Aripiprazole,a novel antipsychotic,is a high-affinity partial agonist at human dopamine D2 receptors

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.     

Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist

Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of Galphao induces constitutive activity in the human D2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D2 and D3 inverse agonists, whereas none was D4 inverse agonist, although many were potent D4 antagonists. The inverse agonist activity of haloperidol at D2 and D3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D2 and D3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.     

Differential effects of antipsychotic drugs on serotonin-1A receptor-mediated disruption of prepulse inhibition

Serotonin-1A (5-HT(1A)) receptors have been implicated in the symptoms of schizophrenia. However, there is limited in vivo evidence for an interaction of antipsychotic drugs with 5-HT(1A) receptor-mediated behavioral effects. We therefore investigated in rats the action of several antipsychotic drugs on prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Disruption of PPI at the 100-ms interstimulus interval (ISI), but not the 30-ms ISI, was induced by treatment with 0.5 mg/kg 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), the 5-HT(1A) receptor agonist. In rats pretreated with 0.25 mg/kg haloperidol (4-[-4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluoro butyrophenone) or raclopride [3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide tartrate], the disruption of PPI was no longer significant. Of the atypical antipsychotic drugs clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine), olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine), risperidone [3-[2-[-4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one)], amisulpride (4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-o-anisamide), and aripiprazole (7-[4-[-4[-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyrilor 7-[4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butoxy]-1,2,3,4,-tetrahydroquinolin-2-one), only aripiprazole significantly reduced the effect of 8-OH-DPAT on PPI. This effect was mimicked by pretreatment with the 5-HT(1A) receptor partial agonist, buspirone [N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride]. On the other hand, some of the antipsychotic drugs and other pretreatments showed complex, prepulse-dependent effects on their own. These data show little in vivo interaction of several atypical antipsychotic drugs with the disruption of PPI mediated by 5-HT(1A) receptor stimulation. The action of haloperidol and raclopride suggests a major involvement of dopamine D(2) receptors in this effect, possibly downstream from the initial serotonergic stimulation. The action of aripiprazole could be mediated by its partial agonist properties at 5-HT(1A) receptors or its dopamine D(2)-blocking properties.     

Acute and subchronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic function

The potential antipsychotic drug, MJ-13859, was tested for its acute and subchronic effects on rat brain dopaminergic neurotransmission and function. This drug exhibited an IC50 for displacement of [3H]spiperone binding of 6.35 nM which was similar to trifluoperazine, a potent classical antipsychotic drug. In female rats, MJ-13859 was slightly less potent than trifluoperazine for induction of catalepsy, inhibition of stimulant-induced hyperactivity and for increasing striatal, frontal cortical and olfactory tubercule dopamine metabolism. Both drugs also blocked dopamine autoreceptors on striatal dopamine nerve endings. When administered i.p., rather than s.c., the effect of MJ-13859 on dopamine metabolism was reduced significantly. When administered to male rats, the response of dopamine metabolism to drug was reduced, but a similar inhibition of stimulated activity occurred as in female rats. These results suggest a rapid first pass metabolism of MJ-13859 in the rat and that the antistimulant effect may be partly independent of the antidopaminergic effects. Osmotic minipumps were implanted s.c. for 2 week continuous infusion of MJ-13859 at doses of 1.0 or 3.0 mg/kg/day. Unlike classical antipsychotic drugs, MJ-13859 did not cause a subsensitivity to the ability of acute haloperidol challenge (0.1 mg/kg s.c.) to increase dopamine metabolism. After allowing a 4-day drug washout period before [3H]spiperone binding assay for D2 receptors, neither the maximum binding nor Kd were altered in rats treated for 2 weeks with 3.0 mg/kg/day of MJ-13859. Haloperidol at 1.0 mg/kg/day for 2 weeks caused a 57% increase in D2 receptor maximum binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability

BACKGROUND: Recently approved for the treatment of schizophrenia, aripiprazole represents the sixth second-generation antipsychotic (SGA) introduced to the US market. Aripiprazole is considered a partial dopaminergic agonist, acting on both postsynaptic dopamine(2) receptors and presynaptic autoreceptors, in addition to displaying partial agonism at serotonin(1A) receptors and antagonism at serotonin(2A) receptors. OBJECTIVE: The aim of this study was to comprehensively review all available literature regarding the mechanism of action, pharmacokinetics, clinical efficacy, and adverse effects of aripiprazole. METHODS: Relevant data were collected using MEDLINE and International Pharmaceutical Abstracts searches with the terms aripiprazole and OPC-14597 and with no limitations on year. Abstracts and posters presented at national and international scientific meetings were also reviewed. RESULTS: Aripiprazole exhibits linear pharmacokinetics and is administered once daily. In multiple clinical trials, aripiprazole was effective in significantly reducing symptomatology associated with schizophrenia-related disorders compared with placebo (P < 0.05). Dosages > or =15 mg/d more consistently produced significant reductions from baseline of Positive and Negative Syndrome Scale total scores (P < 0.05) and were more likely to elicit a response than smaller dosages. Effects observed were comparable to those seen with risperidone and haloperidol, which were also significantly more effective than placebo (P < or = 0.05). Aripiprazole exhibited a favorable safety and tolerability profile, with a low propensity to cause extrapyramidal symptoms, weight gain, cardiovascular abnormalities, hyperprolactinemia, hypercholesterolemia, or glucose dysregulation. CONCLUSIONS: Aripiprazole represents a well-tolerated and effective addition to the antipsychotic armamentarium. However, definitive advantages associated with dopamine partial agonism have yet to be determined. Long-term, head-to-head comparisons with other SGAs are needed to establish the effects of chronic administration and the relative safety and efficacy of aripiprazole.     

Detection of Human Retroviruses by PCR

The neurotransmitter dopamine (DA) plays a central role in the control of motor function, emotional states, and endocrine physiology. The discovery that schizophrenic symptoms can be alleviated by neuroleptic drugs and the finding that these drugs interact at dopamine receptors has indicated involvement of the dopamine system in schizophrenia. The dopamine system has recently been shown to rely on the activation of five distinct subtypes of DA receptors (D1-D5) identified by molecular cloning, and pharmacological studies have specifically implicated the D2-like receptors (D2R, D3R and D4R) in antipsychotic action. In addition, the localization of D3R and D4R expression in the mesolimbic/mesocortical DA pathways is consistent with their proposed involvement in affective behaviour, and suggests that drugs developed specifically for these receptor subtypes might have potent antipsychotic activity with a lower propensity for extrapyramidal, endocrine, and cognitive side-effects.     

Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: III. Retinoids

Present antipsychotic drugs, whose clinical activity correlates with direct binding to dopamine D2 or other receptors, alleviate some of the symptoms of schizophrenia, but not all and not completely in many patients. In continuation of our overview of potential novel antipsychotic pharmacotherapy that would be based upon indirect modulation of dopamine or other neurotransmitter functioning, we focus in this article on the postulated use of retinoid analogs as novel antipsychotic agents. Several lines of evidence can be viewed as implicating retinoid dysregulation in schizophrenia, either as a causative or contributory factor. It has been proposed that using retinoid analogs to alter the downstream expression of dopamine D2 receptors might represent a novel approach to the treatment of the disease or amelioration of symptoms when used either as monotherapy or as adjunct pharmacotherapy to dopamine D2 receptor antagonists.     

Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: II. Glutamate (Ant)agonists

OBJECTIVE: To summarize the published preclinical and clinical data that suggest the possible use of glutamate receptor agonists or antagonists as novel antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included. DATA SYNTHESIS: The standard antipsychotic drugs, whose clinical activity correlates with affinity for dopamine D2 receptors, alleviate some of the positive symptoms of schizophrenia, but have limited impact on negative symptoms. Several lines of evidence implicate glutamate-receptor system dysfunction(s) in schizophrenia, either as causative or contributory factors. In addition, several standard antipsychotic drugs modulate glutamate or glutamate receptor activity, suggesting an alternative view of their mechanism of antipsychotic action. Preliminary studies have shown that drugs which modulate glutamate brain concentrations have positive effects in animal models of schizophrenia. CONCLUSIONS: A role for glutamate in the pathogenesis or pharmacotherapy of schizophrenia is suggested from anatomic (interactions between glutamatergic and dopaminergic systems in relevant brain regions), physiologic (implication of glutamate-receptor dysfunction), and pharmacologic (modulation of glutamate or glutamate receptors) evidence. Therefore, compounds that function at glutamate receptors might represent a novel approach to the treatment of the disease or to the amelioration of symptoms, either as monotherapy or as an adjunct to dopamine D2 receptor antagonists.     

Dopamine receptors and psychiatric drug treatment

The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain. Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine-containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals. The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro-striatal and tubero-infundibular mechanisms in the neurological and neuroendocrine effects of these drugs. Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques, providing more direct evidence of dopamine receptor blockade by neuroleptic drugs. Further research is needed especially in studying the nature of the time-dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain. The different subtypes of dopamine receptors in the brain, currently called D1 and D2 dopamine receptors, seem to be parallel, although in many respects independently-acting regulatory systems. Dopamine D2 receptor-selective antagonists such as sulpiride seem to cause selective D2 receptor up-regulation. Prolactin secretion seems to be regulated by D2 dopamine receptors. The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known. Sulpiride and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action, the former having strong and selective antidopaminergic action, the latter combining a number of non- dopaminergic mechanisms with rather slight effects on dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine receptors--physiological understanding to therapeutic intervention potential

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.     

Aripiprazole-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Aripiprazole is a newer atypical antipsychotic agent used for effective treatment of schizophrenia. It significantly reduces unwanted side effects of older typical antipsychotics by targeting, with high affinity, dopamine D2/D3 and serotonin 5-HT1A/5-HT-2A receptors. Its documented mechanism of action makes it an unlikely agent to cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present the first reported case of SIADH caused by aripiprazole in a patient with history of schizophrenia without other precipitating factors to explain hyponatremia or SIADH.     

The role of serotonin and dopamine in schizophrenia

For many years schizophrenia was attributed to an overabundance of dopamine in the brain, and until recently conventional neuroleptics (dopamine-D₂ receptor antagonists) have been the mainstay of pharmacologic treatment for patients with this illness. The dopaminergic mechanism of action makes conventional neuroleptics effective for the positive symptoms of schizophrenia but not for the negative symptoms. It is now recognized that serotonin also plays an important role in the pathogenesis of schizophrenia. By blocking both dopamine and serotonin receptors, the newer antipsychotic agents such as clozapine, risperidone, and olanzapine are effective for both the positive and negative symptoms of schizophrenia and are less likely than conventional neuroleptics to cause extrapyramidal symptoms at prescribed doses. Although the newer antipsychotics are tolerated better than conventional neuroleptics, each of these newer drugs is associated with some adverse effects, such as hypotension and sedation. Further research into the neurobiology of schizophrenia may lead to the development of even more effective and safe antipsychotic medications for schizophrenia.     

Relationship between dose, drug levels, and D2 receptor occupancy for the atypical antipsychotics risperidone and paliperidone

Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [(18)F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.     

Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain

Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (5-HT)1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to high pressure liquid chromatography with electrochemical detection to examine 5-HT1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone, and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT1A autoreceptors. These decreases were reversed by the selective 5-HT1A antagonist, WAY100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide]. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone, and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan, and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine, and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride, and the D2 partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D2 and 5-HT1A receptors may present distinctive therapeutic properties.     

