RESUMO
OBJECTIVE: To investigate the intrauterine fetal growth pattern and fetoplacental circulation in pregnancies following bariatric surgery. DESIGN: Prospective study. SETTING: Maternity Unit, UK. POPULATION: One hundred and sixty-two pregnant women; 54 with previous bariatric surgery and 108 with no surgery but similar booking body mass index. METHODS: Participants were seen at 11-14, 20-24, 30-33 and 35-37 weeks of gestation and an oral glucose tolerance test (OGTT) was performed at 27-30 weeks. Fetal head and abdominal circumference (AC), femur length (FL), estimated fetal weight (EFW) and fetoplacental Dopplers were measured at three time-points in pregnancy. Birthweight (BW) was recorded. Variables were modelled after adjustment for maternal/pregnancy characteristics. Model estimates are reported as posterior means and quantile-based 90% credible intervals (CrI). MAIN OUTCOME MEASURES: Fetal biometry, fetoplacental Doppler, BW. RESULTS: Compared with the no surgery group, the post-bariatric surgery group had lower EFW during gestation (up to -120 g; [-189 g, -51 g] lighter) at 35-37 weeks, with smaller AC and FL. Similarly, infants of mothers with previous bariatric surgery had lower average BW [-202 g [-330 g, -72 g] lighter). Overall, there was no difference in the fetoplacental Doppler indices between groups but maternal glucose levels at OGTT were positively correlated with third-trimester EFW and BW. CONCLUSIONS: Fetuses of women with previous bariatric surgery are smaller during pregnancy and at birth, compared with those of women without such surgery, and this may be related to the lower maternal glucose levels seen in the former population. The fetoplacental circulation appears not to be altered by maternal weight loss surgery. TWEETABLE ABSTRACT: Offspring of post-bariatric women are smaller during pregnancy and at birth but this is not due to placental insufficiency.
Assuntos
Cirurgia Bariátrica/efeitos adversos , Desenvolvimento Fetal , Circulação Placentária , Complicações Pós-Operatórias/fisiopatologia , Complicações na Gravidez/fisiopatologia , Adulto , Biometria , Peso ao Nascer , Feminino , Retardo do Crescimento Fetal , Peso Fetal , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Obesidade/fisiopatologia , Obesidade/cirurgia , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Gravidez , Complicações na Gravidez/etiologia , Estudos Prospectivos , Ultrassonografia Pré-NatalRESUMO
BACKGROUND: Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. METHODS: To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. RESULTS: In the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. CONCLUSIONS: While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.
Assuntos
Cocaína , Jogo de Azar , Humanos , Ratos , Masculino , Feminino , Animais , Sinais (Psicologia) , Neurônios Dopaminérgicos , Cocaína/farmacologia , Dopamina , Área Tegmentar Ventral , Tomada de Decisões/fisiologiaRESUMO
Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA-mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2-4 week drug washout. In vivo neurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D(2) or D(1) agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA-mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA-mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure.
Assuntos
Anfetamina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Emoções/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Esquema de Medicação , Interações Medicamentosas , Extinção Psicológica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Punição/psicologia , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
Male infertility, a condition that has during the last decade raised significant concern, is a diagnostically demanding and socially sensitive topic. The number of unsolved issues on infertility etiology, especially potential environmental causes, in couples demonstrates the need for further investigations into infertility biomarkers. Semen parameters are often insufficient for reliable profiling of male infertility. Thus, this study aims to evaluate for the first time seminal plasma N-glycosylation as a biomarker of environmental exposure in semen samples from 82 normozoospermic men and 84 men with abnormal semen parameters and compare it with genome damage measured by DNA fragmentation. We obtained information about chronic exposure to environmental factors from the self-reported questionnaire, and determined sperm DNA fragmentation by sperm chromatin dispersion, while N-glycans were characterized with liquid chromatography-mass spectrometry (LC-MS). Based on previously published results, ten N-glycans were selected. Results show that the selected seminal plasma N-glycans were significantly associated with smoking, exposure to pesticides, air pollution, agents emitted during photocopying, alcohol consumption, and obesity. Some N-glycans showed a simultaneous association with DNA fragmentation, semen parameters, and environmental stressors. These subgroups of N-glycans are new potential candidates for biomonitoring of exposure to different environmental factors in men with semen abnormalities.
