RESUMO
OBJECTIVES: Comprehensive nationwide monitoring and evaluation of screening through registry-based review of key indicators is necessary for programme optimization, especially as new tests and strategies are introduced. We aimed to investigate and report on the use of these key indicators in the Swedish programme. SETTING AND METHODS: Organized population-based cervical screening targeting women aged 23-50 and 51-60 every three and five years, respectively, is regionally implemented in Sweden. All cytological and histopathological test results and invitations are exported to the National Cervical Screening Registry. We describe the methods to obtain registry-based quality indicators by age, region, and calendar period. RESULTS: In 2013, there were 633,592 cervical smears in Sweden, of which 69% were organized smears resulting from an invitation. Screening test coverage for women aged 23-60 was 80% and similar for the previous decade, but varied greatly between and within counties over-time. Among women aged 23-25, test coverage increased dramatically during the previous six years, reaching 87% in 2013. The proportion of women with cytological high-grade cervical lesions found in cytology that had been followed-up with biopsy within one year was 97%. Major variations in cervical cancer incidence between counties were observed. CONCLUSIONS: Registry-based analyses of key quality indicators provided the basis for prioritizing improvements of the organized cervical screening programme.
Assuntos
Avaliação de Resultados em Cuidados de Saúde , Teste de Papanicolaou/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Neoplasias do Colo do Útero/epidemiologia , Adulto , Feminino , Humanos , Incidência , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Suécia/epidemiologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
RATIONALE: Repeated nicotine exposure causes neuroadaptations in limbic cortico-striatal circuits involved in learning and motivation. Such alterations are relevant to addiction because they are suggested to mediate the ability of smoking-associated stimuli to control behavior and to enhance nicotine-seeking and -taking behaviors. Female smokers report higher cue reactivity relative to their male counter parts, yet little is known about putative gender-specific effects of adolescent nicotine exposure on reward-related learning. Prior repeated nicotine exposure in adult male rats enhances Pavlovian approach behavior and conditioned reinforcement. OBJECTIVE: Given that smoking is typically initiated during adolescence, here we assessed the extent to which adolescent nicotine exposure impacts Pavlovian approach and conditioned reinforcement in male and female rats. METHODS: Rats were injected with nicotine on postnatal days 31-45 prior to training on Pavlovian approach behavior starting on day 51. They were trained to associate a conditioned stimulus (CS), illumination of a magazine light, and tone, with an unconditioned stimulus (US), the delivery of water, for 10-daily sessions, and then were tested on the acquisition of responding with conditioned reinforcement. RESULTS: Adolescent nicotine exposure selectively increased approach to the magazine during the CS in males but decreased approach to the magazine during the CS in female rats. Vehicle-exposed female rats, however, showed greater magazine approach during the CS than did male control rats. Prior nicotine exposure also enhanced conditioned reinforcement in both male and female rats. CONCLUSIONS: Repeated exposure to nicotine during adolescence had opposite effects on Pavlovian approach behavior in male and female rats but enhanced acquisition of a new response with conditioned reinforcement. Novel information on how nicotine exposure influences reward-related learning during adolescence may increase our understanding of neurobiological mechanisms involved in the initiation of smoking behavior.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Caracteres Sexuais , Análise de Variância , Animais , Animais Recém-Nascidos , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND: Repeated or prolonged exposure to stress has profound effects on a wide spectrum of behavioral and neurobiological processes and has been associated with the pathophysiology of depression. The multifaceted nature of this disorder includes despair, anhedonia, diminished motivation, and disrupted cognition, and it has been proposed that depression is also associated with reduced reward-motivated learning. We have previously reported that prior chronic corticosterone exposure to mice produces a lasting depressive-like state that can be reversed by chronic antidepressant treatment. METHODS: In the present study, we tested the effects of prior chronic exposure to corticosterone (50 µg/ml) administered to rats or to mice in drinking water for 14 days followed by dose-tapering over 9 days. RESULTS: The exposure to corticosterone produced lasting deficits in the acquisition of reward-related learning tested on a food-motivated instrumental task conducted 10-20 days after the last day of full dose corticosterone exposure. Rats exposed to corticosterone also displayed reduced responding on a progressive ratio schedule of reinforcement when tested on day 21 after exposure. Amitriptyline (200 mg/ml in drinking water) exposure for 14 days to mice produced the opposite effect, enhancing food-motivated instrumental acquisition and performance. Repeated treatment with amitriptyline (5 mg/kg, intraperitoneally; bid) subsequent to corticosterone exposure also prevented the corticosterone-induced deficits in rats. CONCLUSIONS: These results are consistent with aberrant reward-related learning and motivational processes in depressive states and provide new evidence that stress-induced neuroadaptive alterations in cortico-limbic-striatal brain circuits involved in learning and motivation may play a critical role in aspects of mood disorders.
Assuntos
Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Corticosterona/farmacologia , Motivação/efeitos dos fármacos , Recompensa , Amitriptilina/administração & dosagem , Amitriptilina/farmacologia , Amitriptilina/uso terapêutico , Animais , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Corticosterona/administração & dosagem , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/psicologia , Esquema de Medicação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral amygdala disrupted reconsolidation of auditory fear memories. In contrast, manipulations of CREB in the amygdala did not modify extinction of fear. These findings suggest that the role of CREB in modulation of memory after retrieval is dynamic and that CREB activity in the basolateral amygdala is involved in fear memory reconsolidation.
Assuntos
Tonsila do Cerebelo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Extinção Psicológica/fisiologia , Memória/fisiologia , Animais , Medo/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM-dependent signaling. RCS expression is high in the dorsal striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic-striatal function. To test this hypothesis, we examined RCS knockout (KO) mice in behavioral models dependent on these brain areas. Mice were tested for food-reinforced instrumental conditioning and responding under a progressive ratio (PR) schedule of reinforcement and in models of anxiety (elevated plus maze and open field). While RCS KO mice showed normal acquisition of a food-motivated instrumental response, they exhibited a lower breakpoint value when tested on responding under a PR schedule of reinforcement. RCS KO mice also displayed decreased exploration in both the open arms of an elevated plus maze and in the center region of an open field, suggesting an enhanced anxiety response. Biochemical studies revealed a reduction in the levels of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the striatum of RCS KO mice. DARPP-32 is important in reward-mediated behavior, suggestive of a possible role for DARPP-32 in mediating some of the effects of RCS. Together these results implicate a novel PKA-regulated phosphoprotein, RCS, in the etiology of motivational deficits and anxiety.
Assuntos
Ansiedade/genética , Comportamento Animal/fisiologia , Motivação/genética , Fosfoproteínas/genética , Animais , Ansiedade/metabolismo , Calmodulina/metabolismo , Corpo Estriado/metabolismo , Immunoblotting , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fosfoproteínas/metabolismoRESUMO
RATIONALE: We recently demonstrated that blocking specific nicotinic acetylcholine receptors (nAChRs) abolishes the conditioned reinforcing properties of ethanol-associated cues in rat, suggesting nAChRs as promising pharmacological targets for prevention of cue-induced relapse. OBJECTIVES: The present study investigated the involvement of nAChR subtypes in the conditioned reinforcing properties of stimuli associated with a natural reward (sucrose). METHODS: Water-deprived rats were trained to associate a tone + light stimulus (CS) with the presentation of a 0.1 M sucrose solution for 10 consecutive days. On the subsequent day, the animals were tested on the stringent acquisition of a new instrumental response with conditioned reinforcement, following a systemic injection of the nonselective nAChR antagonist mecamylamine (MEC) or the selective α7 and α6/α3ß2ß3* nAChR antagonist methyllycaconitine (MLA). At testing, the rats were presented with two novel levers. Responding on the lever assigned as active (CR lever) resulted in a presentation of the CS alone, while pressing the inactive lever (NCR lever) had no programmed consequences. RESULTS: Control animals pressed the CR lever significantly more than the NCR lever, demonstrating that the CR had acquired conditioned reinforcing properties. Systemic MEC as well as MLA reduced the CR lever responses to the same level as for the NCR lever. CONCLUSIONS: These results demonstrate a role for the α7 and/or α6/α3ß2ß3* nAChRs in conditioned reinforcement to a natural reward and suggest neuronal nAChRs as common mediators of the impact of cues on incentive processes.
