RESUMEN
OBJECTIVE: To identify key mood, social, and functional correlates of current participation in mental health treatment and barriers to participation in mental health treatment among older HIV infected (HIV+) veterans. METHODS: HIV+ veterans (N = 150) aged ≥ 50 years receiving HIV-related medical care at the VA San Diego Healthcare System, San Diego, California, anonymously completed a survey assessing current self-reported mood, social support, daily functioning problems, mental health service utilization, and barriers to participating in mental health services. Veterans also completed the 2-item Patient Health Questionnaire (PHQ-2), a validated depression screening instrument frequently used in primary care settings. Data were collected from February 2014 to May 2014. RESULTS: Overall, 44% of participants screened positive for depressive symptomatology on the PHQ-2; 55% of those who screened positive were participating in mental health treatment. Of the 45% of veterans who screened positive on the PHQ-2 and were not in treatment, two-thirds (66%) stated they had been offered services; however, they were not engaging in or accepting the services. Regardless of PHQ-2 status, current self-reported depressive symptoms emerged as an independent, significant positive predictor of participation in mental health treatment (odds ratio = 5.98; 95% CI, 1.16-30.72; P = .03), whereas anxiety, HIV-related stigma, sufficiency of social support, and daily functioning problems were not associated with mental health treatment utilization. Primary reported barriers to mental health treatment included scheduling/availability, travel time and transportation, and discomfort with group settings. CONCLUSIONS: Results of this study suggest there may be a need to better engage older HIV+ veterans in depression-related treatment. The use of telehealth technology, such as teletherapy, electronic devices, and cell phone-based programs, may be beneficial in helping older HIV+ veterans overcome many barriers that restrict their participation in mental health treatment.
Asunto(s)
Trastorno Depresivo/complicaciones , Trastorno Depresivo/terapia , Infecciones por VIH/complicaciones , Aceptación de la Atención de Salud , Veteranos , Afecto , Anciano , Anciano de 80 o más Años , Ansiedad/epidemiología , California , Trastorno Depresivo/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/psicología , Infecciones por VIH/terapia , Hospitales de Veteranos , Humanos , Persona de Mediana Edad , Aceptación de la Atención de Salud/psicología , Prevalencia , Autoinforme , Estigma Social , Estados Unidos , United States Department of Veterans Affairs , Veteranos/psicologíaRESUMEN
It is well established that traumatic brain injury (TBI) is associated with the development of psychiatric disorders. However, the impact of psychiatric disorders on TBI outcome is less well understood. We examined the outcomes of patients who experienced a traumatic subdural hemorrhage and whether a comorbid psychiatric disorder was associated with a change in outcome. A retrospective observational study was performed in the California Office of Statewide Health Planning and Development (OSHPD) and the Nationwide Inpatient Sample (NIS). Patients hospitalized for acute subdural hemorrhage were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Patients with coexisting psychiatric diagnoses were identified. Outcomes studied included mortality and adverse discharge disposition. In OSPHD, diagnoses of depression (OR = 0.64, p < 0.001), bipolar disorder (OR = 0.45, p < 0.05), and anxiety (OR = 0.37, p < 0.001) were associated with reduced mortality during hospitalization for TBI, with a trend toward psychosis (OR = 0.56, p = 0.08). Schizophrenia had no effect. Diagnoses of psychosis (OR = 2.12, p < 0.001) and schizophrenia (OR = 2.60, p < 0.001) were associated with increased adverse discharge. Depression and bipolar disorder had no effect, and anxiety was associated with reduced adverse discharge (OR = 0.73, p = 0.01). Results were confirmed using the NIS. Analysis revealed novel associations between coexisting psychiatric diagnoses and TBI outcomes, with some subgroups having decreased mortality and increased adverse discharge. Potential mechanisms include pharmacological effects of frequently prescribed psychiatric medications, the pathophysiology of individual psychiatric disorders, or under-coding of psychiatric illness in the most severely injured patients. Because pharmacological mechanisms, if validated, might lead to improved outcome in TBI patients, further studies may provide significant public health benefit.
