RESUMO
BACKGROUND: HIV-associated neurocognitive disorder (HAND) is commonly observed in persons living with HIV (PWH) and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in animals. METHODS: PPI was measured in male and female HIVtg rats and wild-type controls following acute, nonconcurrent treatment with the primary constituents of cannabis: Δâ9-tetrahydrocannabinol (THC; 1 and 3 mg/kg, s.c.) and cannabidiol (1, 10, and 30 mg/kg, i.p.). RESULTS: HIVtg rats exhibited a significant PPI deficit relative to wild-type controls. THC reduced PPI in controls but not HIVtg rats. Cannabidiol exerted only minor, genotype-independent effects on PPI. CONCLUSIONS: HIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use among PWH.
Assuntos
Canabinoides/farmacologia , Infecções por HIV/fisiopatologia , Filtro Sensorial/efeitos dos fármacos , Estimulação Acústica , Animais , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Feminino , Alucinógenos/farmacologia , Masculino , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Transgênicos , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.
Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Estimulação Acústica , Amissulprida , Aripiprazol , Percepção Auditiva/efeitos dos fármacos , Percepção Auditiva/fisiologia , Compostos Benzidrílicos/farmacologia , Encéfalo/fisiologia , Método Duplo-Cego , Eletroencefalografia , Eletromiografia , Humanos , Lorazepam/farmacologia , Masculino , Modafinila , Piperazinas/farmacologia , Inibição Pré-Pulso/fisiologia , Psicometria , Psicotrópicos/farmacologia , Quinolonas/farmacologia , Risperidona/farmacologia , Filtro Sensorial/fisiologia , Sulpirida/análogos & derivados , Sulpirida/farmacologia , Ácido Valproico/farmacologia , Adulto JovemRESUMO
HIV infection is frequently comorbid with methamphetamine (METH) dependence. Both factors are associated with impairment in inhibitory function that continues even after abstinence from the drug. Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are induced by acute stimulant administration, but the combined effect of HIV and chronic METH exposure on PPI is not well characterized. We quantified baseline acoustic startle and PPI in mice expressing the HIV-1 gp120 envelope protein (gp120tg) and in wild-type (WT) littermates; thereafter, we administered a chronic regimen of METH or vehicle and tested startle and PPI after 7 days of drug withdrawal. We hypothesized that METH-treated gp120tg mice would exhibit PPI deficits compared with vehicle-treated WT or gp120tg animals. Before METH administration, drug-naive female gp120tg mice exhibited decreased PPI compared with female WT mice, whereas male gp120tg mice exhibited increased startle compared with other groups. After drug withdrawal, no consistent genotype effect was observed, but METH-treated mice exhibited increased PPI compared with vehicle, in contrast to previous reports of acute METH-induced PPI deficits. In summary, PPI impairment in HIV could depend on factors such as sex, whereas changes in PPI following METH withdrawal may depend on the quantity and duration of drug exposure.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Coxeadura Animal/etiologia , Metanfetamina/efeitos adversos , Inibição Neural/fisiologia , Reflexo de Sobressalto/fisiologia , Síndrome de Abstinência a Substâncias/complicações , Estimulação Acústica , Análise de Variância , Animais , Esquema de Medicação , Feminino , Proteína gp120 do Envelope de HIV/genética , Humanos , Coxeadura Animal/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Fatores Sexuais , Fatores de TempoRESUMO
Sensorimotor inhibition, or the ability to filter out excessive or irrelevant information, theoretically supports a variety of higher-level cognitive functions. Impaired inhibition may be associated with increased impulsive and risky behavior in everyday life. Individuals infected with HIV frequently show impairment on tests of neurocognitive function, but sensorimotor inhibition in this population has not been studied and may be a contributor to the profile of HIV-associated neurocognitive disorders (HAND). Thirty-seven HIV-infected individuals (15 with HAND) and 48 non-infected comparison subjects were assessed for prepulse inhibition (PPI), an eyeblink startle paradigm measuring sensorimotor gating. Although HIV status alone was not associated with PPI deficits, HIV-positive participants meeting criteria for HAND showed impaired PPI compared to cognitively intact HIV-positive subjects. In HIV-positive subjects, PPI was correlated with working memory but was not associated with antiretroviral therapy or illness factors. In conclusion, sensorimotor disinhibition in HIV accompanies deficits in higher-order cognitive functions, although the causal direction of this relationship requires investigation. Subsequent research on the role of sensorimotor gating on decision-making and risk behaviors in HIV may be indicated.
