RESUMO
In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.
Assuntos
Alcoolismo/patologia , Alcoolismo/terapia , Pesquisa Translacional Biomédica/organização & administração , Dissuasores de Álcool/uso terapêutico , Ensaios Clínicos como Assunto/organização & administração , Terapia Cognitivo-Comportamental/métodos , Humanos , Assistência Centrada no Paciente/organização & administração , Terminologia como Assunto , Estados UnidosRESUMO
RATIONALE: GLT-1 is the major glutamate transporter in the brain and is expressed predominantly in astrocytes but is also present in excitatory axon terminals. To understand the functional significance of GLT-1 expressed in neurons, we generated a conditional GLT-1 knockout mouse and inactivated GLT-1 in neurons using Cre-recombinase expressed under the synapsin 1 promoter, (synGLT-1 KO). OBJECTIVES: Abnormalities of glutamate homeostasis have been shown to affect hippocampal-related behaviors including learning and memory as well as responses to drugs of abuse. Here, we asked whether deletion of GLT-1 specifically from neurons would affect behaviors that assessed locomotor activity, cognitive function, sensorimotor gating, social interaction, as well as amphetamine-stimulated locomotor activity. METHODS/RESULTS: We found that the neuronal GLT-1 KO mice performed similarly to littermate controls in the behavioral tests we studied. Although performance in open field testing was normal, the acute locomotor response to amphetamine was significantly blunted in the synGLT-1 KO (40% of control). We found no change in amphetamine-stimulated extracellular dopamine in the medial shell of the nucleus accumbens, no change in electrically stimulated or amphetamine-induced dopamine release, and no change in dopamine tissue content. CONCLUSIONS: These results support the view that GLT-1 expression in neurons is required for amphetamine-induced behavioral activation, and suggest that this phenotype is not produced through a change in dopamine uptake or release. Although GLT-1 is highly expressed in neurons in the CA3 region of the hippocampus, the tests used in this study were not able to detect a behavioral phenotype referable to hippocampal dysfunction.
Assuntos
Anfetamina/farmacologia , Dopamina/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Deleção de Genes , Locomoção/fisiologia , Neurônios/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/deficiência , Transportador 2 de Aminoácido Excitatório/genética , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Relações Interpessoais , Locomoção/efeitos dos fármacos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , FenótipoRESUMO
INTRODUCTION: Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front-line treatment for alcoholism in humans. Although roles for mu- and delta-opioid receptors have been characterized, the contribution of kappa-opioid receptors (KORs) is less clear. There is evidence that changes in KOR system function can decrease or increase EtOH drinking, depending on test conditions. For example, female mice lacking preprodynorphin - the precursor to the endogenous KOR ligand dynorphin - have reduced EtOH intake. Considering that KORs can regulate dopamine (DA) transmission, we hypothesized that KORs expressed on DA neurons would play a prominent role in EtOH intake in females. METHODS: We used a Cre/loxP recombination strategy to ablate KORs throughout the body or specifically on dopamine uptake transporter (DAT)-expressing neurons to investigate the role of KORs on preference for and intake of EtOH (2-bottle choice), the transition from moderate to excessive EtOH drinking (intermittent EtOH access), and binge EtOH drinking (drinking in the dark [DID]). RESULTS: KOR deletion decreased preference for EtOH, although this effect was less pronounced when EtOH intake increased beyond relatively low levels. DISCUSSION: Our findings indicate that KOR activation increases EtOH drinking via effects mediated, at least in part, by KORs on DA neurons. While the mechanisms of this regulation remain unknown, previous work suggests that alterations in negative reinforcement processes or sensitivity to the sensory properties of EtOH can affect preference and intake.
RESUMO
Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cocaína/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Esquizofrenia/complicações , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Operante/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Racemases e Epimerases/deficiência , Racemases e Epimerases/genética , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológicoRESUMO
Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.
