RESUMO
Translational biomarkers, such as prepulse inhibition (PPI) of the acoustic startle response, are playing an increasingly important role in the development of antipsychotic drugs for schizophrenia and related conditions. However, attempts to reliably induce a PPI deficit by psychotomimetic drugs have not been successful, leaving an unmet need for a cross-species psychosis model sensitive to this widely studied surrogate treatment target. Sleep deprivation (SD) might be such a model as it has previously been shown to induce PPI deficits in rats, which could be selectively prevented with antipsychotic but not anxiolytic or antidepressant compounds. Here, in a first proof-of-concept study we tested whether SD induces a deficit in PPI and an increase in psychosis-like symptoms in healthy humans. In two counterbalanced sessions, acoustic PPI and self-reported psychosis-like symptoms (Psychotomimetic States Inventory) were measured in 24 healthy human volunteers after a normal night's sleep and after a night of total SD. SD decreased PPI (p = 0.001) without affecting the magnitude or habituation of the startle response (all p > 0.13). SD also induced perceptual distortions, cognitive disorganization, and anhedonia (all p < 0.02). Thus, extending previous rodent work, we conclude that SD, in combination with the PPI biomarker, might be a promising translational surrogate model for psychosis as this method represents a possibility to partially and reversibly mimic the pathogenesis of psychotic states.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos da Percepção/etiologia , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/fisiologia , Privação do Sono/fisiopatologia , Estimulação Acústica , Adolescente , Adulto , Anedonia , Transtornos Cognitivos/fisiopatologia , Feminino , Habituação Psicofisiológica/fisiologia , Humanos , Masculino , Modelos Psicológicos , Transtornos da Percepção/fisiopatologia , Testes Psicológicos , Transtornos Psicóticos/fisiopatologia , Privação do Sono/psicologia , Adulto JovemRESUMO
RATIONALE: Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence. OBJECTIVES: We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI. METHODS: We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured. RESULTS: Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation. CONCLUSIONS: The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.
Assuntos
Nicotina/administração & dosagem , Polimorfismo Genético/genética , Receptores Nicotínicos/genética , Reflexo de Sobressalto/genética , Filtro Sensorial/genética , Estimulação Acústica/métodos , Administração Cutânea , Adulto , Método Duplo-Cego , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Adulto JovemRESUMO
Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.
Assuntos
Asparagina/genética , Isoleucina/genética , Memória/fisiologia , Receptores Acoplados a Proteínas G/genética , Reflexo de Sobressalto/genética , Esquizofrenia/genética , Estimulação Acústica , Adulto , Algoritmos , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/fisiologia , Análise de Variância , Piscadela/genética , Piscadela/fisiologia , DNA/genética , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Genótipo , Humanos , Masculino , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Reflexo de Sobressalto/fisiologia , Psicologia do Esquizofrênico , Filtro Sensorial/efeitos dos fármacosRESUMO
Attentional gating deficits, commonly measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), have been established as an endophenotype of schizophrenia. Prepulse inhibition is heritable and has been associated with polymorphisms in serotonin and dopamine system genes. Prepulse inhibition can be enhanced by nicotine, and therefore it has been proposed that schizophrenia patients smoke to ameliorate their early attentional deficits. The PPI-enhancing effects of nicotine in rodents are strain dependent, suggesting a genetic contribution to PPI within the nicotinic acetylcholine receptor (nAChR) system. Recent human genetic studies also imply that tobacco dependence is affected by polymorphisms in the alpha3/alpha5 subunits of the nAChR (CHRNA3/CHRNA5) gene cluster. We, therefore, investigated the impact of two common CHRNA3 polymorphisms (rs1051730/rs1317286) on PPI, startle reactivity, and habituation of the ASR in two independent samples of 107 healthy British volunteers and 73 schizophrenia patients hailing from Germany. In both samples, PPI was influenced by both CHRNA3 polymorphisms (combined p-value=0.0027), which were strongly linked. Moreover, CHRNA3 genotype was associated with chronicity, treatment, and negative symptoms in the schizophrenia sample. These results suggest that sensorimotor gating is influenced by variations of the CHRNA3 gene, which might also have an impact on the course and severity of schizophrenia.
Assuntos
Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/genética , Predisposição Genética para Doença , Polimorfismo Genético/genética , Receptores Nicotínicos/genética , Esquizofrenia/complicações , Estimulação Acústica/métodos , Adolescente , Adulto , Europa (Continente) , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Metanálise como Assunto , Inibição Neural/genética , Escalas de Graduação Psiquiátrica , Psicofísica , Reflexo de Sobressalto/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adulto JovemRESUMO
BACKGROUND: Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT(2A)R) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers. METHODS: We analyzed the 5-HT(2A)R A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. RESULTS: Subjects homozygous for the 5-HT(2A)R T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms. CONCLUSIONS: We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT(2A)R gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating.