RESUMO
BACKGROUND: Few studies have examined the association between APOE genotype and alcohol use. Although some of these studies have reported outcomes associated with a history of drinking, none have examined alcohol-seeking behavior. In addition, no preclinical studies have examined alcohol use as a function of APOE genotype with or without traumatic brain injury. METHODS: Male and female human APOE3- and APOE4-targeted replacement (TR) mice were used to assess voluntary alcohol seeking longitudinally using a 2-bottle choice paradigm conducted within the automated IntelliCage system prior to and following repeated mild TBI (rmTBI). Following an acquisition phase in which the concentration of ethanol (EtOH) was increased to 12%, a variety of drinking paradigms that included extended alcohol access (EAA1 and EAA2), alcohol deprivation effect (ADE), limited access drinking in the dark (DID), and progressive ratio (PR) were used to assess alcohol-seeking behavior. Additional behavioral tasks were performed to measure cognitive function and anxiety-like behavior. RESULTS: All groups readily consumed increasing concentrations of EtOH (4-12%) during the acquisition phase. During the EAA1 period (12% EtOH), there was a significant genotype effect in both males and females for EtOH preference. Following a 3-week abstinence period, mice received sham or rmTBI resulting in a genotype- and sex-independent main effect of rmTBI on the recovery of righting reflex and a main effect of rmTBI on spontaneous home-cage activity in females only. Reintroduction of 12% EtOH (EAA2) resulted in a significant effect genotype for alcohol preference in males with APOE4 mice displaying increased preference and motivation for alcohol compared with APOE3 mice independent of TBI while in females, there was a significant genotype × TBI interaction under the ADE and DID paradigms. Finally, there was a main effect of rmTBI on increased risk-seeking behavior in both sexes, but no effect on spatial learning or cognitive flexibility. CONCLUSION: These results suggest that sex and APOE genotype play a significant role in alcohol consumption and may subsequently influence long-term recovery following traumatic brain insults.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Apolipoproteínas E/metabolismo , Comportamento Aditivo/metabolismo , Genótipo , Consumo de Bebidas Alcoólicas/genética , Animais , Apolipoproteínas E/genética , Comportamento Aditivo/genética , Condicionamento Clássico/fisiologia , Feminino , Humanos , Masculino , CamundongosRESUMO
OBJECTIVE: Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable. METHODS: We performed extracellular recordings, as well as whole-cell patch clamp recordings from pyramidal cells and interneurons, in the CA1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA1 pyramidal cells as well as parvalbumin-positive interneurons. In addition, we performed video-electroencephalography (EEG) recordings from the dorsal hippocampal CA1 region. RESULTS: We observed that juvenile knock-in mice carrying the above mutation reproduce the human phenotype of AHC. We then demonstrated in the CA1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in CA1 fast-spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons. SIGNIFICANCE: Our data indicate that, in our genetic model of Atp1α3 mutation, there is increased excitability and marked dysfunction in GABAergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABAergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.
Assuntos
Modelos Animais de Doenças , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , ATPase Trocadora de Sódio-Potássio/fisiologia , Animais , Criança , Análise Mutacional de DNA , Eletroencefalografia , Epilepsia/genética , Potenciais Evocados , Triagem de Portadores Genéticos , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Técnicas In Vitro , Interneurônios/fisiologia , Camundongos , Camundongos Mutantes Neurológicos , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , ATPase Trocadora de Sódio-Potássio/genética , Ácido gama-Aminobutírico/fisiologiaRESUMO
Traumatic brain injury (TBI) is a leading cause of death and disability among young adults and is highly prevalent among recently deployed military personnel. Survivors of TBI often experience cognitive and emotional deficits, suggesting that long-term effects of injury may disrupt neuronal function in critical brain regions, including the amygdala, which is involved in emotion and fear memory. Amygdala hyperexcitability has been reported in both TBI and posttraumatic stress disorder patients, yet little is known regarding the effects of combined stress and TBI on amygdala structure and function at the neuronal level. The present study seeks to determine how the long-term effects of preinjury foot-shock stress and TBI interact to influence synaptic plasticity in the lateral amygdala (LA) of adult male C57BL/6J mice by using whole-cell patch clamp electrophysiology 2-3 months postinjury. In the absence of stress, TBI resulted in a significant increase in membrane excitability and spontaneous excitatory postsynaptic currents (sEPSCs) in LA pyramidal-like neurons. Foot-shock stress in the absence of TBI also resulted in increased sEPSC activity. In contrast, when preinjury stress and TBI occurred in combination, sEPSC activity was significantly decreased compared with either condition alone. There were no significant differences in inhibitory activity or total dendritic length among any of the treatment groups. These results demonstrate that stress and TBI may be contributing to amygdala hyperexcitability via different mechanisms and that these pathways may counterbalance each other with respect to long-term pathophysiology in the LA.