Asunto(s)
Trastornos de Ansiedad , Trastorno Bipolar , Lesiones Traumáticas del Encéfalo/terapia , Trastorno Depresivo , Hematoma Subdural Agudo/terapia , Evaluación de Resultado en la Atención de Salud , Trastornos Psicóticos , Esquizofrenia , Adulto , Anciano , Anciano de 80 o más Años , Trastornos de Ansiedad/epidemiología , Trastorno Bipolar/epidemiología , Lesiones Traumáticas del Encéfalo/mortalidad , Comorbilidad , Trastorno Depresivo/epidemiología , Femenino , Hematoma Subdural Agudo/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/epidemiología , Esquizofrenia/epidemiologíaRESUMEN
Activation of the maternal innate immune system, termed "maternal immune activation" (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14. Glutamic acid decarboxylase-67 (GAD67) mRNA expression was examined in male offspring at postnatal day (P)14, P30 and P60. At P60, GAD67 mRNA was elevated in hippocampus and thalamus and decreased in prefrontal cortex of MIA offspring. MIA-induced alterations in GAD expression could contribute to the pathophysiology of schizophrenia.
Asunto(s)
Encéfalo/enzimología , Regulación Enzimológica de la Expresión Génica/fisiología , Glutamato Descarboxilasa/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Factores de Edad , Animales , Animales Recién Nacidos , Autorradiografía , Modelos Animales de Enfermedad , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Inductores de Interferón/toxicidad , Masculino , Poli I-C/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Neurregulina-1/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Prosencéfalo/metabolismo , Receptor ErbB-4/metabolismo , Receptor trkB/metabolismo , Factores de Edad , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Inductores de Interferón/toxicidad , Masculino , Neurregulina-1/genética , Poli I-C/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor ErbB-4/genética , Receptor trkB/genéticaRESUMEN
Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague-Dawley rats from E14 to 18 with 8mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) group) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light-dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that degree of maternal immune activation predicts severity of effects on offspring behavior.
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Anfetamina/farmacología , Maleato de Dizocilpina/farmacología , Inductores de Interferón/toxicidad , Poli I-C/toxicidad , Efectos Tardíos de la Exposición Prenatal , Inhibición Prepulso/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Estimulación Acústica , Adaptación Ocular/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Femenino , Tamaño de la Camada/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Razón de MasculinidadRESUMEN
We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D(2) and serotonin 5HT(1A) receptors. In contrast, serotonin 5HT(2A) receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D(2), serotonin 5HT(1A) and 5HT(2A) receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures.
Asunto(s)
Antipsicóticos/uso terapéutico , Muerte Celular , Ácido Glutámico/metabolismo , Antipsicóticos/farmacología , HumanosRESUMEN
Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABA(B) receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABA(B) receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague-Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5-5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABA(B) receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABA(B) receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release.
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Maleato de Dizocilpina/farmacología , Ácido Glutámico/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico/metabolismo , Corteza Prefrontal/efectos de los fármacos , Receptores de GABA-B/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Maleato de Dizocilpina/toxicidad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/toxicidad , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Agonistas de Receptores GABA-B/farmacología , Agonistas de Receptores GABA-B/uso terapéutico , Masculino , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/prevención & control , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/toxicidad , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/química , Esquizofrenia/metabolismo , Esquizofrenia/prevención & controlRESUMEN
Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).
Asunto(s)
Dopaminérgicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Exposición Materna , Poli I-C/farmacología , Anfetamina/farmacología , Animales , Maleato de Dizocilpina/farmacología , Femenino , Aprendizaje/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Aumento de Peso/inmunología , Aumento de Peso/fisiologíaRESUMEN
RATIONALE: Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized. OBJECTIVES: To determine effects of prenatal immune activation and developmental stress on conditioned place preference to amphetamine, and reversal learning. METHODS: Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or vehicle on gestational day 14. Half of the male offspring received 2 h of restraint stress at post-natal day 35. Behavioral testing was performed in adulthood. RESULTS: Restraint stress inhibited acquisition of place preference to low-dose amphetamine (0.5 mg/kg), while poly I:C treatment had no measurable effect on place preference acquisition. In contrast, drug-induced reinstatement of preference for drug-paired chamber was enhanced in offspring of poly I:C-treated dams [F(1,25)05.31, p00.03]. Performance on a Morris water maze reversal learning task was impaired in poly I:C offspring. Reversal learning performance was correlated with place preference reinstatement in non-stressed (r200.42, p00.0095), but not stressed rats (r2 00.04, p00.49). CONCLUSIONS: Prenatal immune activation enhances drug induced reinstatement of conditioned place preference. These data demonstrate longstanding impact on behaviors with potential influence on risk for drug relapse as a consequence of prenatal immune activation. Further study is needed to determine clinical and epidemiological consequences of similar exposures in human populations.
