RESUMO
Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurologic disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost. Because endocannabinoid (eCB) signaling facilitates goal seeking and NAc DA release, we further investigated whether repeated augmentation of the eCB 2-arachidonoylglycerol with a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling without the development of tolerance. We find that chronic MAGL treatment stably facilitates goal seeking and DA encoding of prior reward cost, providing critical insight into the neurobiological mechanisms of a viable treatment for motivational deficits.SIGNIFICANCE STATEMENT Decades of work has established a fundamental role for dopamine neurotransmission in motivated behavior and cue-reward learning, but how dopaminergic encoding of cues associates with motivated action has remained unclear. Specifically, how dopamine neurons signal future and prior reward cost, and whether this can be modified to influence motivational set points is not known. The current study provides important insight into how dopamine neurons encode motivationally relevant stimuli to influence goal-directed action and supports cannabinoid-based therapies for treatment of motivational disorders.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/metabolismo , Motivação/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Animais , Sinais (Psicologia) , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoacilglicerol Lipases/farmacologia , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacosRESUMO
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
There is a compelling evidence that midbrain dopamine (DA) neurons and their projections to the ventral striatum provide a mechanism for motivating reward-seeking behavior, and for utilizing information about unexpected reward prediction errors (RPEs) to guide behavior based on current, rather than historical, outcomes. When this mechanism is compromised in addictions, it may produce patterns of maladaptive behavior that remain obdurate in the face of contrary information and even adverse consequences. Nonetheless, DAergic contributions to performance on behavioral tasks that rely on the ability to flexibly update stimulus-reward relationships remains incompletly understood. In the current study, we used a discrimination and reversal paradigm to monitor subsecond DA release in mouse NAc core (NAc) using in vivo fast-scan cyclic voltammetry (FSCV). We observed post-choice elevations in phasic NAc DA release; however, increased DA transients were only evident during early reversal when mice made responses at the newly rewarded stimulus. Based on this finding, we used in vivo optogenetic (eNpHR) photosilencing and (Channelrhodopsin2 [ChR2]) photostimulation to assess the effects of manipulating VTA-DAergic fibers in the NAc on reversal performance. Photosilencing the VTA â NAc DAergic pathway during early reversal increased errors, while photostimulation did not demonstrably affect behavior. Taken together, these data provide additional evidence of the importance of NAc DA release as a neural substrate supporting adjustments in learned behavior after a switch in expected stimulus-reward contingencies. These findings have possible implications for furthering understanding the role of DA in persistent, maladaptive decision-making characterizing addictions.
Assuntos
Cognição/fisiologia , Condicionamento Operante/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Animais , Neurônios Dopaminérgicos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Motivação/fisiologia , Área Tegmentar Ventral/fisiologiaRESUMO
UNLABELLED: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. SIGNIFICANCE STATEMENT: Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood. We used a mouse HD model and assessed whether impaired dopamine release in the nucleus accumbens (NAc), a brain region critical to goal-directed behaviors, accompanies motivational deficits, one of the most common early HD symptoms. HD mice exhibited blunted motivation to work for food reward coincident with diminished dopamine release to reward receipt. Motivational and NAc dopaminergic deficits were not associated with gross motor deficits or impaired food seeking when effortful demands were low. This work identifies a specific prodromal HD phenotype associated with a prominent and previously unidentified neurobiological impairment.
Assuntos
Dopamina , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Recompensa , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Dopamina/metabolismo , Espaço Extracelular/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Locomoção/fisiologia , Masculino , Camundongos , Motivação , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Sintomas ProdrômicosRESUMO
The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.