Assuntos
Ansiedade/induzido quimicamente , Núcleo Central da Amígdala/metabolismo , Depressão/induzido quimicamente , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Caínico/análogos & derivados , Animais , Núcleo Central da Amígdala/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Medo , Ácido Caínico/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders. These findings suggest that the proliferation and survival of glial cells may be important in the pathogenesis of mood disorders and may be possible targets for the development of new treatments. In this article we review the evidence for glial abnormalities in mood disorders, and we discuss glial cell biology and evidence from postmortem studies of mood disorders. The goal is not to carry out a comprehensive review but to selectively discuss existing evidence in support of an argument for the role of glial cells in mood disorders.
Assuntos
Transtornos do Humor/fisiopatologia , Neuroglia/fisiologia , Animais , Encéfalo/citologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Transtornos do Humor/patologia , Neuroglia/patologiaRESUMO
BACKGROUND: Alcoholism is associated with specific brain abnormalities revealed through postmortem studies, including a reduction in glial cell number and dysregulated glutamatergic neurotransmission. Whether these abnormalities contribute to the etiology of alcoholism, are consequences of alcohol use, or both is still unknown. METHODS: We investigated the role of astrocytic glutamate uptake in ethanol (EtOH) binge drinking in mice, using the "drinking in the dark" (DID) paradigm by blocking the astrocytic glutamate transporter (GLT-1) with intracerebroventricular (ICV) administration of dihydrokainic acid (DHK). To determine whether astrocytic glutamate uptake regulates the conditioned rewarding effects of EtOH, we examined the effects of ICV DHK on the acquisition and expression of EtOH-induced conditioned place preference. RESULTS: Blocking central astrocytic glutamate uptake selectively attenuated EtOH binge drinking behavior in mice. DHK did not alter the acquisition or expression of preference for EtOH-associated cues, indicating that reduced astrocytic glutamate trafficking may decrease binge-like drinking without altering the conditioned rewarding effects of EtOH. CONCLUSIONS: Several alternative conclusions are plausible, however, interpreting these data in the context of the human literature, these findings suggest that the reduction of glia in the alcoholic brain may not be a predisposing factor to developing alcoholism and could be a consequence of EtOH toxicity that decreases excessive EtOH intake.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Astrócitos/fisiologia , Etanol/farmacologia , Ácido Glutâmico/metabolismo , Recompensa , Sistema X-AG de Transporte de Aminoácidos/antagonistas & inibidores , Animais , Astrócitos/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Infusões Intraventriculares , Ácido Caínico/análogos & derivados , Ácido Caínico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBARESUMO
Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR(-/-)) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR(lox/lox)). Autoradiography demonstrated complete ablation of KOR binding in the KOR(-/-) mutants, and reduced binding in the DAT-KOR(lox/lox) mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR(-/-) mice appeared normal in the open field and light/dark box tests, DAT-KOR(lox/lox) mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR(-/-) mutants, but was exaggerated in DAT-KOR(lox/lox) mutants. Increased sensitivity to cocaine in the DAT-KOR(lox/lox) mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR(-/-) mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function.
Assuntos
Ansiolíticos/metabolismo , Encéfalo/metabolismo , Cocaína/farmacologia , Neurônios Dopaminérgicos/metabolismo , Plasticidade Neuronal/fisiologia , Receptores Opioides kappa/deficiência , Animais , Benzenoacetamidas/metabolismo , Benzenoacetamidas/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Ligação Proteica/fisiologia , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Receptores Opioides kappa/agonistasRESUMO
Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test. In the first experiment, rats were treated acutely with the anxiolytic, chlordiazepoxide (2.5 or 5 mg/kg, i.p.). In separate experiments, animals were implanted with osmotic minipumps delivering vehicle or fluoxetine (5 or 20 mg/kg per day s.c.) for 3 or 28 days. NIH was assessed by giving animals access to a familiar palatable food in a novel environment. Associated brain areas were identified using c-fos immunohistochemistry. NIH was mitigated by acute chlordiazepoxide and chronic fluoxetine. Both drugs reversed novelty-induced changes in c-fos expression in the lateral division of the posterolateral part of the bed nucleus of the stria terminalis (STLP), cingulate cortex (Cg), and dorsal field CA2 of the hippocampus (dCA2). Chronic fluoxetine additionally increased c-fos expression in the anterior nucleus accumbens (aAcb) and the piriform cortex (Pir). The effects of the drugs on c-fos expression in many regions correlated with anxiolytic efficacy. These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs.
