Binding of Typical and Atypical Antipsychotic Drugs to Multiple Neurotransmitter Receptors

Roth, Bryan L.; Meltzer, Herbert Y.; Khan, Naseem

doi:10.1016/s1054-3589(08)60793-0

Cited by 118 publications

(142 citation statements)

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“…Thus, for instance, mice with targeted deletions of the 5-HT 2C receptor are obese (Tecott et al, 1995). Additionally, many typical and atypical antipsychotic drugs have high 5-HT 2C receptor affinities (Canton et al, 1990;Roth et al, 1992), and many antipsychotic drugs are potent 5-HT 2C inverse agonists (Herrick-Davis et al, 2000;Rauser et al, 2001). Finally, 5-HT 2C knockout mice are resistant to the anorectic effects of fenfluramine (Vickers et al, 1999), although chronic administration of potent and selective 5-HT 2C antagonists does not induce weight gain in rats (Wood et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Altered glucose homeostasis and metabolism as well as increased food intake have been proposed as mechanisms responsible for antipsychotic-drug-induced weight gain. Typical and atypical antipsychotic drugs have a complex pharmacology, interacting with a number of serotonergic (eg 5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 (Roth et al, 1992(Roth et al, , 1994(Roth et al, , 1998, dopaminergic (eg D 2 , D 3 , and D 4 (Seeman and Lee, 1975;Seeman et al, 1997;Van Tol et al, 1991), histaminergic (eg H 1 (Peroutka et al, 1980) and H 4 (Nguyen et al, 2001)), adrenergic, and muscarinic acetylcholine receptors (Bolden et al, 1992;Zeng et al, 1997). In mice, targeted deletion of some of these receptors can have effects on body weight; for example, 5-HT 2C receptor knockout mice are obese (Tecott et al, 1995), whereas m3-muscarinic receptor knockout mice are lean (Yamada et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

698

494

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As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT 2A and 5-HT 2C serotonin receptors, H 1 -histamine receptors, a 1 -and a 2 -adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H 1 -histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman r ¼ À0.72; po0.01), as were affinities for a 1A adrenergic (r ¼ À0.54; po0.05), 5-HT 2C (r ¼ À0.49; po0.05) and 5-HT 6 receptors (r ¼ À0.54; po0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H 1 , a 2A , a 2B , 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors were most highly correlated with the first principal component, and affinities for the D 2 , 5-HT 1A , and 5-HT 7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H 1 and a 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H 1 -histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H 1 -histamine receptor antagonists are known to induce weight gain with chronic use, and because H 1 -histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H 1 -histamine receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

698

494

View full text Add to dashboard Cite

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“…Serotonin (5-hydroxytryptamine (5-HT)) hypothesis of schizophrenia has been reanalyzed with the effectiveness of clozapine, the best known atypical antipsychotic drug, 1 as an antagonist for several 5-HT receptors. 2,3 Moreover, 5-HT has been shown to regulate the development of the central nervous system. As the 5-HT transporter (5-HTT) regulates the 5-HT system, 4 alterations in the function of this protein could be involved in the development of schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…5 The serotonin transporter (SLC6A4) gene spanning 37.8 kb is located on chromosome 17q11. 2,6,7 and has 14 exons encoding a protein of 630 amino acids. 8 SLC6A4 has received attention as a candidate in schizophrenia and mood disorders, owing to its influence on mood, emotion, cognition and also because 5-HTT is the principal site of action for some antidepressants, particularly for the selective serotonin reuptake inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

et al. 2009

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Serotonin (5-hydroxytryptamine (5-HT)) transporter (SLC6A4) is known to influence mood, emotion, cognition and efficacy of antidepressants, particularly that of selective serotonin reuptake inhibitors. Atypical antipsychotics exert their effects partially through serotinergic systems, and hence, variation in 5-HT uptake may affect antipsychotic action mediated through the serotinergic system. Therefore, investigating the role of SLC6A4 as a risk factor for developing schizophrenia and treatment response had been a point of concern for many investigators, but with variable outcome. In this study, we examined the genetic roles of five polymorphisms of SLC6A4, including those of the widely studied 44 base pair variable number of tandem repeat (VNTR) in the promoter region of SLC6A4 (the serotonin transporter gene-linked polymorphic region: 5HTTLPR) and a VNTR polymorphism (STin2) in the second intron, in schizophrenia and its influence on the severity of symptoms in a South Indian population from Kerala, comprising 586 individuals. We detected significant allelic and genotypic associations with rs2066713 (both allelic and genotypic P-value o0.001), 5HTTLPR (allelic P-value¼0.008 and genotypic P-value¼0.03) and STin2 polymorphisms (allelic P-value¼0.001 and genotypic P-value¼0.002). A haplotype linking these three risk alleles, 5HTTLPR/ S-rs2066713/C-STin2/12-repeat (P-value¼0.0059), was also significantly associated with disease in our population. Patients with STin2 12-repeat homozygotes showed a greater severity of blunted effect symptom. These results suggest a strong role of SLC6A4 in schizophrenia, possibly with a specific behavioral endophenotype in a South Indian population. Keywords: case-control; SLC6A4; schizophrenia; South India; symptom profile INTRODUCTION Schizophrenia is a common and complex psychiatric disorder, with proven genetic causes. Research to unravel the genetic basis of schizophrenia has revealed several molecules, including those involved in dopamine and serotonin neurotransmitter systems for the past few decades. Serotonin (5-hydroxytryptamine (5-HT)) hypothesis of schizophrenia has been reanalyzed with the effectiveness of clozapine, the best known atypical antipsychotic drug, 1 as an antagonist for several 5-HT receptors. 2,3 Moreover, 5-HT has been shown to regulate the development of the central nervous system. As the 5-HT transporter (5-HTT) regulates the 5-HT system, 4 alterations in the function of this protein could be involved in the development of schizophrenia. 5 The serotonin transporter (SLC6A4) gene spanning 37.8 kb is located on chromosome 17q11.2, 6,7 and has 14 exons encoding a protein of 630 amino acids. 8 SLC6A4 has received attention as a candidate in schizophrenia and mood disorders, owing to its influence on mood, emotion, cognition and also because 5-HTT is the principal site of action for some antidepressants, particularly for the selective

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“…[1][2][3] While typical antipsychotic drugs (e.g., chlorpromazine, haloperidol, and fluphenazine) demonstrate potent DA D 2 receptor blockade and effectively treat the positive symptoms of schizophrenia, atypical antipsychotic drugs (e.g., clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) demonstrate a higher affinity for serotonin (particularly 5-HT 2A ) receptors than for D 2 receptors, [3][4][5] and effectively treat both the positive and negative symptoms of schizophrenia. Aripiprazole is an unusual atypical antipsychotic drug that has functionally selective partial agonist actions at D 2 receptors and several 5-HT receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

et al. 2005

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The 5-HT 2A -serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT 2A -serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT 2A -serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT 2A receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.

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Binding of Typical and Atypical Antipsychotic Drugs to Multiple Neurotransmitter Receptors

Cited by 118 publications

References 3 publications

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

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