Dopamine D2 Antagonist Research Articles

Dopamine antagonists can inhibit methamphetamine sensitization, but not cocaine sensitization, when assessed by ambulatory activity in mice.

The repeated subcutaneous administration of methamphetamine (2 mg kg-1) and cocaine (10 mg kg-1) at 3-4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.003-0.03 mg kg-1) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide; 0.003-0.03 mg kg-1), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151-2 in the repeated administration schedule. Although SCH 23390 (0.01-0.1 mg kg-1) and YM-09151-2 (0.01-0.1 mg kg-1) also reduced the ambulation-increasing effect of cocaine (10 mg kg-1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0.03 mg kg-1) or YM-09151-2 (0.03 and 0.1 mg kg-1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D1 and D2 antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.

Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice.

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Crystallographic, theoretical and molecular modelling studies on the conformations of the salicylamide, raclopride, a selective dopamine-D2 antagonist.

The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamid e (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (less than 4.0 kcal mol-1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Previous findings suggest differences in the neuroanatomical substrates of short- (seconds) vs longer-duration (minutes) fear responses. We now report that phasic and sustained fear can also be differentiated pharmacologically, based on their response to several treatments that either are or are not clinically effective anxiolytics. For these experiments, short- or long-duration clicker stimuli were paired with footshock. Acoustic startle amplitude was later measured in the absence of the clicker, or within seconds (phasic fear) or minutes (sustained fear) of its onset. Before testing, rats received a single injection of vehicle, the benzodiazepine chlordiazepoxide, the 5HT(1A) agonist and dopamine D2 antagonist buspirone, the selective serotonin reuptake inhibitor fluoxetine, or a 3-week treatment with either vehicle or fluoxetine. Chlordiazepoxide blocked sustained, but not phasic startle increases. Acute buspirone, which is not anxiolytic in human beings, did not affect sustained startle increases, but did disrupt phasic increases. Chronic fluoxetine blocked sustained startle increases and unreliably reduced phasic increases; acute fluoxetine affected neither. The results indicate that phasic and sustained fear responses can be pharmacologically dissociated, further validating this distinction, and suggest that sustained startle increases may be especially useful as anxiety models and anxiolytic screens.

Iloperidone for the Management of Adults with Schizophrenia

Background Iloperidone is a second-generation antipsychotic drug approved in May 2009 by the US Food and Drug Administration (FDA) for the acute treatment of schizophrenia in adults. It is a piperidinyl-benzisoxazole derivative with mixed serotonin (5HT2A) and D2 dopamine antagonist properties. Objective The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, safety, and role in treatment for iloperidone in schizophrenia. Methods Scientific and clinical data were collected through searches of PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts, and the FDA, using the search term iloperidone, and limited to English-language articles. Reference lists were reviewed for additional publications. Dates included the beginning of the database through 2010. No limits were placed on study design. Results In a 4-week Phase III trial, iloperidone 12 mg twice daily lowered the Positive and Negative Syndrome Scale (PANSS) total scores to a significantly greater extent than did placebo (−12 vs −7.1; P < 0.01). The ziprasidone active control also separated from placebo (−12.3 vs −7.1; P < 0.05). A pooled analysis of 3 Phase III trials compared iloperidone in divided doses to placebo. The primary outcome was reduction in PANSS scores. Study 1 included iloperidone 4, 8, or 12 mg/d, haloperidol as an active control, and placebo. The PANSS reduction in the 12 mg/d group was significantly greater at end point versus baseline when compared with placebo (−9.9 vs −4.6; P = 0.047). Study 2 included iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, or placebo. The primary efficacy measure was change from baseline to end point in the Brief Psychiatric Rating Scale (BPRS). Improvement from baseline on all iloperidone doses was significantly greater than with placebo (4–8 mg/d group: −6.2, P = 0.012; 10–16 mg/d group: −7.2, P = 0.001; placebo, −2.5). Study 3 included iloperidone 12 to 16 mg/d, risperidone 6 to 8 mg/d, and placebo. The results on the primary efficacy variable, reduction in the BPRS score, was not significant for the 12 to 16 mg/d group versus placebo (−7.1 vs −5.0; P = 0.09), but was significant for the 20 to 24 mg/d iloperidone group (−8.6 vs −5.0; P = 0.01) and for the risperidone group (−11.5 vs 5.0; P < 0.001). A 52-week maintenance trial included iloperidone versus haloperidol as an active control. The primary efficacy variable was time to relapse. Comparison of mean time to relapse of the 2 arms showed no significant difference. The most common adverse events (AEs) associated with iloperidone were dizziness (5.1%–23.2%), dry mouth (5.2%–10.4%), somnolence (4%–13%), and dyspepsia (4.8%–7.8%). AEs appeared dose related. Prescribing information recommends a starting dosage of 1 mg twice daily and then titrated over 7 days to reach a target dosage of 12 to 24 mg/d. The titration is necessary to reduce the risk of orthostatic hypotension-related dizziness. Conclusions Data support that when titrated slowly to a therapeutic dosage, iloperidone is generally well tolerated, has a favorable safety profile, and is an effective treatment option in patients with schizophrenia. Its place in therapy and performance in a typical patient population remain to be established. Slow initial titration and twice-daily dosing are potential disadvantages.

Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2ncv = 0.829, R2pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2ncv =0.838, R2pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

Neuroleptic Malignant Syndrome Induced by Blonanserin

Back to table of contents Previous article Next article LettersFull AccessNeuroleptic Malignant Syndrome Induced by BlonanserinKeiko Ohoyama, M.D., Hisashi Tanii, M.D., Ph.D., Eishi Motomura, M.D., Ph.D., Yoshiaki Konishi, M.S., Masanori Nakagawa, M.D., Takuya Matsumoto, M.D., Ph.D., Takashi Shiroyama, M.D., Ph.D., and Motohiro Okada, M.D., Ph.D.Keiko OhoyamaDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSuisawa Psychiatric Hospital Yokkaichi, Mie, JapanSearch for more papers by this author, M.D., Hisashi TaniiDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu Mie, Japan; Brain Science and Animal Model Research Center (BSAM), Mie University, Tsu, Mie, JapanSearch for more papers by this author, M.D., Ph.D., Eishi MotomuraDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.D., Ph.D., Yoshiaki KonishiDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.S., Masanori NakagawaDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.D., Takuya MatsumotoDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.D., Ph.D., Takashi ShiroyamaDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.D., Ph.D., and Motohiro OkadaDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSearch for more papers by this author, M.D., Ph.D.Published Online:1 Jan 2011AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We report herein, what is, to our knowledge, the first case of neuroleptic malignant syndrome (NMS) related to blonanserin.Case ReportA 30-year-old woman with a diagnosis of mental retardation and with profound intellectual impairment (IQ<45) was admitted to a psychiatric hospital for the first time because of insomnia, psychomotor agitation, monologue, and persecutory delusions. After a 7-day period of medication withdrawal, blonanserin, 8 mg/day, was introduced for psychiatric symptoms such as emotional agitation, auditory hallucinations, and delusions. Her disturbed behavior with high agitation was slightly improved by the medication. After treatment with blonanserin for 7 days, the patient had a high fever (100.4°F) and was obtunded with muscle rigidity. She had a high pulse rate (104 bpm), and an elevated leukocyte level (8.5×109/liter), with extrapyramidal symptoms and perspiration. The patient was suspected to be developing NMS. Blonanserin was discontinued, and the patient received diazepam treatment. The next day, the fever disappeared and the serum leukocyte level was normalized (5.7∼5.9×109/liter). The possibility of infectious disease was excluded since the level of C-reactive protein was within the normal range and all the symptoms disappeared rapidly after treatment for neuroleptic malignant syndrome.DiscussionThis case report shows that neuroleptic malignant syndrome can occur after the introduction of blonanserin treatment. Blonanserin is a novel dopamine-serotonin antagonist with potent dopamine D2 and serotonin 5HT2 antagonist properties.1 Because of the receptor binding profile and pharmacological property of blonanserin, side effects such as extrapyramidal symptoms tend to occur less often with blonanserin than haloperidol.2 This patient had not been medicated with antipsychotic drugs before. Another important issue to be mentioned in this case is mental retardation, which is one of the risk factors for neuroleptic malignant syndrome.3 Several other risk factors should be taken into account in cases involving mentally retarded patients, whose symptoms often include dehydration, agitation, malnutrition, and exhaustion. Special caution with regard to patients who have risk factors for neuroleptic malignant syndrome is therefore necessary when starting to administer antipsychotic drugs.Department of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, JapanSuisawa Psychiatric Hospital Yokkaichi, Mie, JapanDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu Mie, Japan; Brain Science and Animal Model Research Center (BSAM), Mie University, Tsu, Mie, JapanDepartment of Psychiatry, Mie University Graduate School of Medicine, Tsu, Mie, Japan1. Oka M , Noda Y , Ochi Y, et al.: Pharmacological profile of AD-5423, a novel antipsychotic with both potent dopamine-D2 and serotonin-S2 antagonist properties. J Pharmacol Exp Ther 1993; 264:158–165Medline, Google Scholar2. Garcia E , Robert M , Peris F, et al.: The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, double-blind, placebo-controlled, multicentre study. CNS Drugs 2009; 23:615–625Crossref, Medline, Google Scholar3. Viejo LF , Morales V , Punal P, et al.: Risk factors in neuroleptic malignant syndrome: a case-control study. Acta Psychiatr Scand 2003; 107:45–49Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 23Issue 1 Winter 2011Pages E13-E13 Metrics PDF download History Published online 1 January 2011 Published in print 1 January 2011

Glutamatergic antipsychotic drugs: a new dawn in the treatment of schizophrenia?

Growing evidence for glutamate abnormalities in schizophrenia support the development of novel antipsychotic agents targeting this system. Early studies investigating modulation of the glutamate system using glycine, D-serine and sarcosine in patients with schizophrenia have demonstrated significant effects, particularly on negative symptoms, conventionally thought to be refractory to antipsychotic drug treatment. Drugs targeting the glutamate system also have a completely different side-effect profile to dopamine D2 antagonists, with no propensity to extrapyramidal side effects, prolactinaemia or weight gain. It has been hypothesized that glutamatergic drugs may be of benefit to the 20-30% of individuals with schizophrenia who fail to show any response to dopaminergic agents, and may be particularly useful in the early stages of the illness, where they may be disease-modifying. A number of glutamatergic compounds have been reported as having promising results in phase II drug trials. If these reach the clinic, they will represent the first truly novel approach to pharmacotherapy in schizophrenia for more than 50 years.

The role of neurotensin and dopamine interaction in conditioned place preference

Event Abstract Back to Event The role of neurotensin and dopamine interaction in conditioned place preference K. László1, A. Madarassy-Sz1, Á. Kiss1, K. Tóth1, T. Ollmann1, L. Péczely2, E. Kertes2 and L. Lénárd1, 2* 1 Pécs University Medical School, Institute of Physiology, Hungary 2 Pécs University Medical School, Neurophysiology Research Group of the HAS, Hungary Tridecapeptide Neurotensin (NT) in the central nervous system acts as a neurotransmitter and neuromodulator. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. We recently showed that NT microinjected into the CeA plays a role in positive reinforcement. We supposed that these effects might be due to modulations of mesolimbic-mesocortical dopamine (DA) system. The aim of our study was to examine in the CeA the possible effects of NT and dopamine interaction on reinforcement in conditioned place preference test. Male wistar rats were microinjected bilaterally with 100 ng NT or 250 ng NT (Sigma: N 3010, injected in volume of 0.4 μl) or 35 ng NTS1 antagonist SR 48692 (Sanofi-Synthelabo) alone, or NTS1 antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA. Other animals received 5 µg D2 receptor antagonist (sulpiride: Sigma: S7771, injected in volume of 0.4 μl) alone, or D2 receptor antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA. Rats that received 100 ng NT or 250 ng NT spent significantly more time in the treatment quadrant during the test session. Prior treatment with the non-peptide NTS1 antagonist, equimolar to NT treatment (60 pM and 60 pM, respectively) blocked the effects of NT. Prior treatment with dopamine D2 receptor antagonist blocked the positive reinforcing effects of NT. Antagonists in themselves did not influence the place preference. Our results show that in the rat CeA NT has positive reinforcing effect via NTS1, because selective NTS1 antagonist can block this action. The rewarding effect of NT may be due to the modulation of DA system, since it could be blocked by DA D2 antagonist preteatment. Acknowledgements Supported by NKTH-OTKA K68431 and by the HAS. Keywords: Behaviour and cognition, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Behaviour and cognition Citation: László K, Madarassy-Sz A, Kiss Á, Tóth K, Ollmann T, Péczely L, Kertes E and Lénárd L (2011). The role of neurotensin and dopamine interaction in conditioned place preference. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00168 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. L. Lénárd, Pécs University Medical School, Institute of Physiology, Pécs, Hungary, Laszlo.Lenard@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers K. László A. Madarassy-Sz Á. Kiss K. Tóth T. Ollmann L. Péczely E. Kertes L. Lénárd Google K. László A. Madarassy-Sz Á. Kiss K. Tóth T. Ollmann L. Péczely E. Kertes L. Lénárd Google Scholar K. László A. Madarassy-Sz Á. Kiss K. Tóth T. Ollmann L. Péczely E. Kertes L. Lénárd PubMed K. László A. Madarassy-Sz Á. Kiss K. Tóth T. Ollmann L. Péczely E. Kertes L. Lénárd Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies

Motor stereotypy is a key symptom of various disorders such as Tourette's syndrome and punding. Administration of nicotine or cholinesterase inhibitors is effective in treating some of these symptoms. However, the role of cholinergic transmission in motor stereotypy remains unknown. During strong cocaine-induced motor stereotypy, we showed earlier that increased dopamine release results in decreased acetylcholine release in the territory of the dorsal striatum related to the prefrontal cortex. Here, we investigated the role of striatal cholinergic transmission in the arrest of motor stereotypy. Analysis of N-methyl-d-aspartic acid-evoked release of dopamine and acetylcholine during declining intensity of motor stereotypy revealed a dissociation between dopamine and acetylcholine release. Whereas dopamine release remained increased, the inhibition of acetylcholine release decreased, mirroring the time course of motor stereotypy. Furthermore, pharmacological treatments restoring striatal acetylcholine release (raclopride, dopamine D2 antagonist; intraperitoneal or local injection in prefrontal territory of the dorsal striatum) rapidly stopped motor stereotypy. In contrast, pharmacological treatments that blocked the post-synaptic effects of acetylcholine (scopolamine, muscarinic antagonist; intraperitoneal or striatal local injection) or induced degeneration of cholinergic interneurons (AF64A, cholinergic toxin) in the prefrontal territory of the dorsal striatum robustly prolonged the duration of strong motor stereotypy. Thus, we propose that restoration of cholinergic transmission in the prefrontal territory of the dorsal striatum plays a key role in the arrest of motor stereotypy.

In vitro and in vivo comparison of [3H](+)‐PHNO and [3H]raclopride binding to rat striatum and lobes 9 and 10 of the cerebellum: A method to distinguish dopamine D3 from D2 receptor sites: A method to distinguish dopamine D3 from D2 receptor sites

In vitro binding characteristics of the dopamine D₃/D₂ antagonist [³H]raclopride were compared to the D₃/D₂ agonist [³H](+)-PHNO in membrane preparations from rat striatum, cerebellum Lobules 9 and 10 (CB L9,10), and other cerebellar regions. In striatum, both radioligands labeled a single binding site. [³H](+)-PHNO showed higher affinity, though lower B(max) , compared with [³H]raclopride and was sensitive to inhibition by Gpp(NH)p. [³H](+)-PHNO showed significant specific binding to CB L9,10 membranes with higher affinity compared to striatal membranes. [³H](+)-PHNO binds to a high- and a low-affinity binding site in CB L9,10 membranes; the high-affinity site was not Gpp(NH)p-sensitive. [³H](+)-PHNO did not significantly bind cerebellum left hemisphere membranes. Very low specific binding of [³H]raclopride was found in CB L9,10. The selective dopamine D₃ antagonist SB-277011 did not displace the binding of either ligand to striatal membranes but potently inhibited the binding of [³H](+)-PHNO in CB L9,10 membranes. The highly selective D₂ antagonist SV-156 showed the opposite profile. In vivo experiments were consistent with and supported by in vitro results. In summary, [³H](+)-PHNO and [³H]raclopride mainly label dopamine D₂ receptors in rat striatum, with [³H](+)-PHNO labeling a D₂(High) population. In vitro and in vivo, [³H](+)-PHNO labels CB L9,10 dopamine D₃ receptors that are apparently in a high affinity state whereas [³H]raclopride gave only very low signal in this region. The present approaches appear useful for selectively labeling dopamine D₃ and D₂ receptors in different rat brain regions and offer the possibility to demonstrate D₃ versus D₂ receptor selectivity of compounds using native rat brain tissue.

Dopamine D3 receptor knock-out mice display deficits in locomotor sensitization after chronic morphine administration

Locomotor sensitization is the progressive and enduring enhancement of locomotion induced by stimulants such as drugs, which alter rodent locomotion in a long-standing manner. The dopamine D3 receptor has been reported to play a role in morphine addiction. The aim of the present study was to investigate the role of dopamine D3 receptor in the morphine induced locomotor sensitization using dopamine D3 receptor knock-out mice. The dopamine D3 receptor knock-out mice did not display an enhanced behavioral response to acute morphine administration or develop an increased rate of locomotor sensitization to intermittent morphine administration. When 2 mg/kg naloxone was co-administered with 10 mg/kg morphine, morphine-induced locomotion sensitization in wild-type mice was significantly blocked while the locomotion in the D3 receptor knock-out mice was decreased. Then the wild-type mice were administered with dopamine D3 antagonist nafadotride. It was found that co-administration of morphine with nafadotride could effectively suppress the level of morphine induced behavioral sensitization. It was concluded that a loss of the dopamine D3 receptor gene may inhibit acute morphine induced hyperlocomotor activity and chronic morphine induced behavioral sensitization.

Droperidol Analgesia for Opioid-Tolerant Patients

Background Patients with acute and chronic pain syndromes such as migraine headache, fibromyalgia, and sickle cell disease represent a significant portion of emergency department (ED) visits. Certain patients may have tolerance to opioid analgesics and often require large doses and prolonged time in the ED to achieve satisfactory pain mitigation. Droperidol is a unique drug that has been successfully used not only as an analgesic adjuvant for the past 30 years, but also for treatment of nausea/vomiting, psychosis, agitation, sedation, and vertigo. Objectives In this review, we examine the evidence supporting the use of droperidol for analgesia, adverse side effects, and controversial United States (US) Food and Drug Administration (FDA) black box warning. Discussion Droperidol has myriad pharmacologic properties that may explain its efficacy as an analgesic, including: dopamine D2 antagonist, dose-dependent GABA agonist/antagonist, α2 adrenoreceptor agonist, serotonin antagonist, histamine antagonist, muscarinic and nicotinic cholinergic antagonist, anticholinesterase activity, sodium channel blockade similar to lidocaine, and μ opiate receptor potentiation. Conclusion Droperidol is an important adjuvant for patients who are tolerant to opioid analgesics. The FDA black box warning does not apply to doses below 2.5 mg.

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition

Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism

Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice. However, less is known about the effects of adenosine A1 antagonists. Despite anatomical data showing that A1 and D1 receptors are co-localized on the same striatal neurons, it is uncertain if A1 antagonists can reverse the effects DA D1 antagonists. The present work systematically compared the ability of adenosine A1 and A2A receptor antagonists to reverse the effects of DA D1 and D2 antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D1 antagonist ecopipam (0.2 mg/kg i.p.) and the D2 antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D1 or D2 antagonist. In contrast, the adenosine A2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of ecopipam. Adenosine A2A and DA D2 receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.

Id1, Id2 and Id3 are induced in rat melanotrophs of the pituitary gland by dopamine suppression under continuous stress

In rats under continuous stress (CS) there is decreased hypothalamic dopaminergic innervation to the intermediate lobe (IL) of the pituitary gland, which causes hyperactivation and subsequent degeneration of melanotrophs in the IL. In this study, we investigated the molecular basis for the changes that occur in melanotrophs during CS. Using microarray analysis, we identified several genes differentially expressed in the IL under CS conditions. Among the genes up-regulated under CS conditions, we focused on the inhibitor of DNA binding/differentiation (Id) family of dominant negative basic helix-loop-helix (bHLH) transcription factors. RT-PCR, Western blotting and in situ hybridization confirmed the significant inductions of Id1, Id2 and Id3 in the IL of CS rats. Administration of the dopamine D2 receptor agonist bromocriptine prevented the inductions of Id1–3 in the IL of CS rats, whereas application of the dopamine D2 antagonist sulpiride induced significant expressions of Id1–3 in the IL of normal rats. Moreover, an in vitro study using primary cultured melanotrophs demonstrated a direct effect on Id1–3 inductions by dopamine suppression. These results suggest that the decreased dopamine levels in the IL during CS induce Id1–3 expressions in melanotrophs. Because Id family members inhibit various bHLH transcription factors, it is conceivable that the induced Id1–3 would cooperatively modulate gene expressions in melanotrophs under CS conditions to induce hormone secretion.

Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation

Brain dopamine, particularly in the nucleus accumbens, has been implicated in activational aspects of motivation and effort-related processes. Accumbens dopamine depletions reduce the tendency of rats to work for food, and alter effort-related decision making, but leave aspects of food motivation such as appetite intact. Recent evidence indicates that the purine neuromodulator adenosine, largely through actions on adenosine A2Areceptors, also participates in regulating effort-related processes. Adenosine A2Aantagonists can reverse the effects of dopamine D2antagonists on effort-related choice, and intra-accumbens injections of adenosine A2Aagonists produce effects that are similar to those induced by accumbens dopamine depletion or antagonism. These studies have implications for the understanding and treatment of energy-related disorders such as anergia and fatigue in psychiatry and neurology.

Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats

There appears to be a relatively narrow range of contingencies in which intravenous (i.v) infusions of nicotine will maintain responding in rats. The schedule of reinforcement typically used when investigating i.v. nicotine self-administration is a simple fixed-ratio (FR) schedule. This study determined if responding in rats could be established using a multiple schedule of either i.v. cocaine or nicotine and sucrose reinforcement. Following training of individual components with each reinforcer, rats were placed on an FR15 60-s timeout multiple schedule of cocaine (0.3 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement or an FR5 60-s timeout multiple schedule of nicotine (0.03 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement. Both cocaine and nicotine maintained significant levels of responding under the multiple schedule. Pretreatment with the dopamine D1 antagonist SCH 23390 increased cocaine-maintained responding, but not sucrose responding. Acute pretreatment with the nicotinic antagonist mecamylamine or SCH 23390 specifically decreased nicotine self-administration. Extinction of the individual nicotine and sucrose components resulted in decreases in responding in each component under extinction. These results indicate that i.v. nicotine maintains responding under a multiple schedule. This procedure may be useful when studying the specificity of drug pretreatments on nicotine self-administration.

Detailed analysis of food-reinforced operant lever pressing distinguishes effects of a cannabinoid CB1 inverse agonist and dopamine D1 and D2 antagonists

Overt similarities exist between the effects of systemic cannabinoid CB1 inverse agonists and dopamine (DA) antagonists on appetitive behavior. The present set of studies was undertaken to apply a fine-grained analysis of food-reinforced operant lever pressing in rats in order to compare the pattern of effects produced by administration of the CB1 inverse agonist AM 251 and those induced by the DA D1 antagonist SKF 83566, and the D2 antagonist raclopride. Three groups of rats were trained on a fixed-ratio 5 (FR5) schedule and administered these compounds over a range of doses expected to suppress responding. All three drugs produced a dose-related suppression of total lever pressing. In addition to main effects of dose, regression analyses were performed to determine which of several response timing- and rate-related variables correlated most strongly with overall responding in each group. It was found that total session time spent pausing from responding was significantly better at predicting responding in the AM 251 group, while both DA antagonists produced significantly stronger regression coefficients (versus AM 251) from fast responding measures. These results suggest that, while several similarities exist, CB1, D1, and D2 antagonists are not identical in their pattern of suppression of food-maintained lever pressing.

Characterization of dopamine receptor subtypes involved in experimentally induced gastric and duodenal ulcers in rats.

There are conflicting reports about the role of dopamine in gastric and duodenal ulcers. This investigation was undertaken to characterize the specific subtypes of dopamine receptor involved in gastric and duodenal ulceration. Administration of dopamine D1 agonist fenoldopam and dopamine D2 antagonist sulpiride elicited a significant decrease in acid secretion, total acid output, pepsin output and histamine content in the gastric juice, and reduced ulcer-index values, in pylorus-ligated rats. However, dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo (d) naptho -(2,1-b) azepine) and the D2 receptor agonist quinpirole led to significant augmentation of these parameters compared with respective controls. In the restraint plus water-immersion stress model the score for intraluminal bleeding and the cumulative gastric lesion length was significantly lower for rats treated with fenoldopam and sulpiride. The opposite effects were observed after pretreatment of rats with SCH 39166 and quinpirole. In the cysteamine-induced duodenal ulcer model the mean ulcer area and the score for intensity were significantly lower for fenoldopam and sulpiride and higher for SCH 39166 and quinpirole. Our data suggest that the dopamine D1 and D2 receptors have opposite effects on gastric and duodenal ulcers. Whereas stimulation of dopamine D1 receptors inhibits the formation of gastric and duodenal ulcers, stimulation of dopamine D2 receptors has a pro-ulcerogenic effect.