Assuntos
Infertilidade Masculina , Praguicidas , Biomarcadores/análise , Cromatina , Fragmentação do DNA , Exposição Ambiental/efeitos adversos , Humanos , Infertilidade Masculina/genética , Masculino , Praguicidas/análise , Polissacarídeos/análise , Sêmen/química , Análise do Sêmen , Motilidade dos Espermatozoides , EspermatozoidesRESUMO
Projections from the basolateral amygdala (BLA) and dopamine (DA) input from the ventral tegmental area (VTA) converge in the medial prefrontal cortex (mPFC), forming a neural circuit implicated in certain cognitive and emotional processes. However, the role that DA plays in modulating activity in the BLA-mPFC pathway is unknown. The present study investigated the mechanisms by which DA modulates BLA-evoked changes in mPFC neural activity, using extracellular single-unit recordings in urethane-anesthetized rats. BLA stimulation evoked two distinct types of responses in separate populations of mPFC neurons: monosynaptic, excitatory responses and, more commonly, inhibition of spontaneous firing. Stimulation of the VTA or local iontophoretic application of DA attenuated BLA-evoked inhibition of PFC neuron firing. Administration of selective DA receptor agonists revealed that these effects were mediated by D2 and D4 (but not D1) receptors. In addition, VTA stimulation or DA application attenuated BLA-evoked firing of a separate population of mPFC neurons in a frequency-dependent manner; firing evoked by higher-frequency stimulation of the BLA was less inhibited than that evoked by single-pulse stimulation. Attenuation of BLA-evoked firing was also induced by of D1 (but not D2 or D4) receptor agonists. These data indicate that dissociable DA receptor mechanisms regulate the balance of excitatory and inhibitory transmission in BLA-mPFC circuits, biasing toward an increase in the excitatory influence that the BLA exerts over populations of mPFC neurons. These findings may have important implications for understanding the pathophysiology underlying emotional and cognitive disturbances present in disorders such as depression and drug addiction.
Assuntos
Tonsila do Cerebelo/fisiologia , Dopamina/fisiologia , Inibição Neural/fisiologia , Córtex Pré-Frontal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Dopamina/administração & dosagem , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Estimulação Elétrica/métodos , Eletrofisiologia , Iontoforese , Masculino , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/fisiologia , Tegmento Mesencefálico/fisiologiaRESUMO
Cost/benefit decisions regarding the relative effort or delay costs associated with a particular response are mediated by distributed dopaminergic and glutamatergic neural circuits. The present study assessed the contribution of dopamine and NMDA glutamate receptors in these different forms of decision making using novel effort- and delay-discounting procedures. In the effort-discounting task, rats could either emit a single response on a low-reward lever to receive two pellets, or make 2, 5, 10, or 20 responses on a high-reward (HR) lever to obtain four pellets. In the delay-discounting task, one press of the HR lever delivered four pellets after a delay (0.5-8 s). A third task (effort-discounting with equivalent delays) was similar to the effort-discounting procedure, except that the relative delay to reward delivery was equalized across response options. The dopamine receptor antagonist flupenthixol reduced choice of the HR lever under all three testing conditions, indicating that dopamine antagonism alters effort-based decision making independent of any contribution of delay. Amphetamine exerted dose-dependent, biphasic effects; a higher dose (0.5 mg/kg) increased effort discounting, whereas a lower dose (0.25 mg/kg) reduced delay discounting. The noncompetitive NMDA antagonist ketamine (5 mg/kg) increased effort and delay discounting, but did not affect choice on the effort with equivalent delays task, indicating a reduced tolerance for delayed rewards. These findings highlight the utility of these procedures in pharmacologically dissociating the neurochemical mechanisms underlying these different, yet interrelated forms of decision making. Furthermore, they suggest that dopamine and NMDA receptors make dissociable contributions to these different types of cost-benefit analyses.
