RESUMO
Recent clinical and preclinical studies suggest that selective activators of the M4 muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M4 activation inhibits striatal dopamine release by mobilizing endocannabinoids, providing a mechanism for local effects on dopamine signaling in the striatum but not in extrastriatal areas. G protein-coupled receptors (GPCRs) typically induce endocannabinoid release through activation of Gαq/11-type G proteins whereas M4 transduction occurs through Gαi/o-type G proteins. We now report that the ability of M4 to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gαq/11-coupled mGlu1 subtype of metabotropic glutamate (mGlu) receptor. This is especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the "druggable genome" that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu1 signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu1 positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M4, mGlu1 does not directly inhibit dopamine D1 receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu1 and M4 and demonstrate that highly selective mGlu1 PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/metabolismo , Receptor Muscarínico M4/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Ácido Glutâmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
This letter describes the further optimization of a series of mGlu3 NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca2+ flux via a promiscuous G protein (Gα15) versus native coupling to GIRK channels), identified both full and partial mGlu3 NAMs and a new in vivo tool compound, VU6017587. This mGlu3 NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu3 affords anxiolytic-like and antidepressant-like phenotypes in mice.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antidepressivos/síntese química , Antidepressivos/química , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the ß-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.
Assuntos
Regulação Alostérica/imunologia , Receptor Muscarínico M4/imunologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Motivation has been defined as the process that allows organisms to regulate their internal and external environment, and control the probability, proximity and availability of stimuli. As such, motivation is a complex process that is critical for survival, which involves multiple behavioural functions mediated by a number of interacting neural circuits. Classical theories of motivation suggest that there are both directional and activational aspects of motivation, and activational aspects (i.e. speed and vigour of both the instigation and persistence of behaviour) are critical for enabling organisms to overcome work-related obstacles or constraints that separate them from significant stimuli. The present review discusses the role of brain dopamine and related circuits in behavioural activation, exertion of effort in instrumental behaviour, and effort-related decision-making, based upon both animal and human studies. Impairments in behavioural activation and effort-related aspects of motivation are associated with psychiatric symptoms such as anergia, fatigue, lassitude and psychomotor retardation, which cross multiple pathologies, including depression, schizophrenia, and Parkinson's disease. Therefore, this review also attempts to provide an interdisciplinary approach that integrates findings from basic behavioural neuroscience, behavioural economics, clinical neuropsychology, psychiatry, and neurology, to provide a coherent framework for future research and theory in this critical field. Although dopamine systems are a critical part of the brain circuitry regulating behavioural activation, exertion of effort, and effort-related decision-making, mesolimbic dopamine is only one part of a distributed circuitry that includes multiple neurotransmitters and brain areas. Overall, there is a striking similarity between the brain areas involved in behavioural activation and effort-related processes in rodents and in humans. Animal models of effort-related decision-making are highly translatable to humans, and an emerging body of evidence indicates that alterations in effort-based decision-making are evident in several psychiatric and neurological disorders. People with major depression, schizophrenia, and Parkinson's disease show evidence of decision-making biases towards a lower exertion of effort. Translational studies linking research with animal models, human volunteers, and clinical populations are greatly expanding our knowledge about the neural basis of effort-related motivational dysfunction, and it is hoped that this research will ultimately lead to improved treatment for motivational and psychomotor symptoms in psychiatry and neurology.
Assuntos
Transtorno Depressivo Maior/fisiopatologia , Motivação/fisiologia , Vias Neurais/fisiologia , Doença de Parkinson/fisiopatologia , Esforço Físico/fisiologia , Esquizofrenia/fisiopatologia , Animais , Tomada de Decisões/fisiologia , Dopamina/fisiologia , HumanosRESUMO
Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of tetrabenazine were reversed by oral ingestion of curcumin (80.0-160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0-8.0 µg). Curcumin attenuates the effort-related effects of tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms.
Assuntos
Curcumina/farmacologia , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Administração Oral , Animais , Comportamento de Escolha , Curcuma/química , Depressão , Comportamento Alimentar/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Estrutura Molecular , Motivação , Ratos , Ratos Sprague-DawleyRESUMO
Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Depressão/psicologia , Motivação/efeitos dos fármacos , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Antagonistas do Receptor A2 de Adenosina/farmacologia , Inibidores da Captação Adrenérgica/antagonistas & inibidores , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Encefalinas/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Substância P/metabolismo , Tetrabenazina/antagonistas & inibidores , Xantinas/farmacologiaRESUMO
BACKGROUND: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. METHODS: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. RESULTS: Bupropion (10.0-40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. CONCLUSION: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans.
