RESUMO
Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.
Assuntos
Neurônios GABAérgicos/fisiologia , Núcleo Accumbens/fisiologia , Estresse Fisiológico/fisiologia , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/fisiologia , Animais , Antecipação Psicológica/fisiologia , Comportamento Animal , Relógios Biológicos/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Feminino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos da radiação , Imuno-Histoquímica , Sistema Límbico/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos da radiação , Optogenética , Restrição Física/fisiologia , Restrição Física/psicologia , Recompensa , Área Tegmentar Ventral/efeitos da radiaçãoRESUMO
Survival depends on a balance between seeking rewards and avoiding potential threats, but the neural circuits that regulate this motivational conflict remain largely unknown. Using an approach-food vs. avoid-predator threat conflict test in rats, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Inactivation of aPVTCRF neurons during conflict biases animal's response toward food, whereas activation of these cells recapitulates the food-seeking suppression observed during conflict. aPVTCRF neurons project densely to the nucleus accumbens (NAc), and activity in this pathway reduces food seeking and increases avoidance. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVTCRF neurons, and demonstrated that VMH-aPVT neurons mediate defensive behaviors exclusively during conflict. Together, our findings describe a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats.
Assuntos
Aprendizagem da Esquiva/fisiologia , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/fisiologia , Núcleos da Linha Média do Tálamo/metabolismo , Rede Nervosa/fisiologia , Neurônios/metabolismo , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Escala de Avaliação Comportamental , Conflito Psicológico , Feminino , Hipotálamo/metabolismo , Masculino , Núcleos da Linha Média do Tálamo/citologia , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/efeitos da radiação , Neurônios/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Optogenética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Recompensa , Núcleo Hipotalâmico Ventromedial/citologiaRESUMO
Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGCâdpHbâNAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.
Assuntos
Ritmo Circadiano/fisiologia , Ritmo Circadiano/efeitos da radiação , Depressão/fisiopatologia , Luz/efeitos adversos , Vias Visuais/fisiologia , Animais , Depressão/etiologia , Habenula/fisiologia , Habenula/efeitos da radiação , Camundongos , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação , Vias Visuais/efeitos da radiaçãoRESUMO
The nucleus accumbens (NAc) contributes to behavioral inhibition and compulsions, but circuit mechanisms are unclear. Recent evidence suggests that amygdala and thalamic inputs exert opposing control over behavior, much like direct and indirect pathway output neurons. Accordingly, opponent processes between these NAc inputs or cell types may underlie efficient reward seeking. We assess the contributions of these circuit elements to mouse operant behavior during recurring conditions when reward is and is not available. Although direct pathway stimulation is rewarding and indirect pathway stimulation aversive, the activity of both cell types is elevated during periods of behavioral suppression, and the inhibition of either cell-type selectively increases unproductive reward seeking. Amygdala and thalamic inputs are also necessary for behavioral suppression, even though they both support self-stimulation and innervate different NAc subregions. These data suggest that efficient reward seeking relies on complementary activity across NAc cell types and inputs rather than opponent processes between them.
Assuntos
Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Recompensa , Tonsila do Cerebelo/citologia , Animais , Comportamento Animal/efeitos da radiação , Corpo Celular/efeitos da radiação , Feminino , Luz , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Neurônios/efeitos da radiação , Núcleo Accumbens/efeitos da radiação , Tálamo/citologiaRESUMO
Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1Gy of 500MeV/u (12)C particles with a relatively moderate linear energy transfer (10.6keV/µm). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to (12)C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems' functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer.
Assuntos
Aminas/metabolismo , Comportamento Animal , Encéfalo/metabolismo , Carbono/química , Íons , Proteção Radiológica/métodos , Animais , Encéfalo/efeitos da radiação , Radiação Cósmica , Relação Dose-Resposta à Radiação , Hipotálamo/efeitos da radiação , Transferência Linear de Energia , Masculino , Núcleo Accumbens/efeitos da radiação , Córtex Pré-Frontal/efeitos da radiação , Doses de Radiação , Lesões por Radiação , Radiação Ionizante , Ratos , Ratos Sprague-Dawley , Voo EspacialRESUMO
The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.