Assuntos
Tonsila do Cerebelo/patologia , Lesões Encefálicas Traumáticas/patologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Neurônios/fisiologia , Estresse Psicológico/patologia , Tonsila do Cerebelo/fisiopatologia , Análise de Variância , Animais , Biofísica , Dendritos/patologia , Modelos Animais de Doenças , Estimulação Elétrica , Eletrochoque/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Técnicas de Patch-Clamp , Estresse Psicológico/etiologiaRESUMO
Large-conductance calcium-activated potassium BK channels are widely expressed in the brain and are involved in the regulation of neuronal functions such as neurotransmitter release. However, their possible role in mediating ethanol-induced GABA release is still unknown. We assessed the role of BK channels in modulating the action of ethanol on inhibitory synaptic transmission mediated via GABAA receptors in the rat central nucleus of the amygdala (CeA). Evoked IPSCs (eIPSCs) mediated by GABAA receptors were isolated from CeA neurons under whole-cell voltage clamp, and their response to selective BK channel antagonists, channel activators, or ethanol was analyzed. Blocking BK channels with the specific BK channel antagonist paxilline significantly increased the mean amplitude of eIPSCs, whereas the activation of BK channels with the channel opener NS1619 reversibly attenuated the mean amplitude of eIPSCs. Ethanol (50 mM) alone enhanced the amplitude of eIPSCs but failed to further enhance eIPSCs in the slices pretreated with paxilline. Bath application of either BK channel blockers significantly increased the frequency of miniature IPSCs (mIPSCs). Similarly, 50 mM ethanol alone also enhanced mIPSC frequency. Increases in mIPSC frequency by either selective BK channel antagonists or ethanol were not accompanied with changes in the amplitude of mIPSCs. Furthermore, following bath application of BK channel blockers for 10 min, ethanol failed to further increase mIPSC frequency. Together, these results suggest that blocking BK channels mimics the effects of ethanol on GABA release and that presynaptic BK channels could serve as a target for ethanol effects in CeA.
Assuntos
Tonsila do Cerebelo/fisiologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Terminações Pré-Sinápticas/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Canais de Cálcio/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Técnicas In Vitro , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The corticotropin-releasing factor (CRF) and kappa-opioid receptor (KOR) systems are both implicated in stress-related behaviors and drug dependence. Although previous studies suggest that antagonism of each system blocks aspects of experimental models of drug dependence, the possible interaction between these systems at the neuronal level has not been completely examined. We used an in vitro brain slice preparation to investigate the interaction of these two peptide systems on inhibitory neurotransmission in the central nucleus of the amygdala (CeA). Application of exogenous CRF increased the mean frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSC) by 20.2%, suggesting an increase in presynaptic GABA release. Although the pharmacological blockade of KORs by norBNI alone did not significantly affect mIPSC frequency, it significantly enhanced the effect of CRF (by 43.9%, P = 0.02). Similarly, the CRF effects in slices from KOR knockout (KO) mice (84.0% increase) were significantly greater than in wild-type (WT) mice (24.6%, P = 0.01), although there was no significant difference in baseline mIPSC frequency between slices from KOR KO and WT mice. The increase in CRF action in the presence of norBNI was abolished by a CRF-1 receptor antagonist but was unaffected by a CRF-2 receptor antagonist. We hypothesize that CRF facilitates the release of an endogenous ligand for KORs and that subsequent activation of KOR receptors modulates presynaptic effects of CRF in CeA. These results suggest that potential pharmacotherapies aimed at neurobehavioral and addictive disorders may need to involve both the KOR/dynorphin and the CRF systems in CeA.