Markers of D(2) and D(3) receptor activity in vivo: PET scan and prolactin

Positrons Emission Tomography (PET) allows to evaluate the dopaminergic activity of antipsychotic, by measuring post synaptic D(2) dopaminergic receptors occupancy. A good correlation was brought forward between a rate of occupancy of 80% of striatal D(2) receptors and the occurrence of extrapyramidal effects. These PET studies have also established that at least 60% D(2) receptors occupancy was predictive of clinical antipsychotic response. The PET studies in healthy volunteers can then be used to help choose doses to be tested during the clinical trials of new antipsychotic drugs. The increase in prolactin level is one other of the markers of the antagonist dopaminergic activity which concerns D(2) receptors of the pituitary gland. The example of S 33138, a potential antipsychotic, preferential D(3) versus D(2) receptor antagonist will be given to illustrate these data. The results of two PET studies as well as the effects on prolactin and extrapyramidal signs will be presented.     

Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data

The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele Nco I C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while there is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hvpersensitivity.     

Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.     

Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors

Although antagonism of mesolimbic dopamine D(2) receptors by neuroleptics such as haloperidol attenuates positive symptoms of schizophrenia, a significant population of "resistant" patients fails to respond while negative and cognitive symptoms are little modified. Furthermore, concomitant blockade of striatal D(2) receptors is associated with extrapyramidal motor side effects. The superior "atypical" antipsychotic profile of clozapine appears to reside in its broad pattern of interaction with D(2) receptors and a diversity of other monoaminergic sites. In this regard, serotonergic mechanisms are of particular relevance both in view of their modulation of dopaminergic transmission and their key role in the control of mood, cognition, and motor behavior. While most attention has focused on potential advantages of preferential 5-HT(2A) versus D(2) receptor blockade, 5-HT(1A) receptors likewise represent a valid target for improved antipsychotic agents. In this regard, rather than selective agents, ligands interacting with both 5-HT(1A) and D(2) receptors appear of interest. A modest level of efficacy appears optimal, that is, sufficient to engage highly sensitive 5-HT(1A) autoreceptors while blocking their low-sensitivity postsynaptic counterparts. Such a profile may counter negative and cognitive symptoms, improve mood, diminish extrapyramidal 5-HT(1A) motor side effects, and, perhaps, enhance efficacy in refractory patients. Notably, "partial agonist" properties of clozapine at 5-HT(1A) receptors may contribute to its distinctive functional profile. However, notwithstanding this compelling body of experimental data, clinical studies of antipsychotics interacting with 5-HT(1A) receptors are required to establish their genuine pertinence to the-hopefully improved-treatment of schizophrenia.     

Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors

Clozapine is the prototype atypical antipsychotic drug, producing little or no extrapyramidal side effects, while improving negative symptoms of psychosis. Clozapine's high affinity for serotonin receptors has been hypothesized to confer the unique antipsychotic properties of this drug. Recently, we demonstrated that both typical and atypical antipsychotic drugs are inverse agonists at constitutively active 5-hydroxytryptamine2A (5-HT(2A)) receptors. To determine whether inverse agonist activity at 5-HT(2C) receptors plays a role in antipsychotic efficacy, typical and atypical antipsychotic drugs were tested for inhibition of basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. Atypical antipsychotic drugs (sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine, tenilapine) displayed potent inverse agonist activity at rat and human 5-HT(2C) receptors. Typical antipsychotic drugs (chlorpromazine, loxapine, thioridazine, prochlorperazine, perphenazine, mesoridazine, trifluperidol, fluphenazine, spiperone, haloperidol, pimozide, penfluridol, thiothixene) were devoid of inverse agonist activity, with the exception of loxapine. We review the evidence that loxapine has unique properties characteristic of both atypical and typical antipsychotic drugs. Several typical antipsychotic drugs (chlorpromazine, thioridazine, spiperone, thiothixene) displayed neutral antagonist activity by reversing clozapine inverse agonism. These data suggest that 5-HT(2C) inverse agonist activity is associated with atypical antipsychotic drugs with moderate to high affinity for 5-HT(2C) receptors, and imply that effects of atypical antipsychotic drugs on the 5-HT(2C) receptor may play a role in their unique clinical properties. These data also imply that dysfunction of brain 5-HT(2C) receptor systems may be one of the factors involved in the etiology of psychosis.