Assuntos
Bupropiona/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Motivação/efeitos dos fármacos , Psicotrópicos/farmacologia , Esquema de Reforço , Animais , Comportamento de Escolha/fisiologia , Cromatografia Líquida de Alta Pressão , Dopamina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Relação Dose-Resposta a Droga , Alimentos , Imuno-Histoquímica , Masculino , Microdiálise , Motivação/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D2 receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M1/M4-preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.
RESUMO
Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Humanos , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/uso terapêutico , Receptores Muscarínicos , Esquizofrenia/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Acetilcolina , Receptor Muscarínico M1/agonistasRESUMO
Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.
Assuntos
Antipsicóticos , Agonistas Muscarínicos , Transtornos Psicóticos , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Humanos , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Receptores Muscarínicos , Esquizofrenia/tratamento farmacológicoRESUMO
RATIONALE: Depressed individuals demonstrate debilitating symptoms, including depressed mood, anhedonia, and effort-related deficits. Effort-related decision-making can be measured through providing subjects with a choice between high effort/reward and low effort/reward options, which is a dopamine (DA)-dependent behavior. While previous research has shown sex differences in depression rates, this has not been examined within operant-based effort-related decision-making tasks nor has DA been shown to underlie this behavior in female rats. OBJECTIVES: The current study investigated sex differences in an effort-related decision-making task prior to and following administration of the DA D2 receptor antagonist haloperidol (HAL). METHODS: Adult rats were food restricted or fed freely and trained in an effort-related progressive ratio choice task. After stable responding, HAL was administered acutely (0.05-0.2 mg/kg) prior to testing. RESULTS: Results indicate a significant effect of sex on training variables, with males having a greater number of lever presses, higher ratios, and longer active lever times. Pretreatment with HAL significantly reduced the same measures in both sexes for the high-valued reward, while increasing chow consumption in the food restricted males. Food restricted rats showed a greater number of total lever presses and achieved higher ratios; however, the effect in male food restricted rats was greatest. CONCLUSIONS: These data suggest that, although there are sex differences in training, HAL decreases behavior across sexes, demonstrating that the D2 mechanism is similar in both sexes. These findings provide a better understanding of motivational dysfunction in both sexes and potential treatment targets for depression.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Haloperidol/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Dopamina/metabolismo , Feminino , Alimentos , Masculino , Motivação , Ratos , Ratos Sprague-Dawley , Recompensa , Fatores SexuaisRESUMO
While the negative symptoms comprise one of the cardinal symptom domains of schizophrenia, there are numerous deficits that are included in this category of symptoms. Therefore, when modeling negative symptoms preclinically, it is important to consider which symptom is being modeled by a specific assay and to try to gain an understanding of the translational value of the findings. It is hoped that enhancing the translational value of animal models will allow for better treatment outcomes for the negative symptoms of schizophrenia in the future.
Assuntos
Modelos Animais de Doenças , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Humanos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Roedores , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Especificidade da EspécieRESUMO
Accumulated data from clinical and preclinical studies suggest that, in drug addiction and states of overeating, such as obesity and binge eating disorder (BED), there is an imbalance in circuits that are critical for motivation, reward saliency, executive function, and self-control. Central to these pathologies and the extensive topic of this Review are the aberrations in dopamine (DA) and glutamate (Glu) within the mesolimbic pathway. Group I metabotropic glutamate receptors (mGlus) are highly expressed in the mesolimbic pathway and are poised in key positions to modulate disruptions in synaptic plasticity and neurotransmitter release observed in drug addiction, obesity, and BED. The use of allosteric modulators of group I mGlus has been studied in drug addiction, as they offer several advantages over traditional orthosteric agents. However, they have yet to be studied in obesity or BED. With the substantial overlap between the neurocircuitry involved in drug addiction and eating disorders, group I mGlus may also provide novel targets for obesity and BED.
Assuntos
Transtorno da Compulsão Alimentar/metabolismo , Neurônios Dopaminérgicos/metabolismo , Rede Nervosa/metabolismo , Obesidade/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Dopamina/metabolismo , HumanosRESUMO
Behavioral approaches utilizing rodents to study mood disorders have focused primarily on negative valence behaviors associated with potential threat (anxiety-related behaviors). However, for disorders such as depression, positive valence behaviors that assess reward processing may be more translationally valid and predictive of antidepressant treatment outcome. Chronic corticosterone (CORT) administration is a well-validated pharmacological stressor that increases avoidance in negative valence behaviors associated with anxiety1-4. However, whether chronic stress paradigms such as CORT administration also lead to deficits in positive valence behaviors remains unclear. We treated male C57BL/6J mice with chronic CORT and assessed both negative and positive valence behaviors. We found that CORT induced avoidance in the open field and NSF. Interestingly, CORT also impaired instrumental acquisition, reduced sensitivity to a devalued outcome, reduced breakpoint in progressive ratio, and impaired performance in probabilistic reversal learning. Taken together, these results demonstrate that chronic CORT administration at the same dosage both induces avoidance in negative valence behaviors associated with anxiety and impairs positive valence behaviors associated with reward processing. These data suggest that CORT administration is a useful experimental system for preclinical approaches to studying stress-induced mood disorders.