Assuntos
Ansiolíticos/farmacologia , Mapeamento Encefálico , Encéfalo/efeitos dos fármacos , Clordiazepóxido/farmacologia , Fluoxetina/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Serotonin (5-HT)(1A) and 5-HT(1B) receptors have been implicated in the incidence and treatment of depression in part through the examination of animals lacking these receptors. Although these receptors have been repeatedly implicated in ingestive behavior there is little information about how 5-HT(1A) and 5-HT(1B) receptor mutant mice react to solutions of varying palatability. In the present experiment male and female 5-HT(1A) and 5-HT(1B) mutant and wild-type mice were presented with increasing concentrations of sucrose using a two-bottle choice procedure. In addition fasting blood glucose levels were assessed. Both male and female 5-HT(1B) mutant mice drank more sucrose than WT mice but also consumed more water. Female, but not male, 5-HT(1A) mutant mice similarly showed increased sucrose consumption, but did not demonstrate increased consumption of water. In addition, the pattern of increased sucrose consumption over genotype and sex was related to fasting blood glucose concentrations such that levels in male 5-HT(1B) mutant mice were reduced relative to wild-type and 5-HT(1A) mutant males, but similar to those of females. The findings in 5-HT(1B) mutant mice emphasize the role of the 5-HT(1B) receptor in regulating ingestive behavior, whereas female sex hormones and 5-HT(1A) receptors may interact to alter sucrose consumption in 5-HT(1A) mutant mice. In addition, these findings may have implications for the role of these receptors in the incidence and treatment of depression since the intake of sucrose has been used as an index of anhedonia in animal models of depression and antidepressant efficacy.
Assuntos
Glicemia/fisiologia , Comportamento de Ingestão de Líquido/fisiologia , Jejum/sangue , Receptor 5-HT1A de Serotonina/deficiência , Receptor 5-HT1B de Serotonina/deficiência , Sacarose , Análise de Variância , Animais , Comportamento Animal , Peso Corporal/genética , Comportamento de Escolha/fisiologia , Ingestão de Líquidos/genética , Feminino , Preferências Alimentares/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fatores Sexuais , Sacarose/administração & dosagemRESUMO
cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB(alpha delta) mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB(alpha delta) mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB(alpha delta) mutant mice. Serotonin depletion decreased neurogenesis in CREB(alpha delta) mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB(alpha delta) mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB(alpha delta) mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB(alpha delta) mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB(alpha delta) mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.
Assuntos
Antidepressivos/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Desipramina/administração & dosagem , Neurônios/efeitos dos fármacos , Análise de Variância , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Elevação dos Membros Posteriores/métodos , Hipocampo/citologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Tempo de Reação/efeitos dos fármacos , Serotonina/metabolismo , NataçãoRESUMO
RATIONALE: Few studies have investigated whether the behavioral effects elicited by different types of antidepressant drugs are mediated by either serotonin (5-HT) or the catecholamines norepinephrine (NE) and dopamine (DA). OBJECTIVES: By depleting 5-HT, or NE and DA, the present study investigated the contributions of these monoamines to the acute behavioral effects of selective serotonin reuptake inhibitors (SSRIs; fluoxetine and citalopram) and norepinephrine reuptake inhibitors (NRIs; desipramine and reboxetine) in the mouse tail suspension test (TST). RESULTS: Depletion of 5-HT tissue content by para-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, completely blocked reductions of immobility by the SSRIs in the TST. In contrast, PCPA did not alter the behavioral effects of the NRIs. Inhibition of catecholamine synthesis by alpha-methyl-para-tyrosine (AMPT) reduced brain NE and DA tissue content, whereas disruption of vesicular storage with reserpine decreased brain NE, DA and 5-HT tissue content. However, neither treatment completely prevented responses to desipramine, fluoxetine, or citalopram in the TST. Depleting both newly synthesized and vesicular components of NE and DA transmission with a combination of reserpine and AMPT completely prevented the behavioral effects of desipramine, reboxetine, and fluoxetine and attenuated those of citalopram. Although PCPA did not alter baseline immobility, AMPT and reserpine increased baseline values in the TST. CONCLUSIONS: These studies demonstrated that endogenous 5-HT synthesis mediates the behavioral effects of SSRIs, but not NRIs, in the TST. In contrast, disruption of the behavioral effects of NRI and SSRI antidepressants required disruption of both catecholamine synthesis and vesicular storage and release mechanisms.