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Anfetamina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Poli I-C/farmacología , Efectos Tardíos de la Exposición Prenatal/inmunología , Anfetamina/administración & dosificación , Animales , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Aprendizaje Inverso/efectos de los fármacos , Estrés Psicológico/psicologíaRESUMEN
AIM: Studies characterizing treatment interventions in a naturalistic setting suggest that antidepressant and antipsychotic medications may be equally effective in improving clinical outcome in individuals at high risk for first-episode psychosis. Of interest, both beneficial as well as potentially adverse effects have been observed following fluoxetine treatment in a mouse prenatal immune activation model of relevance to psychosis prevention. We sought to extend those findings by examining the effects of fluoxetine, as well as the antipsychotic medication aripiprazole, in a rat prenatal immune activation model. METHODS: Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received fluoxetine (10.0 mg/kg/d), aripiprazole (0.66 mg/kg/d), or vehicle from postnatal days 35 to 70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following drug discontinuation. RESULTS: Both fluoxetine and aripiprazole had beneficial effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Significantly, both drugs also exerted effects in offspring of control (saline-treated) dams on locomotor response to injection. CONCLUSIONS: Fluoxetine and aripiprazole pretreatment of poly I:C offspring from postnatal days 35 to 70 stabilized response to amphetamine exposure persisting through 3 months of age, similar to earlier findings in mice that fluoxetine treatment following prenatal immune activation prevented altered locomotor response to amphetamine. The current data also confirm earlier findings of potential adverse behavioral effects in offspring of control dams following treatment with fluoxetine and antipsychotic medications, highlighting the potential for both therapeutic as well as safety concerns with exposure to preventive pharmacological treatments over the course of adolescent development. Further study is needed to determine clinical and epidemiological consequences of these pre-clinical findings.
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Fluoxetina/efectos adversos , Fluoxetina/farmacología , Sistema Inmunológico/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Piperazinas/efectos adversos , Piperazinas/farmacología , Efectos Tardíos de la Exposición Prenatal/psicología , Quinolonas/efectos adversos , Quinolonas/farmacología , Reacción de Fase Aguda/inducido químicamente , Reacción de Fase Aguda/complicaciones , Anfetamina/farmacología , Animales , Antipsicóticos/efectos adversos , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Aripiprazol , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fluoxetina/uso terapéutico , Masculino , Piperazinas/uso terapéutico , Poli I-C/farmacología , Embarazo , Quinolonas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Esquizofrenia/inducido químicamente , Esquizofrenia/complicaciones , Esquizofrenia/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.
Asunto(s)
Antipsicóticos/farmacología , Maleato de Dizocilpina/farmacología , Ácido Glutámico/metabolismo , Isoxazoles/farmacología , Corteza Prefrontal/efectos de los fármacos , Pirimidinas/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Risperidona/farmacología , Esquizofrenia/metabolismo , Animales , Modelos Animales de Enfermedad , Espacio Extracelular/metabolismo , Femenino , Masculino , Exposición Materna/efectos adversos , Palmitato de Paliperidona , Poli I-C/inmunología , Corteza Prefrontal/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/etiología , Esquizofrenia/inmunologíaRESUMEN
AIM: Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment. METHODS: Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35-70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation. RESULTS: Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection. CONCLUSIONS: Risperidone and paliperidone pre-treatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention.
Asunto(s)
Antipsicóticos/farmacología , Isoxazoles/farmacología , Actividad Motora/efectos de los fármacos , Pirimidinas/farmacología , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Anfetamina/efectos adversos , Animales , Animales Recién Nacidos , Estimulantes del Sistema Nervioso Central , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Palmitato de Paliperidona , Poli I-C/inmunología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Esquizofrenia/etiología , Esquizofrenia/fisiopatología , Factores de TiempoRESUMEN
Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation.