Assuntos
Potenciais de Ação , Anfetamina/administração & dosagem , Dopaminérgicos/administração & dosagem , Dopamina/metabolismo , Endocanabinoides/fisiologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Animais , Antagonistas de Receptores de Canabinoides/administração & dosagem , Masculino , Neurônios/fisiologia , Núcleo Accumbens/metabolismo , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/fisiologia , Rimonabanto , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagem , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
Background: Cannabis and its primary psychoactive constituent delta-9-tetrahydrocannabinol (D9-THC) produce biphasic, dose-dependent effects on anxiety. In addition to D9-THC, cannabis contains other "minor" cannabinoids and terpenes with purported therapeutic potential for the treatment of anxiety. Empirical data on potential therapeutic effects of these compounds is limited. The current study evaluated the effects of selected minor cannabinoids and terpenes in a battery of tests sensitive to anxiolytic and anxiogenic drugs. Methods: In Experiment 1, adult male Sprague Dawley rats (N=7-8/group) were administered acute oral doses of one of five minor cannabinoids: delta-8-tetrahydrocannabinol (D8-THC; 10 mg/kg), tetrahydrocannabivarin (32 mg/kg), cannabidiolic acid (32 mg/kg), cannabidivarin (32 mg/kg), and cannabigerol (100 mg/kg), or one of five terpenes: D-limonene (17 mg/kg), âº-pinene (100 mg/kg), âº-terpineol (10 mg/kg), bisabolol (100 mg/kg), and ß-caryophyllene (17 mg/kg), or vehicle (medium-chain triglycerides [MCT] oil). Ethyl alcohol was tested as an active comparator. Thirty minutes post-administration, the marble burying test, the three-chamber social interaction test, and the novelty-induced hypophagia test were completed; motor activity was assessed throughout testing. Experiment 2 examined the potential anxiolytic effects of minor cannabinoids when administered chronically; rats administered MCT oil or minor cannabinoids in Experiment 1 continued receiving once-daily doses for 21 days and were assessed using the same test battery after 7, 14, and 21 days of administration. Results and Conclusions: When compared to vehicle, acute administration of bisabolol and D-limonene increased the amount of food consumed and bisabolol-, D-limonene-, âº-pinene-, and ß-caryophyllene decreased percent time spent in the outer zone in the novelty-induced hypophagia test, suggestive of an anxiolytic effect. Only ethanol increased social interaction. After acute administration, anxiogenic effects in the marble burying test were observed for D8-THC, but not for other minor cannabinoids and terpenes. Throughout chronic administration, only D8-THC displayed anxiogenic effects in the novelty-induced hypophagia test. The other cannabinoids did not show anxiolytic or anxiogenic effects in any of the tests at the doses or times tested. The minor cannabinoids and terpenes did not impair or stimulate general motor activity. These data provide a foundation for future studies investigating cannabinoid/terpene interactions.
Assuntos
Ansiolíticos , Canabinoides , Cannabis , Alucinógenos , Masculino , Ratos , Animais , Terpenos/farmacologia , Ansiolíticos/farmacologia , Limoneno , Ratos Sprague-Dawley , Agonistas de Receptores de Canabinoides , Administração Oral , Terebintina , Carbonato de Cálcio , Canabinoides/farmacologiaRESUMO
Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion from VTA dopamine neurons prevents depolarization-induced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cue-driven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.
Assuntos
Dopamina , Neurônios Dopaminérgicos , Camundongos , Animais , Neurônios Dopaminérgicos/metabolismo , Dopamina/metabolismo , Endocanabinoides/metabolismo , Área Tegmentar Ventral/fisiologia , RecompensaRESUMO
High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata. An equivalent high dose of cocaine (40 mg/kg) was also examined for comparison to psychostimulants acting preferentially by DAT inhibition. Parameters describing exocytotic DA release and neuronal DA uptake were determined from dynamic DA signals evoked by mild electrical stimulation previously established to be reinforcing. High-sensitivity FSCV with nanomolar detection was used to monitor changes in the background voltammetric signal as an index of DA efflux. Both doses of AMPH and cocaine markedly elevated evoked DA levels over the entire 2-h time course in the dorsal and ventral striatum. These increases were mediated by augmented vesicular DA release and diminished DA uptake typically acting concurrently. AMPH, but not cocaine, induced a slow, DA-like rise in some baseline recordings. However, this effect was highly variable in amplitude and duration, modest, and generally not present at all. These data thus describe a mechanistically similar activation of action potential-dependent dopaminergic neurotransmission by AMPH and cocaine in vivo. Moreover, DA efflux appears to be a unique, but secondary, AMPH action.
Assuntos
Anfetaminas/farmacologia , Anestésicos Locais/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Dopamina/metabolismo , Exocitose/efeitos dos fármacos , Análise de Variância , Animais , Gânglios da Base/citologia , Gânglios da Base/efeitos dos fármacos , Biofísica , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Estimulação Elétrica/métodos , Eletroquímica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The nucleus accumbens (NAc) is located in the ventromedial portion of the striatum and is vital to valence-based predictions and motivated action. The neural architecture of the NAc allows for complex interactions between various cell types that filter incoming and outgoing information. Dopamine (DA) input serves a crucial role in modulating NAc function, but the mechanisms that control terminal DA release and its effect on NAc neurons continues to be elucidated. The endocannabinoid (eCB) system has emerged as an important filter of neural circuitry within the NAc that locally shapes terminal DA release through various cell type- and site-specific actions. Here, we will discuss how eCB signaling modulates terminal DA release by shaping the activity patterns of NAc neurons and their afferent inputs. We then discuss recent technological advancements that are capable of dissecting how distinct cell types, their afferent projections, and local neuromodulators influence valence-based actions.