Assuntos
Núcleo Central da Amígdala/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Receptores Opioides kappa/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Potenciais Pós-Sinápticos Inibidores , Camundongos Endogâmicos C57BL , Camundongos Knockout , Potenciais Pós-Sinápticos em Miniatura , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/genética , Transmissão SinápticaRESUMO
BACKGROUND: Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. METHODS: We conducted Western blot analysis on TSPs 1 to 4 and α2δ-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta). RESULTS: Adolescent AIE reduced α2δ-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while α2δ-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. CONCLUSIONS: Repeated EtOH exposure during adolescence results in long-term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE.
Assuntos
Etanol/toxicidade , Hipocampo/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo , Trombospondinas/biossíntese , Fatores Etários , Animais , Etanol/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
BACKGROUND: Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. METHODS: We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. RESULTS: We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. CONCLUSIONS: Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE.
Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiopatologia , Etanol/efeitos adversos , Envelhecimento/psicologia , Animais , Região CA1 Hipocampal/anormalidades , Região CA1 Hipocampal/patologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Proteína 4 Homóloga a Disks-Large , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Neuropeptídeos/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologiaRESUMO
BACKGROUND: The necessity for, or redundancy of, distinctive KChIP proteins is not known. RESULTS: Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons. CONCLUSION: KChIP2 is essential for homeostasis in hippocampal neurons. SIGNIFICANCE: Mutations in K(A) channel auxiliary subunits may be loci for epilepsy. The somatodendritic IA (A-type) K(+) current underlies neuronal excitability, and loss of IA has been associated with the development of epilepsy. Whether any one of the four auxiliary potassium channel interacting proteins (KChIPs), KChIP1-KChIP4, in specific neuronal populations is critical for IA is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for IA regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V½ for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of IA, hippocampal neurons from Kchip2(-/-) mice showed increased excitability. WT cultured neurons fired only occasional single action potentials, but the average spontaneous firing rate (spikes/s) was almost 10-fold greater in Kchip2(-/-) neurons. In slice preparations, spontaneous firing was detected in CA1 pyramidal neurons from Kchip2(-/-) mice but not from WT. Additionally, when seizures were induced by kindling, the number of stimulations required to evoke an initial class 4 or 5 seizure was decreased, and the average duration of electrographic seizures was longer in Kchip2(-/-) mice compared with WT controls. Together, these data demonstrate that the KChIP2 is essential for physiologic IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.
Assuntos
Potenciais de Ação , Homeostase , Proteínas Interatuantes com Canais de Kv/fisiologia , Subunidades Proteicas/fisiologia , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Células Cultivadas , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores , Excitação Neurológica , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , ConvulsõesRESUMO
Human and animal studies indicate that κ-opioid receptors (KORs) are involved in ethanol drinking and dependence (Xuei et al., 2006; Walker and Koob, 2008; Walker et al., 2011). Using in vitro single-cell recording techniques in mouse brain slices, we examined the physiologic effects of KOR activation in the central amygdala (CeA) on GABAergic neurotransmission and its interaction with acute ethanol. A selective KOR agonist (U69593, 1 µM) diminished evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 18% (n = 10), whereas blockade of KORs with a selective antagonist (nor-binaltorphimine, 1 µM) augmented the baseline evoked GABAergic IPSCs by 14% (P < 0.01; n = 34), suggesting that the KOR system contributes to tonic inhibition of GABAergic neurotransmission in the CeA. In addition, the enhancement by acute ethanol of GABAergic IPSC amplitudes was further augmented by pharmacologic blockade of KORs, from 14% (n = 36) to 27% (n = 26; P < 0.01), or by genetic deletion of KORs, from 14% in wild-type mice (n = 19) to 34% in KOR knockout mice (n = 13; P < 0.01). Subsequent experiments using tetrodotoxin to block activity-dependent neurotransmission suggest that KORs regulate GABA release at presynaptic sites. Our data support the idea that KORs modulate GABAergic synaptic responses and ethanol effects as one of multiple opioid system-dependent actions of ethanol in the CeA, possibly in a circuit-specific manner.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Receptores Opioides kappa/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Analgésicos/farmacologia , Animais , Ansiolíticos/farmacologia , Potenciais Evocados/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Antagonistas de Entorpecentes/farmacologia , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/genética , Análise de Célula Única , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