Assuntos
Receptores Nicotínicos/metabolismo , Recompensa , Sacarose/administração & dosagem , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Sinais (Psicologia) , Masculino , Mecamilamina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Esquema de Reforço , Reforço PsicológicoRESUMO
Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior.
Assuntos
Modelos Animais de Doenças , Comportamento Impulsivo/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Comportamento Aditivo/etiologia , Comportamento Aditivo/psicologia , Humanos , Comportamento Impulsivo/complicações , Filogenia , Transtornos Relacionados ao Uso de Substâncias/etiologiaRESUMO
There are well-established links between impulsivity and alcohol use in humans and other model organisms; however, the etiological nature of these associations remains unclear. This is likely due, in part, to the heterogeneous nature of the construct of impulsivity. Many different measures of impulsivity have been employed in human studies, using both questionnaire and laboratory-based tasks. Animal studies also use multiple tasks to assess the construct of impulsivity. In both human and animal studies, different measures of impulsivity often show little correlation and are differentially related to outcome, suggesting that the impulsivity construct may actually consist of a number of more homogeneous (and potentially more meaningful) subfacets. Here, we provide an overview of the different measures of impulsivity used across human and animal studies, evidence that the construct of impulsivity may be better studied in the context of more meaningful subfacets, and recommendations for how research in this direction may provide for better consilience between human and animal studies of the connection between impulsivity and alcohol use.
Assuntos
Alcoolismo/epidemiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/epidemiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Inibição Psicológica , Animais , Modelos Animais de Doenças , Comportamento Exploratório , Humanos , Comportamento Social , Especificidade da EspécieRESUMO
Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressant-like behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained-release alginate implant, produced an antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.
Assuntos
Antidepressivos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Depressão/prevenção & controle , Sistemas de Liberação de Medicamentos/métodos , Hipocampo/efeitos dos fármacos , Alginatos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Materiais Biocompatíveis/administração & dosagem , Western Blotting , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Ácido Glucurônico/administração & dosagem , Ácidos Hexurônicos/administração & dosagem , Masculino , Microesferas , Plasticidade Neuronal/efeitos dos fármacos , Polivinil/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor trkA/efeitos dos fármacos , Receptor trkA/metabolismo , Estresse Psicológico/prevenção & controleRESUMO
Chronic cocaine use has been proposed to induce long-lasting alterations in cognitive functions dependent on the prefrontal cortex, and these alterations may contribute to the development of addiction. However, the underlying cellular mechanisms remain largely unknown, in part because of the lack of suitable animal models of cocaine-induced cognitive dysfunction that are amenable to molecular manipulations. Here, we characterized the effects of repeated cocaine administration on multiple aspects of cognitive function in C57BL/6 mice. Mice received 14 daily injections of either cocaine or saline, followed by a drug-free period of 2 weeks. They were then assessed for (i) cognitive flexibility in an instrumental reversal learning task; (ii) attentional function and response inhibition in a three-choice serial reaction time task; and (iii) working memory in a delayed matching-to-position task. Prior chronic exposure to cocaine resulted in impairments in reversal learning and working memory. Although there were no effects on attentional function or response inhibition, a shift in the pattern of errors committed was observed. These results indicate that prior chronic cocaine exposure in mice induces long-lasting alterations in cognitive functions associated with the prefrontal cortex.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/administração & dosagem , Cognição/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Cocaína/toxicidade , Condicionamento Clássico , Condicionamento Operante , Modelos Animais de Doenças , Comportamento Impulsivo , Inibição Psicológica , Injeções Intraperitoneais , Masculino , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Esquema de Reforço , Reforço Psicológico , Reversão de Aprendizagem , Fatores de TempoRESUMO
Drug addiction is a progressive and compulsive disorder, where recurrent craving and relapse to drug-seeking occur even after long periods of abstinence. A major contributing factor to relapse is drug-associated cues. Here we review behavioral and pharmacological studies outlining novel methods of effective and persistent reductions in cue-induced relapse behavior in animal models. We focus on extinction and reconsolidation of cue-drug associations as the memory processes that are the most likely targets for interventions. Extinction involves the formation of new inhibitory memories rather than memory erasure; thus, it should be possible to facilitate the extinction of cue-drug memories to reduce relapse. We propose that context-dependency of extinction might be altered by mnemonic agents, thereby enhancing the efficacy of cue-exposure therapy as treatment strategy. In contrast, interfering with memory reconsolidation processes can disrupt the integrity or strength of specific cue-drug memories. Reconsolidation is argued to be a distinct process that occurs over a brief time period after memory is reactivated/retrieved - when the memory becomes labile and vulnerable to disruption. Reconsolidation is thought to be an independent, perhaps opposing, process to extinction and disruption of reconsolidation has recently been shown to directly affect subsequent cue-drug memory retrieval in an animal model of relapse. We hypothesize that a combined approach aimed at both enhancing the consolidation of cue-drug extinction and interfering with the reconsolidation of cue-drug memories will have a greater potential for persistently inhibiting cue-induced relapse than either treatment alone.
Assuntos
Condicionamento Operante/fisiologia , Sinais (Psicologia) , Extinção Psicológica , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Condicionamento Operante/efeitos dos fármacos , Humanos , AutoadministraçãoRESUMO
A history of exposure to stressors may be a predisposing factor for developing posttraumatic stress disorder (PTSD) after trauma. Extinction of conditioned fear appears to be impaired in PTSD, but the consequences of prior stress or excess glucocorticoid exposure for extinction learning are not known. We report that prior chronic exposure to the stress hormone, corticosterone (CORT), decreases endogenous CORT secretion upon context reexposure and impairs extinction after contextual fear conditioning in rats, while leaving fear memory acquisition and expression intact. Posttraining administration of the glucocorticoid receptor (GR) antagonist, RU38486, partially mimicked prior CORT exposure effects on freezing during fear extinction training. Extinction of conditioned fear is an active learning process thought to involve glutamatergic targets--including specific NMDA and AMPA receptor subunits--in the ventromedial prefrontal cortex (vmPFC), which includes the prelimbic, infralimbic, and medial orbitofrontal cortices. After CORT exposure, decreases in the NMDA receptor NR2B subunit and AMPA receptor subunits, GluR2/3, as well as brain-derived neurotrophic factor, were detected in cortical regions, but not dorsal hippocampus (CA1). Receptor subunit expression levels in the vmPFC correlated with freezing during training. In addition, prior CORT selectively decreased sucrose preference, consistent with established models of anhedonia and with blunted affect in PTSD. Together, these data suggest a cellular mechanism by which chronically elevated glucocorticoid exposure--as may be experienced during repeated exposure to stressors--interferes with the neural systems that modulate behavioral flexibility and may thereby contribute to psychopathological fear states.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/farmacologia , Extinção Psicológica/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Condicionamento Clássico , Corticosterona/sangue , Corticosterona/metabolismo , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Mifepristona/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , SacaroseRESUMO