RESUMO
The brain dopamine system is central to numerous behavioral processes, including movement, learning, and motivation. Accordingly, disruptions of this neural system underlie numerous neurological and psychiatric disorders. Current understanding of how dopamine neurotransmission contributes to behavior and its dysfunction has been driven by technological advancements that permit spatiotemporally-defined measurements of dopaminergic signaling in behaving animals. In this review, we will discuss the evolution of in vivo neural monitoring technologies for measuring dopamine neuron function. We focus on the dopamine system for two reasons: (1) the central role of dopamine neurotransmission in normal behavior and disease, and (2) dopamine neuron measurements have long been at the forefront of in vivo neural monitoring technologies. We will provide a brief overview of standard techniques for monitoring dopamine function, including electrophysiology, microdialysis, and voltammetry. Then, we will discuss recent advancements in optical technologies using genetically-encoded fluorescent proteins (GEFPs), including a critical evaluation of their advantages and limitations.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Animais , Comportamento Animal , Técnicas Biossensoriais/métodos , Encéfalo/metabolismo , Eletrofisiologia/métodos , Fluorescência , Aprendizagem , Microdiálise/métodos , Motivação , Neuroimagem/métodos , Transmissão SinápticaRESUMO
There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury (TBI). With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option. Pre-clinical TBI research suggests that cannabinoids have neuroprotective and psychotherapeutic properties. In contrast, recreational cannabis use has consistently shown to have detrimental effects. Our review identified a paucity of high-quality studies examining the beneficial and adverse effects of medical cannabis on TBI, with only a single phase III randomized control trial. However, observational studies demonstrate that TBI patients are using medical and recreational cannabis to treat their symptoms, highlighting inconsistencies between public policy, perception of potential efficacy, and the dearth of empirical evidence. We conclude that randomized controlled trials and prospective studies with appropriate control groups are necessary to fully understand the efficacy and potential adverse effects of medical cannabis for TBI.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Canabinoides/farmacologia , Maconha Medicinal/uso terapêutico , HumanosRESUMO
Dopamine (DA) transmission in the nucleus accumbens (NAc) facilitates cue-reward associations and appetitive action. Reward-related accumbal DA release dynamics are traditionally ascribed to ventral tegmental area (VTA) DA neurons. Activation of VTA to NAc DA signaling is thought to reinforce action and transfer reward-related information to predictive cues, allowing cues to guide behavior and elicit dopaminergic activity. Here, we use optogenetics to control DA neuron activity and voltammetry to simultaneously record accumbal DA release in order to quantify how reinforcer-evoked dopaminergic activity shapes conditioned mesolimbic DA transmission. We find that cues predicting access to DA neuron self-stimulation elicit conditioned responding and NAc DA release. However, cue-evoked DA release does not reflect the cost or magnitude of DA neuron activation. Accordingly, conditioned accumbal DA release selectively tracks the expected availability of DA-neuron-mediated reinforcement. This work provides insight into how mesolimbic DA transmission drives and encodes appetitive action.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Animais , Masculino , CamundongosRESUMO
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.
Assuntos
Dopamina/metabolismo , Endocanabinoides/metabolismo , Doença de Huntington/psicologia , Motivação/efeitos dos fármacos , Envelhecimento/psicologia , Animais , Apatia , Ácidos Araquidônicos/farmacologia , Benzodioxóis/farmacologia , Condicionamento Operante/efeitos dos fármacos , Progressão da Doença , Endocanabinoides/agonistas , Endocanabinoides/farmacologia , Glicerídeos/farmacologia , Masculino , Camundongos , Piperidinas/farmacologia , Pirazóis/farmacologia , RecompensaRESUMO
Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
Assuntos
Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/fisiologia , Transmissão Sináptica/fisiologia , Animais , Corpo Estriado/fisiologia , Humanos , Mesencéfalo/fisiologiaRESUMO
Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior. Here we report that extracellular DA increases induced by selective optogenetic activation of cholinergic neurons in the nucleus accumbens (NAc) are inhibited by CB1 agonists and eCBs. This modulation requires CB1 receptors on cortical glutamatergic afferents. Dopamine increases driven by optogenetic activation of prefrontal cortex (PFC) terminals in the NAc are similarly modulated by activation of these CB1 receptors. We further demonstrate that this same population of CB1 receptors modulates optical self-stimulation sustained by activation of PFC afferents in the NAc. These results establish local eCB actions on PFC terminals within the NAc that inhibit mesolimbic DA release and constrain reward-driven behavior.
Assuntos
Dopamina/metabolismo , Endocanabinoides/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Glutamatos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/citologia , Córtex Pré-Frontal/citologia , Receptor CB1 de Canabinoide/agonistas , Recompensa , Autoestimulação , Transmissão Sináptica/efeitos dos fármacosRESUMO
Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Canabinoides/metabolismo , Fumar Maconha/legislação & jurisprudência , Fumar Maconha/psicologia , Recompensa , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Humanos , Abuso de Maconha/metabolismo , Abuso de Maconha/psicologia , Fumar Maconha/metabolismoRESUMO
Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural rewards and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome.