RESUMO
Queer, Black womxn experience sexual assault at an alarming rate in the USA leading to adverse mental and physical health outcomes in survivors. A synthesis of the literature was conducted to understand their unique lived experiences and needs. This article proposes an adapted Meyer's Minoritised Stress framework to understand salient clinical factors impacting Queer, Black womxn sexual assault survivors, including those associated with multiple minoritised identities: Queer-based trauma, race-based trauma, cultural betrayal trauma, and misogynoir. Given the high rates of victimisation, marginalisation and discrimination, psychologists and others working with members of this population should engage with and address these factors to provide culturally responsive, sexually affirming and effective mental health treatment and care.
Assuntos
Vítimas de Crime , Delitos Sexuais , Minorias Sexuais e de Gênero , Humanos , Delitos Sexuais/psicologia , Vítimas de Crime/psicologia , Sobreviventes/psicologiaRESUMO
The mesolimbic dopamine system is strongly implicated in motivational processes. Currently accepted theories suggest that transient mesolimbic dopamine release events energize reward seeking and encode reward value. During the pursuit of reward, critical associations are formed between the reward and cues that predict its availability. Conditioned by these experiences, dopamine neurons begin to fire upon the earliest presentation of a cue, and again at the receipt of reward. The resulting dopamine concentration scales proportionally to the value of the reward. In this study, we used a behavioral economics approach to quantify how transient dopamine release events scale with price and causally alter price sensitivity. We presented sucrose to rats across a range of prices and modeled the resulting demand curves to estimate price sensitivity. Using fast-scan cyclic voltammetry, we determined that the concentration of accumbal dopamine time-locked to cue presentation decreased with price. These data confirm and extend the notion that dopamine release events originating in the ventral tegmental area encode subjective value. Using optogenetics to augment dopamine concentration, we found that enhancing dopamine release at cue made demand more sensitive to price and decreased dopamine concentration at reward delivery. From these observations, we infer that value is decreased because of a negative reward prediction error (i.e., the animal receives less than expected). Conversely, enhancing dopamine at reward made demand less sensitive to price. We attribute this finding to a positive reward prediction error, whereby the animal perceives they received a better value than anticipated.
Assuntos
Comportamento Animal , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Animais , Masculino , Ratos , Ratos Long-EvansRESUMO
Benzodiazepines are commonly prescribed anxiolytics that pose abuse liability in susceptible individuals. Although it is well established that all drugs of abuse increase brain dopamine levels, and benzodiazepines are allosteric modulators of the GABAA receptor, it remains unclear how they alter dopamine release. Using in vivo fast-scan cyclic voltammetry, we measured diazepam-induced changes in the frequency and amplitude of transient dopamine release events. We found that diazepam concurrently increases the frequency and decreases the amplitude of transient dopamine release events in the awake and freely moving rat. The time course during which diazepam altered the frequency and amplitude of dopamine release events diverged, with the decreased amplitude effect being shorter lived than the increase in frequency, but both showing similar rates of onset. We conclude that diazepam increases the frequency of accumbal dopamine release events by disinhibiting dopamine neurons, but also decreases their amplitude. We speculate that the modest abuse liability of benzodiazepines is due to their ability to decrease the amplitude of dopamine release events in addition to increasing their frequency.
