mdl-100907 and Dyskinesia--Drug-Induced

Explaining the underlying mechanisms of antipsychotic drug-induced movement disorders remains a substantial challenge. The association of atypical antipsychotic agents with fewer drug-induced movement disorders than conventional agents has engendered several pathophysiologic hypotheses: (1) the hypothesis that, unlike conventional antipsychotic agents, atypical antipsychotics have greater activity in blocking serotonin-2A (5-HT(2A)) receptors than dopamine-2 (D(2)) receptors, which mitigates extrapyramidal symptoms; (2) the hypothesis that atypical antipsychotics block D(2) receptors only long enough to cause an antipsychotic action, but not as long as conventional agents; (3) the hypothesis that, in tardive dyskinesia, the nigrostriatal dopamine receptor system might develop increased sensitivity to dopamine as a result of treatment with conventional antipsychotic drugs, but this may not occur with atypical antipsychotics; and (4) the hypothesis that there might be a genetic association in tardive dystonia relating to the dopamine D(3) allele. A number of factors contribute to the difficult task of gaining insight into the pathophysiologic processes of antipsychotic agents and why these agents may lead to drug-induced movement disorders.

Topics: Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Models, Biological; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Sex Factors

Antagonising serotonin (5-HT) type 2A receptors (5-HT. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT. EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed.. Our results suggest that combining 5-HT

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Bridged Bicyclo Compounds; Callithrix; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Indoles; Levodopa; Male; Parkinsonian Disorders; Piperazines; Psychotic Disorders; Pyridines; Receptors, Metabotropic Glutamate; Serotonin 5-HT2 Receptor Antagonists; Sulfonamides

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Topics: Antipsychotic Agents; Dopamine; Dyskinesia, Drug-Induced; Excitatory Amino Acid Agents; Humans; Neostriatum; Oxidative Stress; Pharmacogenetics; Pyramidal Cells; Receptors, Serotonin, 5-HT2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord; Tardive Dyskinesia

Pharmacovigilance databases are usually used to detect new potential signals that are relevant for drug safety. They are seldom used for explanatory purposes, e.g. to understand the mechanisms of adverse drug reactions (ADRs). The aim of the present study was to combine pharmacovigilance and pharmacodynamic data to investigate the association between dopamine D2, serotonin 5HT2A, and muscarinic M1 receptor occupancy and the risks of antipsychotic drug (AP)-induced movement disorders.. First, we performed a case-noncase analysis using spontaneous reports from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database, VigiBase®. We thus measured the risk of reporting movement disorders compared with all other ADRs [expressed as a reporting odds ratio (ROR)] for APs. Second, we performed a linear regression analysis to explore the association between the estimated risk of reporting for individual drugs and their receptor occupancy properties, for D2, 5HT2A and M1 receptors.. Compared with second-generation APs, first-generation APs were found to be significantly more associated with the reporting of movement disorders in general but also with dystonia, Parkinsonism, akathisia and tardive dyskinesia, irrespective of gender. A significant inverse correlation was found between the ROR for movement disorders and the receptor occupancy of 5HT2A [P < 0.001; R. Using the example of AP-induced movement disorders, the present study underlines the value of the pharmacoepidemiological-pharmacodynamic method to explore ADR mechanisms in humans and real-life settings.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Muscarinic Antagonists; Pharmacoepidemiology; Pharmacovigilance; Serotonin 5-HT2 Receptor Antagonists; World Health Organization

There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.

Topics: Amphetamines; Animals; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; HEK293 Cells; Humans; Locomotion; Male; Mice; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Tics; Type C Phospholipases

Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear functional interactions between dopaminergic and serotonergic type 2A receptors (5-HT(2A))-mediated neurotransmission. Moreover, 5-HT(2A) receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT(2A)-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [(3)H]-ketanserin, was performed to define 5-HT(2A) receptor levels in brain tissue from macaques: 6 normal; 5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, parkinsonian macaques, without exposure to L-DOPA; 6 MPTP-lesioned, parkinsonian macaques, receiving a single administration of L-DOPA, and exhibiting no dyskinesia; and 6 MPTP-lesioned, parkinsonian, macaques chronically treated with L-DOPA, and exhibiting dyskinesia. 5-HT(2A) receptor binding was increased in the caudate, putamen, and middle layers of the motor cortex in chronically L-DOPA-treated animals, by 50%, 50%, and 45% respectively, compared with normal macaques. 5-HT(2A) binding was not significantly altered in parkinsonian, untreated, or parkinsonian, single treatment, nondyskinetic macaques, compared with normal. These data provide an anatomical basis for mechanisms to explain the efficacy of 5-HT(2A) antagonists against dyskinesia.

Topics: Animals; Autoradiography; Brain; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; MPTP Poisoning; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Synaptic Transmission

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT(2)) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT(2A) antagonist M100,907, the 5-HT(2C) antagonist SB242,084 and the mixed 5-HT(2A/C) antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT(2) receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT(2C) but not 5-HT(2A) mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2(2C) receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT(2C) antagonism could be targeted as a key property in the development of new antipsychotic medications.

Topics: Aminopyridines; Animals; Antipsychotic Agents; Brain Chemistry; Catalepsy; Dyskinesia, Drug-Induced; Fluorobenzenes; Gene Expression Regulation; Haloperidol; Immunohistochemistry; In Situ Hybridization; Indoles; Ketanserin; Male; Mouth; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; RNA, Messenger; Serotonin Antagonists

Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D(2) and 5-HT(2A) receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3-10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3-3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1-3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin.

Topics: Animals; Antipsychotic Agents; Catalepsy; Corpus Striatum; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Haloperidol; Male; Mice; Mice, Inbred Strains; Nucleus Accumbens; Piperazines; Piperidines; Proto-Oncogene Proteins c-fos; Pyridines; Serotonin 5-HT2 Receptor Antagonists

The effects of 7- and 21-day haloperidol treatment on the spinal serotonergic system were examined in vivo in acutely spinalized adult rats. Intravenous administration of a selective 5-HT(2A/2C) receptor agonist, (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (0.1 mg/kg) significantly increased the excitability of spinal motoneurones as reflected by increased monosynaptic mass reflex amplitude. This was significantly reduced in rats treated with haloperidol (1 mg/kg/day, i.p.) for 7 and 21 days. Administration of a 5-HT(1A/7) receptor agonist, (+/-)-8-Hydroxy dipropylaminotetraline hydrobromide (0.1 mg/kg, i.v.) significantly inhibited the monosynaptic mass reflex. This inhibition was greatly prolonged in haloperidol treated animals. These results demonstrate that the effects of haloperidol on the activation and desensitization of 5-HT(1A) and 5-HT(2A/2C) receptors respectively, may be mediated via intracellular mechanisms shared by these receptors with dopamine D(2) receptors in the mammalian spinal cord. The above serotonergic mechanisms may be partly responsible for haloperidol-induced extrapyramidal motor dysfunction.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Antipsychotic Agents; Dyskinesia, Drug-Induced; Electrophysiology; Haloperidol; Male; Rats; Rats, Wistar; Receptors, Dopamine D2; Reflex, Monosynaptic; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Spinal Cord

With the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

Topics: Antipsychotic Agents; Brain; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Weight Gain