Assuntos
Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Vias Neurais , Neurônios/fisiologia , Recompensa , Animais , Condicionamento Clássico , Medo/psicologia , Perfilação da Expressão Gênica , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Reforço Psicológico , Transcrição GênicaAssuntos
Engenharia Genética , Receptores Acoplados a Proteínas G/metabolismo , Rodopsina/metabolismo , Transdução de Sinais/efeitos da radiação , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Espaço Intracelular/metabolismo , Espaço Intracelular/efeitos da radiação , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos da radiação , Receptores Adrenérgicos/genética , Receptores Adrenérgicos/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Recompensa , Rodopsina/genética , Relação Estrutura-AtividadeRESUMO
In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a targetable and temporally precise manner.
Assuntos
Engenharia Genética , Espaço Intracelular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Animais , Bovinos , Linhagem Celular , Cricetinae , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Espaço Intracelular/efeitos da radiação , Camundongos , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes de Fusão/genética , Recompensa , Rodopsina/genética , Rodopsina/metabolismo , Transdução de Sinais/efeitos da radiação , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Preferential enhancement of dopamine transmission within the nucleus accumbens (NAc) shell is a fundamental aspect of the neural regulation of cocaine reward. Despite its importance, the nature of this effect is poorly understood. Here, we used fast-scan cyclic voltammetry to examine specific transmission processes underlying cocaine-evoked increases in dopamine transmission within the NAc core and shell. Initially, we examined altered terminal dopamine concentrations after global autoreceptor blockade. This was the first examination of autoreceptor regulation of naturally occurring phasic dopamine transmission and provided a novel characterization of specific components of dopamine neurotransmission. Comparison of increased dopamine signaling evoked by autoreceptor blockade and cocaine administration allowed robust resolution between increased frequency, concentration, and duration of phasic dopamine release events after cocaine delivery. Cocaine increased dopamine transmission by slowed uptake and increased concentration of dopamine released in the core and shell. However, an additional increase in the number phasic release events occurred only within the NAc shell, and this increase was eliminated by inactivation of midbrain dopaminergic neurons. This represents the first evidence that cocaine directly increases the frequency of dopamine release events and reveals that this is responsible for preferentially increased dopamine transmission within the NAc shell after cocaine administration. Additionally, cocaine administration resulted in a synergistic increase in dopamine concentration, and subregion differences were abolished when cocaine was administered in the absence of autoregulation. Together, these results demonstrate that cocaine administration results in a temporally and regionally specific increase in phasic dopamine release that is significantly regulated by dopamine autoreceptors.
Assuntos
Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Química Encefálica/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica/métodos , Eletroquímica/métodos , Masculino , Microinjeções/métodos , Núcleo Accumbens/efeitos da radiação , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologiaRESUMO
We demonstrated that exposure to extremely low frequency magnetic fields (ELF-MF) enhanced dopamine levels in the rat striatum. To extend our understanding, we examined the role of dopaminergic receptors in ELF-MF-induced behavioral changes. Exposure to ELF-MF (2.4 mT, 1 h/day, for one or seven days) enhanced locomotor activity in a time-dependent manner. This hyperlocomotor activity paralleled an increase in c-Fos-like immunoreactivity (c-Fos-IR). Pretreatment with SCH23390, a dopaminergic D(1)-like receptor antagonist, but not with sulpiride, a dopaminergic D(2)-like receptor antagonist, inhibited ELF-MF-induced increased locomotor activity and c-Fos-IR. Thus, our results suggest that ELF-MF-induced behavioral responses are, at least in part, mediated by activation of dopamine D(1)-like receptors.