Assuntos
Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/farmacologia , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Flupentixol/farmacologia , Ketamina/farmacologia , Masculino , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa , Resposta de Saciedade/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
The medial prefrontal cortex (mPFC) of the rat plays an essential role in behavioral flexibility, as lesions or inactivations of this region impair shifting between strategies or attentional sets using a variety of different behavioral tests. In the present study, we assessed the effects of inactivation of the mPFC on strategy set-shifting and reversal learning, using a novel, automated procedure conducted in an operant chamber. In Experiment 1, inactivation of the mPFC with bupivacaine did not impair the initial learning of a visual-cue (i.e.; always press the lever with a cue light illuminated above it) or a response (i.e.; always press the left lever) discrimination. Control rats required greater number of trials to shift from using a visual-cue to a response strategy than the opposite shift. mPFC inactivation impaired performance of a visual-cue-response set-shift, but not the easier response-visual-cue shift. In Experiment 2, pre-exposure to the visual-cue stimulus lights increased the difficulty of the response-visual-cue shift, reflected by a greater number of trials required by control rats to achieve criterion relative to those in Experiment 1. Under these conditions, inactivation of the mPFC did impair performance of this set-shift. In contrast, mPFC inactivation did not affect reversal learning of a response discrimination. These findings highlight the utility of this automated procedure for assessing set-shifting mediated by the mPFC. Furthermore, they reveal that the relative difficulty of the type of shift rats are required to perform has a direct impact on whether or not the mPFC contributes to this form of behavioral flexibility.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Condicionamento Operante/fisiologia , Córtex Pré-Frontal/fisiologia , Reversão de Aprendizagem/fisiologia , Anestésicos Locais/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Comportamento Animal/fisiologia , Bupivacaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Estimulação Luminosa , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Long-Evans , Reversão de Aprendizagem/efeitos dos fármacosRESUMO
Aging is associated with changes in executive functioning and the mesocorticolimbic dopamine system. However, the effects of aging on different forms of behavioral flexibility are not fully characterized. In young (â¼5 months) and aged (â¼22 months) male Fischer 344 × brown Norway rats, we assessed spatial working memory and different forms of behavioral flexibility using operant tasks: strategy set-shifting (study 1) or probabilistic reversal learning (study 2). We also assessed dopaminergic markers using immunohistochemistry. Compared with young rats, aged rats displayed impairments in working memory. Aged rats also showed nonperseverative impairments in set-shifting, with a subset also showing impairments in initial discrimination learning. In probabilistic reversal learning, aged rats completed more reversals, driven by an increased sensitivity to recent reward and negative feedback. Tyrosine hydroxylase (TH) showed region-specific changes with aging and was correlated with several measures of behavioral flexibility. These data suggest that age-related changes prefrontal cortical function and dopamine synthesis contribute to changes in executive functioning during aging.
Assuntos
Envelhecimento/fisiologia , Dopamina/metabolismo , Função Executiva/fisiologia , Aprendizagem/fisiologia , Memória de Curto Prazo/fisiologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Memória Espacial/fisiologiaRESUMO
Decision making often requires weighing costs and benefits of different options that vary in terms of reward magnitude and uncertainty. Previous studies using pharmacological inactivations have shown that the basolateral amygdala (BLA) to nucleus accumbens (NAc) pathway promotes choice towards larger/riskier rewards. Neural activity in BLA and NAc shows distinct, phasic changes in firing prior to choice and following action outcomes, yet, how these temporally-discrete patterns of activity within BLAâNAc circuitry influence choice is unclear. We assessed how optogenetic silencing of BLA terminals in the NAc altered action selection during probabilistic decision making. Rats received intra-BLA infusions of viruses encoding the inhibitory opsin eArchT and were well trained on a probabilistic discounting task, where they chose between smaller/certain rewards and larger rewards delivered in a probabilistic manner, with the odds of obtaining the larger reward changing over a session (50-12.5%). During testing, activity of BLAâNAc inputs were suppressed with 4- to 7-s pulses of light delivered via optic fibers into the NAc during discrete task events: prior to choice or after choice outcomes. Inhibition prior to choice reduced selection of the preferred option, suggesting that during deliberation, BLAâNAc activity biases choice towards preferred rewards. Inhibition during reward omissions increased risky choice during the low-probability block, indicating that activity after non-rewarded actions serves to modify subsequent choice. In contrast, silencing during rewarded outcomes did not reliably affect choice. These data demonstrate how patterns of activity in BLAâNAc circuitry convey different types of information that guide action selection in situations involving reward uncertainty.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Tomada de Decisões/fisiologia , Núcleo Accumbens/fisiologia , Optogenética , Recompensa , Assunção de Riscos , Potenciais de Ação/fisiologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Complexo Nuclear Basolateral da Amígdala/citologia , Condicionamento Operante , Desvalorização pelo Atraso , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Inibição Psicológica , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Vias Neurais/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Probabilidade , Ratos , Ratos Long-Evans , Transdução GenéticaRESUMO
Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.
Assuntos
Córtex Pré-Frontal/metabolismo , Resolução de Problemas/fisiologia , Receptores Dopaminérgicos/classificação , Receptores Dopaminérgicos/fisiologia , Análise de Variância , Animais , Comportamento Animal , Sinais (Psicologia) , Discriminação Psicológica/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções/métodos , Estimulação Luminosa/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Resolução de Problemas/efeitos dos fármacos , Ratos , Ratos Long-EvansRESUMO
Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia.