BACKGROUND: Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that capture the debilitating and protracted feelings of anhedonia and loss of motivation that are core features of depression. METHODS: In adult male mice, we evaluated persistent effects of oral corticosterone (CORT) exposure on anhedonic-like behavior, immobility in the forced swim test (FST), motivational performance in the progressive ratio task, and later endogenous CORT secretion. After verifying long-term decreases in hippocampal brain-derived neurotrophic factor (BDNF) and cAMP Response Element Binding protein phosphorylation (pCREB), the ability of direct hippocampal BDNF microinfusion after CORT exposure to reverse deficits was investigated. RESULTS: Prior CORT exposure decreased sucrose consumption, appetitive responding, and FST mobility without long-term effects on water/quinine discrimination and endogenous CORT secretion. Critically, BDNF replacement mimicked chronic antidepressant treatment (ADT) by reversing CORT-induced reductions in instrumental performance and FST mobility. CONCLUSIONS: Together these findings link persistent alterations in hippocampal BDNF expression and CREB transcriptional activity with a persistent depressive-like state-as opposed to ADT efficacy. These results identify hippocampal BDNF as an essential molecular substrate that bidirectionally regulates appetitive instrumental behavior. Additionally, we suggest this CORT model might provide a powerful tool for future investigation into the neurobiology of complex stress-associated depressive symptoms that persist long after stress exposure itself.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Corticosterona/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Motivação , Natação , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Corticosterona/sangue , Discriminação Psicológica/efeitos dos fármacos , Interações Medicamentosas , Preferências Alimentares/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinina , Sacarose/administração & dosagemRESUMO
Cyclin-dependent kinase 5 (Cdk5) regulates dopamine neurotransmission and has been suggested to serve as a homeostatic target of chronic psychostimulant exposure. To study the role of Cdk5 in the modulation of the cellular and behavioral effects of psychoactive drugs of abuse, we developed Cre/loxP conditional knock-out systems that allow temporal and spatial control of Cdk5 expression in the adult brain. Here, we report the generation of Cdk5 conditional knock-out (cKO) mice using the alphaCaMKII promoter-driven Cre transgenic line (CaMKII-Cre). In this model system, loss of Cdk5 in the adult forebrain increased the psychomotor-activating effects of cocaine. Additionally, these CaMKII-Cre Cdk5 cKO mice show enhanced incentive motivation for food as assessed by instrumental responding on a progressive ratio schedule of reinforcement. Behavioral changes were accompanied by increased excitability of medium spiny neurons in the nucleus accumbens (NAc) in Cdk5 cKO mice. To study NAc-specific effects of Cdk5, another model system was used in which recombinant adeno-associated viruses expressing Cre recombinase caused restricted loss of Cdk5 in NAc neurons. Targeted knock-out of Cdk5 in the NAc facilitated cocaine-induced locomotor sensitization and conditioned place preference for cocaine. These results suggest that Cdk5 acts as a negative regulator of neuronal excitability in the NAc and that Cdk5 may govern the behavioral effects of cocaine and motivation for reinforcement.
Assuntos
Cocaína/farmacologia , Corpo Estriado/enzimologia , Quinase 5 Dependente de Ciclina/fisiologia , Motivação , Neurônios/enzimologia , Recompensa , Animais , Corpo Estriado/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/deficiência , Quinase 5 Dependente de Ciclina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacosRESUMO
Addiction is characterized by compulsive drug use despite adverse consequences. The precise psychobiological changes that underlie the progression from casual use to loss of control over drug-seeking and drug-taking behavior are not well understood. Here we report that short-term cocaine exposure in monkeys is sufficient to produce both selective deficits in cognitive functions dependent on the orbitofrontal cortex (OFC) concurrent with enhancements in motivational processes involving limbic-striatal regions. Additional findings from behavioral studies and analyses of the synaptic proteome provide new behavioral and biochemical evidence that cocaine-induced neuroadaptations in cortical and subcortical brain regions result in dysfunctional decision-making abilities and loss of impulse control that in combination with enhancements of incentive motivation may contribute to the development of compulsive behavior in addiction.