Assuntos
Comportamento Animal/efeitos da radiação , Campos Eletromagnéticos , Atividade Motora/efeitos da radiação , Receptores de Dopamina D1/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Western Blotting , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/efeitos da radiação , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta à Radiação , Interpretação de Imagem Assistida por Computador/métodos , Imunoquímica , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos da radiação , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ondas de Rádio , Sulpirida/farmacologia , Fatores de TempoRESUMO
Electrical stimulation (ES) in the brain is becoming a new treatment option in patients with treatment-resistant obsessive-compulsive disorder (OCD). A possible brain target might be the nucleus accumbens (NACC). This review aims to summarise the behavioural and physiological effects of ES in the NACC in humans and in animals and to discuss these findings with regard to neuroanatomical, electrophysiological and behavioural insights. The results clearly demonstrate that ES in the NACC has an effect on reward, activity, fight-or-flight, exploratory behaviour and food intake, with evidence for only moderate physiological effects. Seizures were rarely observed. Finally, the results of ES studies in patients with treatment-resistant OCD and in animal models for OCD are promising.
Assuntos
Comportamento Animal/efeitos da radiação , Estimulação Elétrica/métodos , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/efeitos da radiação , Comportamento Exploratório/fisiologia , Comportamento Exploratório/efeitos da radiação , Humanos , Transtorno Obsessivo-Compulsivo/terapia , RecompensaRESUMO
We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.
Assuntos
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Norepinefrina/farmacologia , Núcleo Accumbens/citologia , Transmissão Sináptica/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Tartarato de Brimonidina , Cicloexanos/farmacologia , Dopamina/farmacologia , Interações Medicamentosas , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Inibição Neural/fisiologia , Inibição Neural/efeitos da radiação , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/efeitos da radiação , Ácidos Fosfínicos/farmacologia , Prazosina/farmacologia , Propanolaminas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos da radiaçãoRESUMO
The dopamine D3 receptor, which is highly enriched in nucleus accumbens (NAc), has been suggested to play an important role in reinforcement and reward. To understand the potential cellular mechanism underlying D3 receptor functions, we examined the effect of D3 receptor activation on GABAA receptor (GABAAR)-mediated current and inhibitory synaptic transmission in medium spiny neurons of NAc. Application of PD128907 [(4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a specific D3 receptor agonist, caused a significant reduction of GABAAR current in acutely dissociated NAc neurons and miniature IPSC amplitude in NAc slices. This effect was blocked by dialysis with a dynamin inhibitory peptide, which prevents the clathrin/activator protein 2 (AP2)-mediated GABAA receptor endocytosis. In addition, the D3 effect on GABAAR current was prevented by agents that manipulate protein kinase A (PKA) activity. Infusion of a peptide derived from GABAAR beta subunits, which contains an atypical binding motif for the clathrin AP2 adaptor complex and the major PKA phosphorylation sites and binds with high affinity to AP2 only when dephosphorylated, diminished the D3 regulation of IPSC amplitude. The phosphorylated equivalent of the peptide was without effect. Moreover, PD128907 increased GABAAR internalization and reduced the surface expression of GABAA receptor beta subunits in NAc slices, which was prevented by dynamin inhibitory peptide or cAMP treatment. Together, our results suggest that D3 receptor activation suppresses the efficacy of inhibitory synaptic transmission in NAc by increasing the phospho-dependent endocytosis of GABAA receptors.
Assuntos
Endocitose/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D3/fisiologia , Receptores de GABA-A/fisiologia , Análise de Variância , Animais , Benzopiranos/farmacologia , Compostos de Bifenilo/farmacologia , Western Blotting/métodos , AMP Cíclico/farmacologia , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina , Interações Medicamentosas , Dinaminas/farmacologia , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica/métodos , Técnicas In Vitro , Insulina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Inibição Neural/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/efeitos da radiação , Oxazinas/farmacologia , Técnicas de Patch-Clamp/métodos , Fragmentos de Peptídeos/farmacologia , Fosforilação , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Sulpirida/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Transmissão Sináptica/efeitos da radiação , Ácido gama-Aminobutírico/farmacologiaRESUMO
While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.