Assuntos
Transtornos Cognitivos/etiologia , Córtex Pré-Frontal/metabolismo , Esquizofrenia/complicações , Esquizofrenia/patologia , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , HumanosRESUMO
Phasic increases and decreases in dopamine (DA) transmission encode reward prediction errors thought to facilitate reward-related learning, yet how these signals guide action selection in more complex situations requiring evaluation of different reward remains unclear. We manipulated phasic DA signals while rats performed a risk/reward decision-making task, using temporally discrete stimulation of either the lateral habenula (LHb) or rostromedial tegmental nucleus (RMTg) to suppress DA bursts (confirmed with neurophysiological studies) or the ventral tegmental area (VTA) to override phasic dips. When rats chose between small/certain and larger/risky rewards, LHb or RMTg stimulation, time-locked to delivery of one of these rewards, redirected bias toward the alternative option, whereas VTA stimulation after non rewarded choices increased risky choice. LHb stimulation prior to choices shifted bias away from more preferred options. Thus, phasic DA signals provide feedback on whether recent actions were rewarded to update decision policies and direct actions toward more desirable reward.
Assuntos
Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Dopamina/metabolismo , Recompensa , Assunção de Riscos , Transdução de Sinais/fisiologia , Animais , Masculino , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
BACKGROUND: Perturbations in gamma-aminobutyric acid (GABA)-related markers have been reported in the prefrontal cortex of schizophrenic patients. However, a preclinical assessment of how suppression of prefrontal cortex GABA activity may reflect behavioral and cognitive pathologies observed in schizophrenia is forthcoming. METHODS: We assessed the effects of pharmacologic blockade of prefrontal cortex GABA(A) receptors in rats on executive functions and other behaviors related to schizophrenia, as well as neural activity of midbrain dopamine neurons. RESULTS: Blockade of prefrontal cortex GABA(A) receptors with bicuculline (12.5-50 ng) did not affect working memory accuracy but did increase response latencies, resembling speed of processing deficits observed in schizophrenia. Prefrontal cortex GABA(A) blockade did not impede simple discrimination or reversal learning but did impair set-shifting in a manner dependent on when these treatments were given. Reducing GABA activity before the set-shift impaired the ability to acquire a novel strategy, whereas treatment before the initial discrimination increased perseveration during the shift. Latent inhibition was unaffected by bicuculline infusions before the preexposure/conditioning phases, suggesting that reduced prefrontal cortex GABA activity does not impair "learned irrelevance." GABA(A) blockade increased locomotor activity and showed synergic effects with a subthreshold dose of amphetamine. Furthermore, reducing medial prefrontal cortex GABA activity selectively increased phasic burst firing of ventral tegmental area dopamine neurons, without altering the their overall population activity. CONCLUSIONS: These results suggest that prefrontal cortex GABA hypofunction may be a key contributing factor to deficits in speed of processing, cognitive flexibility, and enhanced phasic dopamine activity observed in schizophrenia.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dopamina/fisiologia , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Ácido gama-Aminobutírico/metabolismo , Anfetamina/farmacologia , Animais , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Sinais (Psicologia) , Aprendizagem por Discriminação/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Fenômenos Eletrofisiológicos , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Microinjeções , Estimulação Luminosa , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Long-Evans , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Sinapses/metabolismoRESUMO
This study examined the effects of long-term cannabinoid administration on the responsivity of 5-HT1A and 5-HT2A receptors, which have been implicated in depression. Animals received 12 d administration of the potent cannabinoid receptor agonist HU-210 (100 microg/kg), following which they were monitored on their behavioural, physiological and hormonal responses to a single challenge of a 5-HT1A and 5-HT2A receptor agonist, 8-OH-DPAT (0.3 mg/kg) and DOI (1 mg/kg) respectively. Chronic HU-210 treatment lead to a significant enhancement of DOI-induced wet-dog shakes, but a reduction of DOI-induced back muscle contractions. DOI-induced corticosterone release was unaffected by HU-210 treatment. The hyperthermic response to DOI appeared to be potentiated by long-term HU-210 treatment, as 50% of these subjects died from an apparent serotonin syndrome with core temperatures exceeding 43 degrees C. The 8-OH-DPAT-induced hypothermic response and elevation of corticosterone were both significantly attenuated by long- term HU-210 treatment. These data imply that chronic cannabinoid treatment may up-regulate 5-HT2A receptor activity while concurrently down-regulating 5-HT1A receptor activity, a finding similar to that sometimes observed in depression. This may partially explain the association between excessive cannabis consumption and the induction of affective disease.