Assuntos
Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/psicologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Lobo Frontal/fisiologia , Primatas/fisiologia , Adaptação Fisiológica , Animais , Cocaína/farmacologia , ProteômicaRESUMO
RATIONALE: Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse. OBJECTIVES: We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat. MATERIALS AND METHODS: First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine (DHbetaE) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone+light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DHbetaE, or alpha-Conotoxin MII (alpha-CtxMII, a selective alpha3beta2* and alpha6* nAChR antagonist). RESULTS: The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHbetaE. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol-associated CR, whereas systemic DHbetaE had no effect. CONCLUSIONS: We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Dopamina/metabolismo , Etanol/farmacologia , Receptores Nicotínicos/fisiologia , Reforço Psicológico , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Conotoxinas/farmacologia , Sinais (Psicologia) , Di-Hidro-beta-Eritroidina/farmacologia , Masculino , Mecamilamina/farmacologia , Microdiálise , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Autoadministração , Área Tegmentar Ventral/metabolismoRESUMO
Neuronal adaptations in striatal dopamine signaling have been implicated in enhanced responses to addictive drugs. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine signaling and is a downstream target gene of the transcription factor DeltaFosB, which accumulates in striatal neurons after chronic cocaine exposure. Here we investigated the role of Cdk5 activity in the nucleus accumbens (NAc) on cocaine-induced locomotor sensitization, responding for reward-associated stimuli (conditioned reinforcement), and cocaine self-administration under a progressive ratio schedule. Repeated infusions of the Cdk5 inhibitor roscovitine into the NAc before cocaine injections augmented both the development and expression of cocaine sensitization without having any intrinsic stimulant actions of its own. Additionally, repeated intra-NAc infusions of roscovitine to saline-injected rats enhanced locomotor responses to a subsequent cocaine challenge. Similar effects were found after infusions of another Cdk5 inhibitor, olomoucine, but not its inactive congener, iso-olomoucine. Repeated inhibition of Cdk5 within the NAc also robustly enhanced the incentive-motivational effects of cocaine, similar to the effect of prior repeated cocaine exposure. The enhanced responding with conditioned reinforcement induced by cocaine persisted at least 2 weeks after the final roscovitine infusion. NAc infusions of olomoucine also produced acute and enduring increases in "breakpoints" achieved on a progressive ratio schedule for cocaine reinforcement. These results demonstrate profound and persistent effects of NAc Cdk5 inhibition on locomotor sensitization and incentive-motivational processes and provide direct evidence for a role for striatal Cdk5-induced alterations in the brain's long-term adaptations to cocaine.
Assuntos
Cocaína/farmacologia , Quinase 5 Dependente de Ciclina/fisiologia , Inibidores Enzimáticos/farmacologia , Cinetina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Animais , Cocaína/metabolismo , Condicionamento Operante , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Masculino , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Roscovitina , Transdução de SinaisRESUMO
BACKGROUND: Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized. METHODS: Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation. RESULTS: STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning. CONCLUSIONS: Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.
Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Neostriado/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Estimulação Acústica , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Condicionamento Clássico/fisiologia , Cicloeximida/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Feminino , Imuno-Histoquímica , Técnicas In Vitro , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neostriado/metabolismo , Técnicas de Patch-Clamp , Mutação Puntual/genética , Mutação Puntual/fisiologia , Gravidez , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Ratos , Ratos Sprague-Dawley , Translocação Genética/fisiologiaRESUMO
Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor deltaFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of deltaFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of deltaFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by deltaFosB, and provide evidence that drug-induced alterations in gene expression via induction of deltaFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.
Assuntos
Apetite/fisiologia , Condicionamento Operante/fisiologia , Comportamento Alimentar/fisiologia , Motivação , Núcleo Accumbens/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reforço Psicológico , Animais , Masculino , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal-cortex-dependent cognitive function, has yet to be determined. OBJECTIVE: Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients. METHODS: Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task, (2) impulsivity in an inhibitory control task, (3) attentional function in a three-choice serial reaction time task, and (4) working memory in a delayed matching-to-position task. RESULTS: No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning. CONCLUSIONS: These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.