational objectives: As a result of reading this paper the reader will describe and explain: (1) how medications may affect fluency and the rationale for selecting medications for treatment trials; (2) the interrelationship between fluency and anxiety; and (3) factors important in developing clinical trials using medications.

Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials.

The pharmacological profiles of the atypical antipsychotics, clozapine, olanzapine, quetiapine and risperidone, all show a combined serotonin (5-HT2) and dopamine type-2 (D2) receptor antagonism. Amisulpride, a highly selective dopamine D2/D3 receptor antagonist that binds preferentially to receptors in the mesolimbic system, is also an 'atypical' antipsychotic despite having a different receptor-affinity profile. A meta-analysis of 18 clinical trials was undertaken to compare the efficacy and safety of amisulpride with conventional antipsychotics. The improvement in mental state was assessed using the Brief Psychiatric Rating Scale (BPRS) or the Scale for the Assessment of Negative Symptoms (SANS). In a pooled analysis of 10 studies of acutely ill patients, amisulpride was significantly more effective than conventional neuroleptics with regard to improvement of global symptoms. Amisulpride is, to date, the only atypical antipsychotic for which several studies on patients suffering predominantly from negative symptoms have been published. In four such studies, amisulpride was significantly superior to placebo. Three small studies with conventional neuroleptics as a comparator showed only a trend in favour of amisulpride in this regard. Amisulpride was associated with fewer extrapyramidal side-effects and fewer drop-outs due to adverse events than conventional neuroleptics. These results clearly show that amisulpride is an 'atypical' antipsychotic, and they cast some doubt on the notion that combined 5-HT2-D2 antagonism is the only reason for the high efficacy against negative symptoms and fewer extrapyramidal side-effects.