Assuntos
Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Dopamina/metabolismo , Extinção Psicológica/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Estimulação Elétrica/métodos , Eletroquímica/métodos , Extinção Psicológica/efeitos dos fármacos , Modelos Lineares , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Naftalenos , Núcleo Accumbens/efeitos da radiação , Oxepinas , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração/métodos , Fatores de TempoRESUMO
Homeostatic regulation is a defining characteristic of sleep but has rarely been examined in infants. This study presents an automated method of sleep deprivation in which 5-day-old rats were shocked whenever the nuchal muscle became atonic. The intensity of shock was always set at the minimal level required to maintain arousal. Deprived pups exhibited rapid increases in sleep pressure, as evidenced by increased attempts to enter sleep and subsequent increases in sensory threshold; this increased sensory threshold was not due to sensory adaptation of peripheral receptors. In addition, myoclonic twitching was suppressed during the 30-min deprivation period, leading to rebound twitching during recovery sleep. These results provide the earliest demonstration of the homeostatic regulation of sleep in an altricial mammal.
Assuntos
Homeostase/fisiologia , Sono/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal , Relação Dose-Resposta à Radiação , Eletromiografia/métodos , Eletrochoque/efeitos adversos , Feminino , Masculino , Mioclonia/etiologia , Mioclonia/fisiopatologia , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Limiar Sensorial , Privação do Sono/fisiopatologia , Fatores de TempoRESUMO
Previous studies have shown that peripheral electrical stimulation (PES) can suppress morphine-induced conditioned place preference (CPP) and the reinstatement of extinguished CPP in the rat. The present study was performed to elucidate if preproenkephalin (PPE) and preprodynorphin (PPD) mRNAs in the nucleus accumbens (NAc) play a role in this event. Rats were trained with morphine for 4 days to establish CPP paradigm. They were then given 15-min test once a day for eight consecutive days for extinction trial. Twenty-four hours after the 8th session of extinction trials, rats were given peripheral electrical stimulation (PES) at 2 or 100 Hz once a day for 3 days, then a morphine-priming injection at a dose of 1, 2, or 4 mg/kg to reinstate the extinguished CPP. At the end of the experiment, PPE and PPD mRNA levels in the nucleus acccumbens (NAc) were determined by the semiquantitative RT-PCR technique. The results showed that PES at 2- and 100-Hz administered 30 min a day for 3 days suppressed both the expression of morphine-induced CPP and the reinstatement of extinguished CPP. PES at 2 Hz increased preproenkephalin (PPE) mRNA levels, whereas PES of 100 Hz that of preprodynorphin (PPD) mRNA levels in the NAc. These findings suggest that enkephalin and dynorphin in NAc may play important roles in the mechanisms underlying the inhibitory effect of PES on the expression and reinstatement of morphine-induced CPP in rats.
Assuntos
Condicionamento Operante/efeitos da radiação , Dinorfinas/metabolismo , Estimulação Elétrica , Encefalinas/metabolismo , Extinção Psicológica/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Núcleo Accumbens/efeitos da radiação , Precursores de Proteínas/metabolismo , Análise de Variância , Animais , Comportamento Animal , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Dinorfinas/genética , Encefalinas/genética , Membro Posterior/inervação , Membro Posterior/efeitos da radiação , Masculino , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Entorpecentes/farmacologia , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de TempoRESUMO
Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug abuse. However, there are still many unanswered questions about the basic mechanisms of acupuncture. Studies have shown that the GABA(B) receptor system may play a significant modulatory role in the mesolimbic system in drug abuse, including ethanol. The in vivo microdialysis study was designed to investigate the effect of acupuncture on acute ethanol-induced dopamine release in the nucleus accumbens and the potential role of the GABA(B) receptor system in acupuncture. Male Sprague-Dawley rats were administered with the highly selective GABA(B) antagonist SCH 50911 (3 mg/kg, i.p.) 1h prior to an intraperitoneal injection of ethanol (1 g/kg). Immediately after ethanol treatment, acupuncture was given at bilateral Shenmen (HT7) points for 1min. Acupuncture at the specific acupoint HT7, but not at control points (PC6 or tail) significantly decreased dopamine release in the nucleus accumbens. Inhibition of dopamine release by acupuncture was completely prevented by SCH 50911. These results suggest that stimulation of specific acupoints inhibits ethanol-induced dopamine release by modulating GABA(B) activity and imply that acupuncture may be effective in blocking the reinforcing effects of ethanol.