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Dopamina/metabolismo , Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citalopram/farmacologia , Desipramina/farmacologia , Fenclonina , Fluoxetina/farmacologia , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Reboxetina , Serotonina/biossínteseRESUMO
Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST). Noradrenergic terminals in the DRN were destroyed selectively by the local application of 6-hydroxydopamine (6-OHDA). Immunohistochemical analysis confirmed the presence of noradrenergic fibers in the mouse DRN, that 6-OHDA-induced destruction of noradrenergic terminals was confined to the DRN, and serotonergic cell bodies were not affected by 6-OHDA treatment. The antidepressants tested included the SSRIs, fluoxetine and citalopram, and the norepinephrine reuptake inhibitor (NRI) desipramine. The behavioral effects of fluoxetine (20 mg/kg, IP) were blocked by the destruction of noradrenergic terminals. In contrast, pretreatment with 6-OHDA did not alter the ability of citalopram (20 mg/kg, IP) or desipramine (10 mg/kg, IP) to reduce immobility in the TST. Destruction of noradrenergic projections from the locus ceruleus (LC) by DSP-4 treatment did not alter the behavioral effects of any of the antidepressants tested, or the presence of noradrenergic terminals in the DRN, thus indicating that noradrenergic pathways originating from the LC do not mediate the acute behavioral effects of antidepressants in this test. Thus, afferent noradrenergic activity at the level of the DRN can modulate serotonergic transmission in forebrain structures and the behavioral effects of SSRIs, such as fluoxetine, which use noradrenergic input to the DRN to increase forebrain serotonin.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Norepinefrina/fisiologia , Núcleos da Rafe/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Benzilaminas/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Citalopram/farmacologia , Desipramina/farmacologia , Dopamina beta-Hidroxilase/genética , Fluoxetina/farmacologia , Elevação dos Membros Posteriores/psicologia , Imuno-Histoquímica , Locus Cerúleo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Oxidopamina/toxicidade , Terminações Pré-Sinápticas/fisiologia , Núcleos da Rafe/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
RATIONALE: Relatively little is known about the neural mechanisms underlying anxiety in the novelty-induced hypophagia test, the only known anxiety test that is responsive to chronic but not acute or subchronic antidepressant treatment. OBJECTIVES: The goal of the present experiment was to characterize the role of serotonin in the ability of novelty to suppress feeding. MATERIALS AND METHODS: Pair-housed male Sprague-Dawley rats were trained to eat graham cracker crumbs individually in their home cage (15 min/day). After stable daily intakes were obtained, the animals were depleted of serotonin using 4-chloro-DL -phenylalanine (150 mg kg(-1) day(-1) x 2 days). Forty-eight hours later, central serotonin was restored by the administration of the peripheral L -aromatic amino acid decarboxylase inhibitor, benserazide (10 mg/kg), followed 15 min later with the immediate precursor of serotonin, 5-hydroxy-L -tryptophan (30 mg/kg). Thirty minutes later, the animals were given access to graham cracker crumbs in a novel environment. RESULTS: The animals demonstrated increased latencies to approach the food and reduced food intake in the novel environment. This effect was attenuated by serotonin depletion. Repletion of central serotonin restored the inhibitory response to novelty. The analysis of serotonin content in different brain regions confirmed that serotonin was depleted by greater than 90%, whereas the repletion treatment resulted in serotonin levels similar to nondepleted animals. CONCLUSIONS: Acute depletion of serotonin acts to reduce anxiety behavior as measured by an inhibitory anxiety response during exposure to novel stimuli. These findings are in agreement with the proposed general role for serotonin in behavioral inhibition and that reductions of serotonin facilitate the adoption of more active coping responses to stress.