Assuntos
Transtornos Cognitivos , Infecções por HIV/complicações , Inibição Psicológica , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Adulto , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Transtornos Cognitivos/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Tempo de Reação/fisiologia , Estatísticas não Paramétricas , Adulto JovemRESUMO
We previously reported that oroxylin A, a γ-aminobutyric acid A (GABAA) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-D-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 µM) inhibited intracellular Cl(-) influx induced by muscimol, a selective GABAA receptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system.
Assuntos
Flavonoides/química , Flavonoides/uso terapêutico , Transtornos da Memória/prevenção & controle , Filtro Sensorial/efeitos dos fármacos , Estimulação Acústica/métodos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Flavonoides/farmacologia , Masculino , Transtornos da Memória/enzimologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/fisiologia , Resultado do TratamentoRESUMO
Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a "Low" or "High" gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the "low gating" group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.
Assuntos
Analgésicos/farmacologia , Filtro Sensorial/efeitos dos fármacos , Ácido gama-Aminobutírico/análogos & derivados , Estimulação Acústica , Animais , Estudos Cross-Over , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletromiografia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pregabalina , Reflexo de Sobressalto/efeitos dos fármacos , Adulto Jovem , Ácido gama-Aminobutírico/farmacologiaRESUMO
Neonatal ventral hippocampal lesions (NVHLs) in rats lead to reduced prepulse inhibition (PPI) of startle and other behavioral deficits in adulthood that model abnormalities in schizophrenia patients. A neurophysiological deficit in schizophrenia patients and their first-degree relatives is reduced gating of the P50 event-related potential (ERP). N40 ERP gating in rats may be a cross-species analog of P50 gating, and is disrupted in experimental manipulations related to schizophrenia. Here, we tested whether N40 gating as well as PPI is disrupted after NVHLs, using contemporaneous measures of these two conceptually related phenomena. Male rat pups received sham or ibotenic acid NVHLs on postnatal day 7. PPI was tested on days 35 and 56, after which rats were equipped with cortical surface electrodes for ERP measurements. One week later, PPI and N40 gating were measured in a single test, using paired S1-S2 clicks spaced 500 ms apart to elicit N40 gating. Compared to sham-lesioned rats, those with NVHLs exhibited PPI deficits on days 35 and 56. NVHL rats also exhibited reduced N40 gating and reduced PPI, when measured contemporaneously at day 65. Deficits in PPI and N40 gating appeared most pronounced in rats with larger lesions, focused within the ventral hippocampus. In this first report of contemporaneous measures of two important schizophrenia-related phenotypes in NVHL rats, NVHLs reproduce both sensory (N40) and sensorimotor (PPI) gating deficits exhibited in schizophrenia. In this study, lesion effects were detected prior to pubertal onset, and were sustained well into adulthood.
Assuntos
Lesões Encefálicas/fisiopatologia , Hipocampo/lesões , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/fisiologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Ácido Ibotênico/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacosRESUMO
Sensorimotor gating, or the ability of a sensory event to suppress a motor response, can be measured operationally via prepulse inhibition (PPI) of the startle response. PPI is deficient in schizophrenia patients as well as other neuropsychiatric disorders, can be measured across species, and has been used widely as a translational tool in preclinical neuropharmacological and genetic research. First developed to assess drug effects in pharmacological and developmental models, PPI has become one of the standard behavioral measures in genetic models of schizophrenia and other neuropsychiatric disorders that exhibit PPI deficits. In this chapter we review the literature on genetic models of sensorimotor gating and discuss the utility of PPI as a tool in phenotyping mutant mouse models. We highlight the approaches to genetic mouse models of neuropsychiatric disease, discuss some of the important caveats to these approaches, and provide a comprehensive table covering the more recent genetic models that have evaluated PPI.