Assuntos
Acupuntura , Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de GABA-B/fisiologia , Pontos de Acupuntura , Animais , Antagonistas de Receptores de GABA-B , Masculino , Morfolinas/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/efeitos da radiação , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos da radiação , Ratos , Ratos Sprague-DawleyRESUMO
Prepulse inhibition (PPI) is a normal reduction in the startle response produced when a brief, low intensity stimulus is presented prior to a startle-evoking stimulus. PPI is often disrupted in humans diagnosed with schizophrenia. As similar stimuli elicit PPI in rodents and humans, interventions in rodents that disrupt PPI may reveal aspects of neuronal dysfunction relevant to schizophrenia. Stimulation of the ventral hippocampus (vHip) with NMDA significantly increases dopamine (DA) efflux in the nucleus accumbens (NAc) and disrupts PPI, whereas NMDA infusion into the dorsal hippocampus (dHip) fails to alter PPI. Our previous research shows that brief periods of 20 Hz electrical vHip stimulation also significantly increase NAc DA efflux. The present experiments assessed the effects of stimulating the vHip or dHip on PPI and NAc DA efflux. As predicted, 20 Hz stimulation (10 s, 300 microA) of the vHip, but not the dHip, reversibly disrupted PPI. In contrast, 2 Hz stimulation (100 s, 300 microA) of the vHip failed to affect PPI. Microdialysis experiments revealed that 20 Hz stimulation of the vHip increased NAc DA efflux only in the hemisphere ipsilateral to the stimulating electrode, whereas 20 Hz stimulation of the dHip failed to affect NAc DA efflux. These data demonstrate the regional specificity and frequency-dependent effects of hippocampal activity on PPI. Additionally, it is intriguing that both chemical and electrical stimulation of the vHip disrupt PPI and increase NAc DA efflux, however, the relevance of these changes in NAc DA efflux to the disruption of PPI remains to be determined.
Assuntos
Estimulação Elétrica/métodos , Hipocampo/efeitos da radiação , Inibição Neural/efeitos da radiação , Reflexo Acústico/efeitos da radiação , Animais , Comportamento Animal/efeitos da radiação , Química Encefálica/efeitos da radiação , Cromatografia Líquida de Alta Pressão/métodos , Dopamina/metabolismo , Eletroquímica , Lateralidade Funcional , Hipocampo/fisiologia , Masculino , Microdiálise/métodos , Inibição Neural/fisiologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos da radiação , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinson's disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. METHODS: We used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. RESULTS: rTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. CONCLUSIONS: Our results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.
Assuntos
Dopamina/metabolismo , Eletroconvulsoterapia , Córtex Motor/efeitos da radiação , Núcleo Accumbens/metabolismo , Putamen/metabolismo , Estimulação Magnética Transcraniana , Animais , Radioisótopos de Carbono/farmacocinética , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/metabolismo , Núcleo Caudado/efeitos da radiação , Dopamina/efeitos da radiação , Antagonistas de Dopamina/farmacocinética , Eletroconvulsoterapia/instrumentação , Eletroconvulsoterapia/métodos , Campos Eletromagnéticos , Macaca fascicularis , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/efeitos da radiação , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/efeitos da radiação , Putamen/diagnóstico por imagem , Putamen/efeitos da radiação , Racloprida/farmacocinética , Tomografia Computadorizada de Emissão , Estimulação Magnética Transcraniana/uso terapêuticoRESUMO
The concentrations of dopamine (DA) and its metabolites and the levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin, were determined in discrete cerebral areas of rats 3 hr after (neutron-gamma) irradiation at 4 and 7 Gy. After the 7 Gy irradiation, no significant effect was observed. After the 4 Gy exposure, the most marked difference between irradiated and control rats was in the levels of DA and its metabolites in the striatum. We observed a decrease of DA, HVA, and DOPAC levels in the striatum and an opposite pattern in the substantia nigra. Whatever the brain area observed, an increase of 5-HIAA levels was noted.