Assuntos
Ansiedade/metabolismo , Comportamento Animal , Comportamento Exploratório , Comportamento Alimentar , Inibição Psicológica , Serotonina/deficiência , 5-Hidroxitriptofano/farmacologia , Análise de Variância , Animais , Ansiolíticos/farmacologia , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Fenclonina/farmacologia , Masculino , Atividade Motora , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Análise de Regressão , Triptofano Hidroxilase/antagonistas & inibidoresRESUMO
Mesencephalic dopamine neurons form synapses with acetylcholine (ACh)-containing interneurons in the nucleus accumbens (NAcc). Although their involvement in drug reward has not been systematically investigated, these large aspiny interneurons may serve an important integrative function. We previously found that repeated activation of nicotinic cholinergic receptors enhanced cocaine intake in rats but the role of muscarinic receptors in drug reward is less clear. Here we examined the impact of local changes in muscarinic receptor activation within the NAcc on cocaine and food self-administration in rats trained on a progressive ratio (PR) schedule of reinforcement. Animals were given a minimum of 9 continuous days of drug access before testing in order to establish a stable breaking point (BP) for intravenous cocaine infusions (0.75 mg/kg/infusion). Rats in the food group acquired stable responding on the PR schedule within 7 days. On the test day, rats were bilaterally infused in the NAcc with the muscarinic receptor agonist oxotremorine methiodide (OXO: 0.1, 0.3 or 1 nmol/side), OXO plus the M(1) selective antagonist pirenzepine (PIRENZ; 0.3 nmol/side) or aCSF 15 min before cocaine or food access. OXO dose dependently reduced BP values for cocaine reinforcement (-17%, -44% [p<0.05] and -91% [p<0.0001] for 0.1, 0.3 and 1.0 nmol, respectively) and these reductions dissipated by the following session. Pretreatment with PIRENZ blocked the BP-reducing effect of 0.3 nmol OXO. Notably, OXO (0.1, 0.3 and 1.0 nmol/side) injection in the NAcc did not affect BP for food reward. The results suggest that muscarinic ACh receptors in the caudomedial NAcc may play a role in mediating the behavior reinforcing effects of cocaine.
Assuntos
Comportamento Aditivo/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Agonistas Muscarínicos/administração & dosagem , Núcleo Accumbens/metabolismo , Oxotremorina/administração & dosagem , Receptores Muscarínicos/metabolismo , Análise de Variância , Animais , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Relação Dose-Resposta a Droga , Comportamento Alimentar/fisiologia , Masculino , Microinjeções , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Recompensa , AutoadministraçãoRESUMO
The authors examined the role of the ventral tegmental area (VTA) and nucleus accumbens (NAc) in the expression of ethanol-induced conditioned place preference (CPP). After cannulas were implanted, male DBA/2J mice underwent an unbiased Pavlovian-conditioning procedure for ethanol-induced CPP. Before preference testing, the mice were injected intra-VTA (Experiments 1 and 3) or intra-NAc (Experiment 2) with the nonselective opioid antagonist methylnaloxonium (0-ng, 375-ng, or 750-ng total infusion; Experiments 1 and 2) or the gamma aminobutyric acid (GABA(B)) agonist baclofen (0-ng, 25-ng, or 50-ng total infusion; Experiment 3). Intra-VTA methylnaloxonium or baclofen decreased ethanol-induced CPP, whereas intra-NAc methylnaloxonium had no effect. These findings indicate that the conditioned rewarding effect of ethanol is expressed through a VTA-dependent mechanism that involves both opioid and GABA(B) receptors.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Clássico , Etanol/farmacologia , Naloxona/análogos & derivados , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Animais , Baclofeno/administração & dosagem , Baclofeno/farmacologia , Agonistas GABAérgicos/administração & dosagem , Agonistas GABAérgicos/farmacologia , Masculino , Camundongos , Naloxona/administração & dosagem , Naloxona/farmacologia , Compostos de Amônio Quaternário , Receptores de GABA-B/fisiologia , Receptores Opioides/fisiologia , Reforço Psicológico , Percepção EspacialRESUMO
Previous findings implicate opioid receptors in the expression of the conditioned rewarding and aversive properties of ethanol. We have recently reported that the conditioned rewarding effect of ethanol is mediated by opioid receptors in the ventral tegmental area (VTA). We attempted to determine whether VTA opioid receptors also mediate the expression of the conditioned aversive properties of ethanol. However, the magnitude of conditioned place aversion (CPA) was not consistent with our previous findings and prevented us from making definitive conclusions. We hypothesized that the handling required to make intracranial infusions in mice alters the expression of CPA, but not conditioned place preference (CPP). Therefore, non-operated animals underwent a Pavlovian conditioning procedure for either ethanol CPA or CPP. Just before testing, half of the animals were held by the scruff of the neck to mimic intracranial infusion handling. Animals conditioned for CPA did not express CPA if they were handled. However, animals conditioned for CPP exhibited robust CPP, regardless of handling. These findings provide additional evidence that the conditioned rewarding and aversive effects of ethanol are mediated by different neural mechanisms.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Etanol/farmacologia , Manobra Psicológica , Animais , Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBARESUMO
Apolipoprotein (apo) E is a glycoprotein that is most commonly associated with cardiovascular and Alzheimer's disease risk. Recent data showing that apoE mRNA expression is reduced in the frontal cortex of alcoholics raise the possibility that apoE may also be related to the rewarding properties of ethanol. In this study, we examined whether Apoe deletion affects the rewarding properties of ethanol in mice. Male and female wild-type (WT; C57BL/6J) and apoE knockout (Apoe(-/-); C57BL/6J-Apoe(tm1Unc)) mice underwent an unbiased place conditioning procedure with ethanol (2 g/kg) or cocaine (5 mg/kg). Female mice were also tested for ethanol intake in a two-bottle choice procedure. Apoe(-/-) mice showed greater ethanol-induced conditioned place preference (CPP). In contrast, cocaine-induced CPP and ethanol intake were similar between the genotypes. These findings suggest that apoE normally reduces the conditioned rewarding properties of ethanol but not of cocaine. While the exact mechanisms underlying these effects of apoE are unknown, these data support a possible role for apoE in modulating the conditioned rewarding properties of ethanol.
Assuntos
Apolipoproteínas E/deficiência , Cocaína/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Etanol/farmacologia , Animais , Apolipoproteínas E/genética , Condicionamento Psicológico/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genéticaRESUMO
RATIONALE: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission. OBJECTIVES: The present study examined the impact of nicotine treatment on the reinforcement efficacy of self-administered cocaine and non-reinforced responding for cocaine in rats. METHODS: Rats were trained to self-administer cocaine (i.v.) on a progressive ratio (PR) schedule of reinforcement. Self-administration training continued until stable responding was obtained. Acute nicotine pretreatment consisted of a subcutaneous injection (0.15, 0.3 and 0.6 mg/kg) 3 min prior to cocaine access. In the repeated treatment condition, a separate group of animals was given nicotine (0.6 mg/kg, s.c.) 3 min prior to cocaine access for 14 consecutive days. During extinction trials, these animals were injected with nicotine (0.6 mg/kg, s.c.) after 45 min of non-reinforced responding. RESULTS: Acute nicotine treatment produced an inverted U-shaped dose-response function with lower doses increasing and the highest dose decreasing the number of cocaine infusions obtained during a session. Animals treated repeatedly with the highest dose of nicotine showed a significant increase in the number of cocaine infusions by day 8 of nicotine treatment. During extinction sessions when cocaine was not available, injections of nicotine in these animals caused a reinstatement of the previously rewarded lever-press behavior. CONCLUSIONS: These findings indicate that nicotine can facilitate cocaine reinforcement, may contribute to the transition from moderate drug-taking to an escalation of drug intake which is characteristic of addiction, and may trigger relapse.