BACKGROUND: Chronic alcohol use, especially exposure to alcohol during adolescence or young adulthood, is closely associated with cognitive deficits that may persist into adulthood. Therefore, it is essential to identify possible neuronal mechanisms underlying the observed deficits in learning and memory. Hippocampal interneurons play a pivotal role in regulating hippocampus-dependent learning and memory by exerting strong inhibition on excitatory pyramidal cells. The function of these interneurons is regulated not only by synaptic inputs from other types of neurons but is also precisely governed by their own intrinsic membrane ionic conductances. The voltage-gated A-type potassium current (IA ) regulates the intrinsic membrane properties of neurons, and disruption of IA is responsible for many neuropathological processes including learning and memory deficits. Thus, it represents a previously unexplored cellular mechanism whereby chronic ethanol (EtOH) may alter hippocampal memory-related functioning. METHODS: Using whole-cell electrophysiological recording methods, we investigated the enduring effects of chronic intermittent ethanol (CIE) exposure during adolescence or adulthood on IA in rat CA1 interneurons. RESULTS: We found that the mean peak amplitude of IA was significantly reduced after CIE in either adolescence or adulthood, but IA density was attenuated after CIE in adolescence but not after CIE in adulthood. In addition, the voltage-dependent steady-state activation and inactivation of IA were altered in interneurons after CIE. CONCLUSIONS: These findings suggest that CIE can cause long-term changes in IA channels in interneurons and thus may alter their inhibitory influences on memory-related local hippocampal circuits, which could be, in turn, responsible for learning and memory impairments observed after chronic EtOH exposure.
Assuntos
Região CA1 Hipocampal/fisiologia , Etanol/administração & dosagem , Interneurônios/fisiologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Fatores Etários , Animais , Condutividade Elétrica , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND: In recent years, it has become clear that acute ethanol (EtOH) affects various neurobiological and behavioral functions differently in adolescent animals than in adults. However, less is known about the long-term neural consequences of chronic EtOH exposure during adolescence, and most importantly whether adolescence represents a developmental period of enhanced vulnerability to such effects. METHODS: We made whole-cell recordings of GABAA receptor-mediated tonic inhibitory currents from dentate gyrus granule cells (DGGCs) in hippocampal slices from adult rats that had been treated with chronic intermittent ethanol (CIE) or saline during adolescence, young adulthood, or adulthood. RESULTS: CIE reduced baseline tonic current amplitude in DGGCs from animals pretreated with EtOH during adolescence, but not in GCs from those pretreated with EtOH during young adulthood or adulthood. Similarly, the enhancement of tonic currents by acute EtOH exposure ex vivo was increased in GCs from animals pretreated with EtOH during adolescence, but not in those from animals pretreated during either of the other 2 developmental periods. CONCLUSIONS: These findings underscore our recent report that CIE during adolescence results in enduring alterations in tonic current and its acute EtOH sensitivity and establish that adolescence is a developmental period during which the hippocampal formation is distinctively vulnerable to long-term alteration by chronic EtOH exposure.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Giro Denteado/fisiologia , Etanol/toxicidade , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Receptores de GABA-A/fisiologia , Fatores Etários , Animais , Giro Denteado/efeitos dos fármacos , Etanol/administração & dosagem , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Smokers with posttraumatic stress disorder (PTSD) smoke at higher prevalence rates and are more likely to relapse early in a quit attempt. Innovative methods are needed to enhance quit rates, particularly in the early quit period. Web-based contingency-management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but are limited by the need for computers. This pilot study builds on the web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). METHODS: Following a 2-week training period, 22 smokers with PTSD were randomized to a 4-week mCM condition or a yoked (i.e., noncontingent 4-week mCM condition). All smokers received 2 smoking cessation counseling sessions, nicotine replacement, and bupropion. Participants could earn up to $690 ($530 for mCM, $25.00 for assessments and office visits [up to 5], and $35.00 for equipment return). The average earned was $314.00. RESULTS: Compliance was high during the 2-week training period (i.e., transmission of videos) (93%) and the 4-week treatment period (92%). Compliance rates did not differ by group assignment. Four-week quit rates (verified with CO) were 82% for the mCM and 45% for the yoked controls. Three-month self-report quit rates were 50% in the mCM and 18% in the yoked controls. CONCLUSIONS: mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among smokers with PTSD, particularly early in a smoking quit attempt.