Assuntos
Transtornos Neurológicos da Marcha/etiologia , Modelos Genéticos , Reflexo de Sobressalto/genética , Esquizofrenia/complicações , Filtro Sensorial/genética , Estimulação Acústica , Animais , Transtornos Neurológicos da Marcha/genética , Humanos , Camundongos , Inibição Neural/genética , Esquizofrenia/genéticaRESUMO
Functional and structural imaging studies suggest that obsessive-compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.
Assuntos
Transtornos Neurológicos da Marcha/etiologia , Transtorno Obsessivo-Compulsivo/complicações , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Adolescente , Adulto , Análise de Variância , Eletromiografia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Habituação Psicofisiológica , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Psicoacústica , Tempo de Reação , Estatísticas não Paramétricas , Adulto JovemRESUMO
The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 µg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system.
Assuntos
Alucinógenos/farmacologia , Inibição Psicológica , Ketanserina/farmacologia , Psilocibina/farmacologia , Antagonistas da Serotonina/farmacologia , Estimulação Acústica , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Inquéritos e QuestionáriosRESUMO
Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatric disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 microg/5 microl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst(1)) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. The non-peptide sst(1) receptor antagonist SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.
Assuntos
Atividade Motora/fisiologia , Reflexo de Sobressalto/fisiologia , Recompensa , Filtro Sensorial/fisiologia , Somatostatina-28/metabolismo , Estimulação Acústica , Análise de Variância , Animais , Cateteres de Demora , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Somatostatina-28/farmacologiaRESUMO
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe preattentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.
Assuntos
Envelhecimento/fisiologia , Inibição Psicológica , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/fisiologia , Tato/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Biofísica , Cognição/fisiologia , Estimulação Elétrica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Estimulação Luminosa/métodos , Psicofísica , Tempo de Reação/fisiologiaRESUMO
RATIONALE: Compounds that activate the 5-HT(2A) receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT(2A) agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT(2A) receptors in rats. OBJECTIVE: We tested whether lisuride disrupts PPI in male Sprague-Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. RESULTS: Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT(2A) antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT(1A) antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D(2)/D(3) receptor antagonist raclopride (0.1 mg/kg, s.c). CONCLUSIONS: The effect of LSD on PPI is mediated by the 5-HT(2A) receptor, whereas activation of the 5-HT(2A) receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT(2A) agonist.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Alucinógenos/farmacologia , Lisurida/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Estimulação Acústica , Animais , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Piperazinas/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologiaRESUMO
The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by the independent processes of sensitization and habituation. While schizophrenia is associated with information processing impairments, there is conflicting evidence regarding the existence of habituation deficits in schizophrenic patients. Recent clinical evidence, however, indicates that patients with schizophrenia display exaggerated startle sensitization and diminished habituation. Given the linkage between dopaminergic abnormalities and schizophrenia, the goal of the present investigation was to examine the effect of deleting D1 and D2-like dopamine receptors on sensitization and habituation of the acoustic startle reflex in mice. For these experiments, the acoustic startle reflex was assessed in dopamine D1, D2, and D3 receptor wild-type (WT) and knockout (KO) mice on a C57BL/6J background, using a methodology that can measure both sensitization and habituation. Mice lacking the D1 receptor gene displayed enhanced sensitization, along with a decrease in the amount of habituation that occurs in response to repetitive presentations of a startling stimulus. Conversely, the loss of the dopamine D2 or D3 receptor gene produced a sensitization deficit and a significant increase in habituation. The behavioral phenotype exhibited by D1 receptor KO mice is clearly distinct from that of the D2 and D3 receptor KO mice. The findings in D1 receptor KO mice are reminiscent of the abnormalities observed in schizophrenic patients tested in comparable startle paradigms, and indicate that D1 agonists may possess therapeutic efficacy against the information processing deficits associated with schizophrenia.
Assuntos
Habituação Psicofisiológica/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Esquizofrenia/fisiopatologia , Psicologia do EsquizofrênicoRESUMO
Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, this review critically discusses the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis is placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible.
Assuntos
Modelos Animais de Doenças , Descoberta de Drogas/métodos , Modelos Animais , Neurociências/métodos , Animais , Biomarcadores Farmacológicos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Ensaios Clínicos como Assunto , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos , Previsões , Humanos , Reprodutibilidade dos TestesRESUMO
Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable tool to study the known inability of a large proportion of individuals with schizophrenia to effectively screen out irrelevant sensory input. The cortico-striato-pallido-thalamic circuitry is thought to be responsible for modulation of PPI in experimental animals. The involvement of this circuitry in human PPI is supported by observations of deficient PPI in a number of neuropsychiatric disorders that are characterised by abnormalities at some level in this circuitry, and findings of recent functional neuroimaging studies in healthy participants. The current study sought to investigate the structural neural correlates of PPI in a sample of 42 stable male outpatients with schizophrenia. Participants underwent magnetic resonance imaging (MRI) at 1.5T and were assessed (off-line) on acoustic PPI using electromyographic recordings of the orbicularis oculi muscle beneath the right eye. Optimised volumetric voxel-based morphometry implemented in SPM2 was used to investigate the relationship of PPI (prepulse onset-to-pulse onset interval 120msec) to regional grey matter (GM) volumes. Significant positive correlations were obtained between PPI and GM volume in the dorsolateral prefrontal, middle frontal and the orbital/medial prefrontal cortices. Our findings are consistent with (a) previous suggestions of susceptibility of PPI to cognitive processes controlled in a 'top down' manner by the cortex and (b) the hypothesis that compromised neural resources in the frontal cortex contribute to reduced PPI in schizophrenia.
Assuntos
Córtex Cerebral/fisiopatologia , Habituação Psicofisiológica/fisiologia , Reflexo de Sobressalto/fisiologia , Esquizofrenia/fisiopatologia , Estimulação Acústica/métodos , Adulto , Piscadela/fisiologia , Córtex Cerebral/patologia , Dominância Cerebral/fisiologia , Eletromiografia/métodos , Músculos Faciais/fisiologia , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Tempo de Reação/fisiologia , Estatística como AssuntoRESUMO
Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-beta-erythroidine hydrobromide (DHbetaE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.
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Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Estresse Psicológico/etiologia , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/etiologia , Estimulação Acústica , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Di-Hidro-beta-Eritroidina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Mecamilamina/farmacologia , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/efeitos da radiação , Fatores de TempoRESUMO
Patients with premenstrual dysphoric disorder (PMDD) experience their most intense symptoms during the late luteal phase. The aim of the current study was to compare acoustic startle response and prepulse inhibition in PMDD patients and controls during the follicular and late luteal phases of the menstrual cycle. Following two months of prospective daily ratings on the Cyclicity Diagnoser scale, 30 PMDD patients and 30 asymptomatic controls, between the ages of 20 and 46, were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. orbicularis oculi. Twenty pulse-alone trials (115 dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115 dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB. PMDD patients had a significantly higher startle response than controls during both phases of the menstrual cycle (p<0.05). PMDD patients exhibited lower levels of prepulse inhibition with 78 dB and 86 dB prepulses compared to control subjects in the luteal (p<0.01) but not in the follicular phase. Whereas control subjects displayed increased PPI during the late luteal phase compared to the follicular phase (p<0.01), PPI magnitude remained unchanged in PMDD patients between cycle phases. Relative to controls, PMDD patients displayed increased startle reactivity across both menstrual cycle phases and deficits in prepulse inhibition of acoustic startle during the late luteal phase. These findings are consistent with an altered response to ovarian steroids among PMDD patients.
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Piscadela/fisiologia , Inibição Psicológica , Fase Luteal/fisiologia , Síndrome Pré-Menstrual/fisiopatologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Adulto , Feminino , Hormônios/metabolismo , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Psicofísica , Estatísticas não Paramétricas , Fatores de TempoRESUMO
BACKGROUND: Studies have implicated the serotonin (5-HT)(7) receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT(7) receptor. METHODS: We examined the role of 5-HT(7) receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT(7) receptor due to a targeted inactivation of this receptor gene and the selective 5-HT(7) receptor antagonist SB-269970. RESULTS: SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT(7)(+/+) and 5-HT(7)(-/-) mice in startle reactivity or PPI regardless of prepulse intensity (74-82 dB), interstimulus interval (25-500 msec), or pulse intensity (90-120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT(7)(-/-) mice, although it was not affected by the 5-HT(7) antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes. CONCLUSIONS: The results indicate a partial role for the 5-HT(7) receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.