Assuntos
Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Corticosterona/farmacologia , Modelos Animais de Doenças , Aprendizagem/efeitos dos fármacos , Esteroides/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Corticosterona/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recompensa , Esteroides/administração & dosagemRESUMO
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.
Assuntos
Ansiolíticos/farmacologia , Benzamidas/farmacologia , Encéfalo/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Triazóis/farmacologia , Regulação Alostérica , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Benzamidas/síntese química , Benzamidas/química , Descoberta de Drogas , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Current antipsychotic drugs provide symptomatic relief for positive symptoms of schizophrenia, but do not offer symptom management for negative and cognitive symptoms. In addition, many patients discontinue treatment due to adverse side effects. Therefore, there is a critical need to develop more effective and safe treatment options. Although the etiology of schizophrenia is unclear, considerable data from post-mortem, neuroimaging and neuropharmacology studies support a role of the muscarinic acetylcholine (mAChRs) in the pathophysiology of schizophrenia. Substantial evidence suggests that activation of mAChRs has the potential to treat all symptom domains of schizophrenia. Despite encouraging results in demonstrating efficacy, clinical trials of nonselective mAChR agonists were limited in their clinical utility due to dose-limiting peripheral side effects. Accordingly, efforts have been made to specifically target centrally located M1 and M4 mAChR subtypes devoid of adverse-effect liability. To circumvent this limitation, there have been tremendous advances in the discovery of ligands that bind at allosteric sites, binding sites distinct from the orthosteric site, which are structurally less conserved and thereby afford high levels of receptor subtype selectivity. The discovery of subtype-specific allosteric modulators has greatly advanced our understanding of the physiological role of various muscarinic receptor subtypes in schizophrenia and the potential utility of M1 and M4 mAChR subtypes as targets for the development of novel treatments for schizophrenia and related disorders. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.
Assuntos
Antipsicóticos/farmacologia , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M4/agonistas , Esquizofrenia/tratamento farmacológico , Regulação Alostérica , Animais , Antipsicóticos/uso terapêutico , Humanos , Agonistas Muscarínicos/uso terapêutico , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo , Esquizofrenia/metabolismoRESUMO
Motivated behaviors often are characterized by a high degree of behavioral activation and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with depression and other disorders frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks measuring effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of the monoamine oxidase -B (MAO-B) inhibitor deprenyl (selegiline) to enhance selection of high-effort lever pressing in rats tested on a concurrent progressive ratio (PROG)/chow feeding choice task. Deprenyl is widely used as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans, and to induce antidepressant-like effects in traditional rodent models of depression. Systemic administration of deprenyl (1.5-12.0â¯mg/kg IP) shifted choice behavior, significantly increasing markers of PROG lever pressing at a moderate dose (6.0â¯mg/kg), and decreasing chow intake at 6.0 and 12.0â¯mg/kg. Intracranial injections of deprenyl into nucleus accumbens (2.0 and 4.0⯵g) also increased PROG lever pressing and decreased chow intake. Microdialysis studies showed that the dose of deprenyl that was effective at increasing PROG lever pressing (6.0â¯mg/kg) also significantly elevated extracellular dopamine in nucleus accumbens. Thus, similar to the well-known antidepressant bupropion, deprenyl is capable of increasing selection of high-effort PROG lever pressing at doses that increase extracellular dopamine in nucleus accumbens. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Selegilina/farmacologia , Ração Animal , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Depressão/tratamento farmacológico , Dopamina/farmacologia , Comportamento Alimentar/psicologia , Masculino , Modelos Animais , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Motivação/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Selegilina/metabolismoRESUMO
People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of monoamine oxidase (MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoamine storage inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of its selective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, but increasing intake of the concurrently available but less preferred lab chow. These effects of 0.75mg/kg tetrabenazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability of deprenyl to reverse the effects of tetrabenazine was marked by an inverted-U shaped dose response curve, with the middle dose (2.5mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemide nor the nonselective drug pargyline reversed the effects of tetrabenazine, and moclobemide decreased lever pressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans and induce antidepressant-like effects in classical rodent models of depression. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.
Assuntos
Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Monoaminoxidase , Motivação/efeitos dos fármacos , Selegilina/administração & dosagem , Tetrabenazina/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Masculino , Motivação/fisiologia , Ratos , Resultado do TratamentoRESUMO
Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown. Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation. This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.