Asunto(s)
Conducta Animal/fisiología , Individualidad , Locomoción , Efectos Tardíos de la Exposición Prenatal/inmunología , Factores de Edad , Anfetamina/farmacología , Análisis de Varianza , Animales , Animales Recién Nacidos , Antivirales/administración & dosificación , Conducta Animal/efectos de los fármacos , Peso Corporal/inmunología , Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Locomoción/efectos de los fármacos , Masculino , Poli I-C/administración & dosificación , Valor Predictivo de las Pruebas , Embarazo , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacos , Aumento de Peso/inmunología , Pérdida de Peso/efectos de los fármacosRESUMEN
Dopamine D3 receptors have the highest dopamine affinity of all dopamine receptors, and may thereby regulate dopamine signaling mediated by volume transmission. Changes in D3 receptor isoform expression may alter D3 receptor function, however, little is known regarding coordination of D3 isoform expression in response to perturbations in dopaminergic stimulation. To determine the effects of dopamine receptor stimulation and blockade on D3 receptor alternative splicing, we determined D3 and D3nf isoform mRNA expression following treatment with the D3 receptor antagonist NGB 2904, and the indirect dopamine agonist amphetamine. Expression of tyrosine hydroxylase (TH) mRNA, the rate-limiting enzyme in dopamine synthesis, was also determined. The D3/D3nf mRNA expression ratio was increased in ventral striatum, prefrontal cortex, and hippocampus 6 h following D3 antagonist NGB 2904 treatment, and remained persistently elevated at 24 h in hippocampus and substantia nigra/ventral tegmentum. D3 mRNA decreased 65% and D3nf mRNA expression decreased 71% in prefrontal cortex 24 h following amphetamine treatment, however, these changes did not reach statistical significance. TH mRNA expression was unaffected by D3 antagonist NGB 2904, but was elevated by amphetamine in ventral striatum, hippocampus, and prefrontal cortex. These findings provide evidence for an adaptive response to altered D3 receptor stimulation involving changes in D3 receptor alternative splicing. Additionally, these data suggest D3 autoreceptor regulation of dopamine synthesis does not involve regulation of TH mRNA expression. Finally, the observation of regulated TH mRNA expression in dopamine terminal fields provides experimental support for the model of local control of mRNA expression in adaptation to synaptic activity.
Asunto(s)
Dopamina/fisiología , ARN Mensajero/biosíntesis , Receptores de Dopamina D3/genética , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Empalme Alternativo/efectos de los fármacos , Empalme Alternativo/genética , Animales , Antagonistas de Dopamina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/biosíntesis , ARN Mensajero/antagonistas & inhibidores , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/biosíntesis , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Factores de Tiempo , Tirosina 3-Monooxigenasa/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Natural reward and drugs of abuse converge on the mesolimbic system, where drugs of abuse induce neuronal alterations. Here, we tested plasticity in this system after natural reward and the subsequent impact on drug responses. METHODS: Effects of sexual experience in male rats on behavioral sensitization and conditioned place preference associated with d-amphetamine (AMPH) and Golgi-impregnated dendrites and spines of nucleus accumbens (NAc) cells were determined. Moreover, the impact of abstinence from sexual behavior in experienced males on these parameters was tested. RESULTS: First, repeated sexual behavior induced a sensitized locomotor response to AMPH compared with sexually naive control subjects observed 1, 7, and 28 days after last mating session. Second, sexually experienced animals formed a conditioned place preference for lower doses of AMPH than sexually naive males, indicative of enhanced reward value of AMPH. Finally, Golgi-Cox analysis demonstrated increased numbers of dendrites and spines in the NAc core and shell with sexual experience. The latter two alterations were dependent on a period of abstinence of 7-10 days. CONCLUSIONS: Sexual experience induces functional and morphological alterations in the mesolimbic system similar to repeated exposure to psychostimulants. Moreover, abstinence from sexual behavior after repeated mating was essential for increased reward for drugs and dendritic arbors of NAc neurons, suggesting that the loss of sexual reward might also contribute to neuroplasticity of the mesolimbic system. These results suggest that some alterations in the mesolimbic system are common for natural and drug reward and might play a role in general reinforcement.