Assuntos
Terapia Comportamental/métodos , Abandono do Hábito de Fumar/métodos , Prevenção do Hábito de Fumar , Transtornos de Estresse Pós-Traumáticos/complicações , Tabagismo/terapia , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Bupropiona/uso terapêutico , Terapia Combinada , Estudos de Viabilidade , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Projetos Piloto , Recidiva , Fumar/psicologia , Abandono do Hábito de Fumar/economia , Abandono do Hábito de Fumar/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Dispositivos para o Abandono do Uso de Tabaco/estatística & dados numéricos , Tabagismo/psicologia , Resultado do TratamentoRESUMO
Three studies were designed to extend a combination of vested interest theory (VI) and the extended parallel process model of fear appeals (EPPM) to provide formative research for creating more effective disaster preparedness social action campaigns. The aim was to develop an effective VI scale for assessing individual awareness and 'vestedness' relevant to disaster preparedness. Typical preparedness behaviours are discussed with emphasis on earthquakes and tornados in particular. Brief overviews of VI and the EPPM are offered, and findings are presented from three studies (one dealing with earthquakes, and two with tornados) conducted to determine the factor structure of the key VI components involved, and to develop and test subscales derived from the two theories. The paper finishes with a discussion of future research needs and suggestions on how the new subscales may be applied in the design and execution of more effective disaster preparedness campaigns.
Assuntos
Planejamento em Desastres , Terremotos , Conhecimentos, Atitudes e Prática em Saúde , Teoria Psicológica , Tornados , Adulto , Idoso , Medo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Psicometria , Estados UnidosRESUMO
The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.
Assuntos
Convulsões , Resposta a Proteínas não Dobradas , Animais , Camundongos , Morte Súbita , Camundongos Transgênicos , Neurônios , Convulsões/genéticaRESUMO
Tobacco-related deaths exceed those resulting from homicides, suicides, motor vehicle accidence, alcohol consumption, illicit substance use, and acquired immunodeficiency syndrome (AIDS), combined. Amongst U.S. veterans, this trend is particularly concerning given that those suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies have revealed the insula as integrally involved in the neurocircuitry of TUD, specifically showing that individuals with brain lesions involving this region had drastically improved quit rates. Some of these studies show a probability of quitting up to 5 times greater compared to non-insula lesioned regions). Altered activity of the insula may be involved in the disruption of the salience network's (SN) connectivity to the executive control network (ECN), which compromises that patient's ability to switch between interoceptive states focused on cravings to executive and cognitive control. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a patterned form of repetitive transcranial magnetic stimulation (rTMS), intermittent theta burst stimulation (iTBS), at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the SN with the ECN to enhance executive control and by decreasing connectivity with the default mode network (DMN) to reduce interoceptive focus on withdrawal symptoms, we will improve smoking cessation outcomes. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to two conditions: active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n=25) or sham-iTBS + CBT + NRT (n=25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.