Asunto(s)
Condicionamiento Operante/fisiología , Sistema Límbico/fisiología , Plasticidad Neuronal/fisiología , Recompensa , Conducta Sexual Animal/fisiología , Amidinas/farmacología , Anfetamina/farmacología , Análisis de Varianza , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Operante/efectos de los fármacos , Dendritas/metabolismo , Dendritas/ultraestructura , Relación Dosis-Respuesta a Droga , Sistema Límbico/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Plasticidad Neuronal/efectos de los fármacos , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley , Conducta Sexual Animal/efectos de los fármacos , Tinción con Nitrato de Plata/métodos , Factores de TiempoRESUMEN
There has been significant recent growth in programmes evaluating preventive treatment for individuals exhibiting prodromal symptoms, at high risk of developing first-episode psychosis. Because of the tremendous human and economic burden of schizophrenia and other psychotic disorders, primary prevention modalities of even modest impact would likely have important public health consequence. Several published clinical trials suggest that antipsychotic medications have beneficial effects in either preventing or postponing the emergence of first-episode psychosis in individuals at high risk of psychosis. It is not clear, however, that antipsychotic drugs are the most effective, or safest, pharmacological treatment for psychosis prevention. Mechanisms for primary prevention (intervening to remove a cause of illness) and treatment are not necessarily similar. All of the medications developed for treatment of psychosis rely on tertiary prevention, and there is no a priori reason to assume that these treatments would be the safest and most effective primary preventive treatment of first-episode psychosis. Evidence suggests that selective serotonin reuptake inhibitors, serotonin 5-HT(2A) and dopamine D3 receptor antagonists, mood-stabilizing medications, GABAergic, glutamatergic and neuroprotective compounds may also be beneficial primary prevention drugs for first-episode psychosis. While there are indications that effective preventive interventions are feasible, data on safety and efficacy of primary preventive treatment interventions are limited and published studies highlight the enrollment challenges facing efforts to identify the safest and most effective preventive treatment interventions through human clinical trials. Treatments preventing behavioural alterations using developmental animal models with relevance to limbic system neurobiology could therefore be useful in focusing hypotheses regarding effective treatments for psychosis prevention. In one such study, low-dose risperidone pre-treatment prevented behavioural abnormalities following neonatal hippocampal lesions, while higher risperidone pre-treatment was ineffective. These findings support the predictive validity of the neonatal hippocampal lesion model in identifying psychosis prevention interventions, provide theoretical support for the use of low-dose risperidone in prevention of first-episode psychosis and suggest the possibility that higher risperidone doses could be less effective than low dosages in this application. These observations also suggest a potential role for selective 5-HT(2A) receptor antagonists as drug development targets for psychosis prevention.
Asunto(s)
Antipsicóticos/uso terapéutico , Dopamina/metabolismo , Serotonina/metabolismo , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéutico , Hipocampo/patología , Humanos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D3/metabolismo , Risperidona/farmacología , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Resultado del TratamientoRESUMEN
In an effort to analyse the contribution of individual serotonin and dopamine receptor subtypes to antipsychotic medication response, we analysed the correlation between clinically effective antipsychotic drug dose and binding affinity to cloned serotonin and dopamine receptor subtypes. Clinically effective dosage and binding affinity to the D(2) dopamine receptor subtype were moderately correlated for typical antipsychotic medications (r=0.57, p=0.04), and were similarly modestly correlated for atypical antipsychotic drugs (r=0.66, p=0.07). Surprisingly for typical antipsychotic medications, a stronger inverse correlation was observed between drug dosage and 5-HT(2C) affinity (r=-0.65, p=0.03). The strongest correlation observed for typical antipsychotic medications was between medication dose and 5-HT(2C)/D(2) binding affinity ratio (r=-0.81, p=0.002). For atypical antipsychotic medications, highly significant correlations were observed between medication dose and receptor-binding affinity to D(3) dopamine receptor (r=0.78, p=0.02), and with the ratios of D(2)/5-HT(1A) (r=0.85, p=0.009), D(3)/5-HT(1A) (r=0.78, p=0.021), D(2) (5-HT(2A)/5-HT(1A)) (r=0.75, p=0.033) and D(3) (5-HT(2A)/5-HT(1A)) (r=0.75, p=0.03) receptor-binding affinities. The correlation between medication dose and D(2) (5-HT(2C)/5-HT(1A)) receptor-binding affinity ratio was of similar magnitude (r=0.70, p=0.055). No significant correlations were identified between atypical antipsychotic medication dose and 5-HT(1A), 5-HT(2A), 5-HT(2C), 5-HT(2C)/D(2) or 5-HT(2A)/D(2) receptor-binding affinities. These observations suggest an interaction between D(2) and 5-HT(2C) receptor-binding effects contributing to the therapeutic response achieved following treatment with typical antipsychotic medications. This suggests that for typical antipsychotic medications, constitutive serotonin 5-HT(2C) receptor signalling interacts with and facilitates the antipsychotic benefit achieved through dopamine D(2) receptor blockade. Additionally, this analysis demonstrates that, in contrast to typical antipsychotic medications, the therapeutic effectiveness of atypical antipsychotic medications results from opposing interactions among three distinct domains: (1) antipsychotic potency is enhanced by increased D(2) and D(3) dopamine receptor-binding affinity; (2) antipsychotic efficacy is also facilitated by increased binding affinity to serotonin 5-HT(2C) and 5-HT(2A) receptors; (3) in contrast, antipsychotic potency is reduced by elevations in 5-HT(1A) receptor-binding affinity.
Asunto(s)
Antipsicóticos , Trastornos Psicóticos/tratamiento farmacológico , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Antipsicóticos/metabolismo , Antipsicóticos/uso terapéutico , Relación Dosis-Respuesta a Droga , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Dopaminérgicos/genética , Receptores de Serotonina/genética , Resultado del TratamientoRESUMEN
Previous antemortem and postmortem tissue fatty acid composition studies have observed significant deficits in the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in red blood cell (RBC) and postmortem cortical membranes of patients with unipolar depression. In the present study, we determined the fatty acid composition of postmortem orbitofrontal cortex (OFC, Brodmann area 10) of patients with bipolar disorder (n=18) and age-matched normal controls (n=19) by gas chromatography. After correction for multiple comparisons, DHA (-24%), arachidonic acid (-14%), and stearic acid (C18:0) (-4.5%) compositions were significantly lower, and cis-vaccenic acid (18:1n-7) (+12.5%) composition significantly higher, in the OFC of bipolar patients relative to normal controls. Based on metabolite:precursor ratios, significant elevations in arachidonic acid, stearic acid, and palmitic acid conversion/metabolism were observed in the OFC of bipolar patients, and were inversely correlated with DHA composition. Deficits in OFC DHA and arachidonic acid composition, and elevations in arachidonic acid metabolism, were numerically (but not significantly) greater in drug-free bipolar patients relative to patients treated with mood-stabilizer or antipsychotic medications. OFC DHA and arachidonic acid deficits were greater in patients plus normal controls with high vs. low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder.
Asunto(s)
Ácido Araquidónico/metabolismo , Trastorno Bipolar/metabolismo , Corteza Cerebral/química , Ácidos Docosahexaenoicos/metabolismo , Ácidos Grasos/metabolismo , Adulto , Alcoholismo/metabolismo , Antipsicóticos/uso terapéutico , Autopsia , Trastorno Bipolar/sangre , Trastorno Bipolar/tratamiento farmacológico , Corteza Cerebral/metabolismo , Cromatografía de Gases , Grupos Control , Ácidos Docosahexaenoicos/análisis , Eritrocitos/química , Eritrocitos/metabolismo , Ácidos Grasos Omega-6/análisis , Ácidos Grasos Omega-6/metabolismo , Femenino , Lóbulo Frontal/química , Lóbulo Frontal/metabolismo , Humanos , Masculino , Ácido Palmítico/análisis , Ácido Palmítico/metabolismo , Ácidos Esteáricos/análisis , Ácidos Esteáricos/metabolismo , Suicidio/estadística & datos numéricosRESUMEN
The principal polyunsaturated fatty acid acids found in brain, arachidonic acid (AA) and docosahexaenoic acid (DHA), preferentially accumulate in synaptic membranes. Although neurochemical studies have found that dietary-induced deficits in rat brain DHA composition significantly alter mesocorticolimbic dopamine (DA) neurotransmission, its impact on DA-mediated behavior remains poorly understood. In the present study, we determined the effects of dietary-induced deficits in brain DHA composition on amphetamine (AMPH)-induced locomotor activity and sensitization in DBA/2J mice, an inbred strain previously found to be hyporesponsive to AMPH, as well as monoamine concentrations in the PFC and ventral striatum following the AMPH challenge. Chronic dietary omega-3 fatty acid deficiency significantly decreased PFC (-25%) and ventral striatum (-20%) DHA composition, increased PFC (+7%) and ventral striatum (+6%) AA composition, and increased the AA:DHA ratio in PFC (+30%) and ventral striatum (+24%). The development and expression of AMPH-induced sensitization was significantly increased in DHA-deficient mice, whereas novelty- and acute AMPH-induced locomotor activity were not altered. DHA-deficient mice exhibited significantly greater ventral striatum, but not PFC, DA and DA metabolite concentrations following the AMPH challenge, whereas serotonin and noradrenalin concentrations were not altered. Ventral striatum AA composition and the AA:DHA ratio were both positively correlated with DA concentrations, and both ventral striatum AA composition and DA concentrations were positively correlated with locomotor activity during the preceding AMPH challenge. These results demonstrate that dietary-induced brain DHA deficiency, and associated elevation in the AA:DHA ratio, augment AMPH-induced sensitization in DBA/2J mice, and that this augmented response is associated with selective alterations in the mesolimbic DA pathway.