RESUMO
BACKGROUND: Alcohol drinking by adolescents is a major public health concern. Adolescents tend to drink in a chronic, intermittent, that is, "binge," pattern, and such patterns of ethanol exposure are associated with increased risk of neurotoxicity and the development of alcohol use disorders (Crews et al., 2000; Hunt, 1993). Both adolescent humans and rats are more sensitive to acute ethanol-induced memory impairment than adults (Acheson et al., 1998; Markwiese et al., 1998). Furthermore, in rats, chronic intermittent ethanol (CIE) exposure during adolescence produces a long-lasting, perhaps permanent, maintenance of the adolescent high sensitivity to ethanol's amnestic effects (White et al., 2000a). We have previously shown that acute ethanol increases tonic inhibitory current mediated by extrasynaptic GABA(A) receptors more efficaciously in dentate granule cells (DGCs) from adolescent than adult rats (Fleming et al., 2007). In this study, we determined if CIE during adolescence produced long-lasting changes in this tonic current. METHODS: Adolescent rats were subjected to a CIE exposure regimen and allowed to mature to full adulthood. Whole-cell voltage-clamp measurements of tonic inhibitory current and mean phasic current were made in vitro in hippocampal brain slices. RESULTS: CIE exposure during adolescence increased the ethanol sensitivity of tonic inhibitory current mediated by extrasynaptic GABA(A) receptors and decreased the ethanol sensitivity of phasic, synaptic GABA(A) receptor-mediated current in adult DGCs. CONCLUSIONS: CIE exposure during adolescence produces long-lasting changes in the function and ethanol sensitivity of extrasynaptic GABA(A) receptors in DGCs. These changes appear to "lock-in" and maintain the high adolescent sensitivity to ethanol in these cells. Furthermore, greater ethanol enhancement of tonic inhibition in the hippocampal formation after CIE is consistent with the greater sensitivity to ethanol-induced memory impairment after adolescent CIE. This finding represents the first demonstration of a long-term, memory-related cellular effect of CIE during adolescence, and the "lock-in" of adolescent ethanol sensitivity that these results suggest could represent a conceptual step forward in understanding the vulnerability of the adolescent brain to alcohol.
Assuntos
Envelhecimento/fisiologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Animais , Interpretação Estatística de Dados , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Fenômenos Eletrofisiológicos , Técnicas In Vitro , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacosRESUMO
Alcohol and tobacco are the 2 most frequently used drugs in the United States and represent the highest co-occurrence of polysubstance use. The objective of this study was to refine an intervention combining mobile contingency management with cognitive-behavioral telephone counseling for concurrent treatment of alcohol and tobacco use disorders. Two cohorts (n = 13 total, n = 5 women) of participants were enrolled, with 10/13 completing treatment and 7/13 completing the 6-month follow-up. At enrollment, participants were drinking a mean of 28.9 drinks per week (SD = 14.1), with a mean of 14.7 heavy drinking days in the past month (SD = 9.9), and a mean of 18.1 cigarettes per day (SD = 11.7). Treatment included a mobile application that participants used to record carbon monoxide and breath alcohol content readings to bioverify abstinence. Participants received up to 4 sessions of phone cognitive-behavioral therapy and monetary reinforcement contingent on abstinence. In cohort 1, 4/6 participants reported abstinent or low-risk drinking post-monitoring. Six weeks post quit-date, 2/6 participants were CO-bioverified abstinent from tobacco use, with 2/6 in dual remission. These results were maintained at 6-months. In cohort 2, 6/7 reported abstinent or low-risk drinking post-monitoring, 5 weeks post quit-date. At the post-monitoring visit, 5/7 were CO-bioverified abstinent from smoking, with 5/7 in dual remission. At 6-months, 3/7 reporting abstinent or low-risk drinking, 1/7 had bioverified abstinence from smoking, with 1/7 in dual remission. Observations suggest that it is possible to develop a concurrent mobile treatment for alcohol and tobacco use disorders.
RESUMO
The central nucleus of the amygdala (CeA) plays a critical role in regulating the behavioral, autonomic and endocrine response to stress. Dopamine (DA) participates in mediating the stress response and DA release is enhanced in the CeA during stressful events. However, the electrophysiological effects of DA on CeA neurons have not yet been characterized. Therefore, the purpose of this study was to identify and characterize the effect of DA application on electrophysiological responses of CeA neurons in coronal brain sections of male Sprague-Dawley rats. We used whole-cell patch-clamp electrophysiological techniques to record evoked synaptic responses and to determine basic membrane properties of CeA neurons both before and after DA superfusion. DA (20-250 µM) did not significantly alter membrane conductance over the voltage range tested. However, DA significantly reduced the peak amplitude of evoked inhibitory synaptic currents in CeA neurons. Pretreatment with the D(2) receptor antagonist eticlopride failed to significantly block the inhibitory effects of DA. In contrast, pretreatment with the D(1) receptor antagonist SCH-23390 significantly reduced the effects of DA on evoked inhibitory neurotransmission in these neurons. Moreover, bath superfusion of the specific D(1) receptor agonist SKF-39393, but not the D(2) receptor agonist quinpirole, significantly reduced peak amplitude of evoked inhibitory synaptic events. DA reduced the frequency of miniature IPSCs without altering the amplitude, while having no effect on the amplitude of IPSCs elicited by pressure application of GABA. These results suggest that DA may modulate inhibitory synaptic transmission in CeA through D(1) receptor activation primarily by a presynaptic mechanism.
Assuntos
Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Dopamina/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Neurônios/citologia , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Salicilamidas/farmacologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
Posttraumatic stress disorder (PTSD) can be a complex disorder, and some studies have found that samples of individuals with PTSD contain subtypes that may relate to health outcomes. The goals were to replicate previously identified PTSD subtypes and examine how subtype membership relates to mortality. Data from the Vietnam Experience Study and a clinical sample of Vietnam veterans were combined (n = 5248) to address these research questions. Consistent with previous studies, 3 PTSD subtypes emerged: externalizers (n = 317), internalizers (n = 579), and low pathology (n = 280). Posttraumatic stress disorder diagnosis was associated with increased risk of all-cause and behavioral-cause (eg, homicide, suicide) mortality. Both externalizing and internalizing subtypes had higher mortality and were more likely to die from cardiovascular causes than those without PTSD. Externalizers were more likely to die from substance-related causes than those without PTSD. The value of considering possible PTSD subtypes is significant in that it may contribute to identifying more specific targets for treatment and rehabilitation in veterans with PTSD.
Assuntos
Causas de Morte , Distúrbios de Guerra/diagnóstico , Distúrbios de Guerra/mortalidade , Controle Interno-Externo , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/mortalidade , Veteranos/psicologia , Guerra do Vietnã , Adulto , Doenças Cardiovasculares/mortalidade , Distúrbios de Guerra/classificação , Distúrbios de Guerra/psicologia , Homicídio/psicologia , Homicídio/estatística & dados numéricos , Humanos , MMPI/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Psicometria , Transtornos de Estresse Pós-Traumáticos/classificação , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Suicídio/psicologia , Suicídio/estatística & dados numéricos , Análise de Sobrevida , Estados Unidos , Veteranos/estatística & dados numéricosRESUMO
RATIONALE: Ethanol can enhance GABA release in various brain regions via presynaptic mechanisms. However, the presynaptic action of ethanol on inhibitory GABA release is still not well understood. OBJECTIVES: Since calcium is required for neurotransmitter release from presynaptic terminals, the purpose of this study was to investigate the role of both internal and external calcium signaling in ethanol-induced enhancement of GABA release within the central amygdala nucleus (CeA) in acute brain slice preparations. METHODS: Whole-cell patch clamp electrophysiology was used to record miniature GABAA receptor-mediated inhibitory postsynaptic currents (mIPSCs) from CeA neurons. Ethanol-enhanced mIPSCs were recorded in the presence of antagonists that regulate internal and external calcium-mediated processes. RESULTS: Bath-applied ethanol dose-dependently increased the mean frequency of mIPSCs without altering mIPSC amplitude. Ethanol-induced increases in mIPSC frequency were antagonized by dantrolene, 2-APB, and the endoplasmic reticulum calcium pump (SERCA) antagonists thapsigargin and cyclopiazonic acid (CPA). Blocking calcium release from mitochondria or via exocytosis with ruthenium red also attenuated mIPSCs while frequency was not altered in the presence of a non-selective calcium channel blocker cadmium. The L-type calcium blocker nifedipine, but not its analogue nimodipine, blocked ethanol-induced enhancement in CeA neurons. CONCLUSIONS: These results demonstrate ethanol-induced presynaptic release of GABA is mediated by internal calcium stores and by disrupting neurotransmitter exocytosis within the CeA, a critical brain area involved in drugs of abuse and alcohol addiction.