Assuntos
Diazepam/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Animais , Flumazenil/farmacologia , Masculino , Ratos , Fatores de TempoRESUMO
The mesolimbic dopamine system is believed to be a pathway that processes rewarding information. While previous studies have also implicated a general role for dopamine in punishment and its avoidance, the precise nature of subsecond dopamine release during these phenomena remains unknown. Here, we used fast-scan cyclic voltammetry to investigate whether subsecond dopamine release events in the nucleus accumbens encode cues predicting the avoidance of punishment during behavior maintained in a signaled footshock avoidance procedure. In this task, rats could initiate an avoidance response by pressing a lever within a warning period, preventing footshock. Alternatively, once footshocks commenced, animals could initiate an escape response by pressing the lever, terminating footshock. This design allowed us to assess subsecond dopamine release events during the presentation of a warning signal, safety periods, and two distinct behavioral responses. We found that release consistently increased upon presentation of the warning signal in a manner that reliably predicted successful punishment avoidance. We also observed subsecond dopamine release during the safety period, as occurs following the receipt of reward. Conversely, we observed a decrease in release at the warning signal during escape responses. Because of this finding, we next assessed dopamine release in a conditioned fear model. As seen during escape responses, we observed a time-locked decrease in dopamine release upon presentation of a cue conditioned to inescapable footshock. Together, these data show that subsecond fluctuations in mesolimbic dopamine release predict when rats will successfully avoid punishment and differentially encode cues related to aversive outcomes.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/fisiologia , Dopamina/metabolismo , Medo/fisiologia , Núcleo Accumbens/metabolismo , Punição , Animais , Medo/psicologia , Previsões , Masculino , Punição/psicologia , Ratos , Ratos Sprague-DawleyRESUMO
A growing body of evidence implicates the endocannabinoid (eCB) system in brain reward function. Previous studies show that antagonizing eCB transmission decreases reward-directed behavior and nucleus accumbens (NAc) encoding of reward predictive cues. We, therefore, hypothesized that elevating eCB levels would uniformly facilitate NAc neural encoding of reward predictive cues and reward-directed behavior. Contrary to our expectations, the eCB transport uptake inhibitor, VDM11, dose dependently decreased both measures.
Assuntos
Ácidos Araquidônicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Endocanabinoides/metabolismo , Núcleo Accumbens/fisiologia , Recompensa , Animais , Sinais (Psicologia) , Eletroencefalografia , Masculino , Rede Nervosa/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Cannabinoids from the cannabis plant were one of the earliest psychoactive phytochemicals harnessed by humanity for their medicinal properties and remain one of the most frequently used and misused classes of chemicals in the world. Despite our long-standing history with cannabinoids, much more is said than is known regarding how these molecules influence the brain and behavior. We are in a rapidly evolving discovery phase regarding the neuroscience of cannabinoids. This period of insight began in the mid-1990s when it was discovered that phytocannabinoids (e.g., delta-9-tetrahydrocannabinol) act on G protein-coupled receptors (i.e., CB1/CB2) in the brain to produce their psychoactive effects. Shortly thereafter, it was discovered that endogenous ligands (i.e., endocannabinoids) exist for these receptor targets and, that they are synthetized on demand under a variety of physiological conditions. Thus, we can now study how phytochemicals, endogenous ligands, and synthetic/metabolic enzymes of the endocannabinoid system influence the brain and behavior by activating known receptor targets. Our increased ability to study cannabinoid interactions with the brain and behavior coincides with an increase in international interest in utilizing cannabinoids as a medicine. At the same time, the potency of, and administration routes by which cannabinoids are used is rapidly changing. And, these trends in cannabinoid misuse are producing lasting neural adaptations that have implications for mental health. In this special edition, we will summarize our recent period of discovery regarding how: 1) phytocannabinoids, synthetic cannabinoids and endocannabinoids act on the brain to produce behavioral effects; 2) cannabinoids can be harnessed to produce pharmacotherapeutic utility in the field of medicine; and 3) use of increasingly more cannabinoid variants through unique routes of administration alter the brain and behavior, especially when used in critical developmental periods like pregnancy and adolescence.
Assuntos
Psiquiatria Biológica/tendências , Canabinoides/uso terapêutico , Desenvolvimento de Medicamentos/tendências , Neurofarmacologia/tendências , Psicofarmacologia/tendências , Animais , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/psicologiaRESUMO
Cannabis sativa, like all known drugs of abuse, leads to increased dopamine activation within the mesolimbic pathway. Consequent dopamine release within terminal regions of the striatum is a powerful mediator of reward and reinforcement and patterned dopamine release is critical for associative learning processes that are fundamentally involved in addiction. The endocannabinoid system modulates dopamine release at multiple sites, and the receptors, endogenous ligands, and synthetic and metabolic enzymes of the endocannabinoid system may provide key targets for pharmacotherapies to treat disorders of motivation including addiction. Disrupting endocannabinoid signaling decreases drug-induced increases in dopamine release as well those dopamine events evoked by conditioned stimuli during reward seeking. Advances in recording techniques for dopamine are allowing unprecedented examinations of these two interacting systems and elucidating the mechanisms of endocannabinoid modulation of dopamine release in reward and addiction.
Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Dopamina/metabolismo , Abuso de Maconha/metabolismo , Recompensa , Animais , Encéfalo/fisiologia , Dronabinol/farmacologia , Endocanabinoides/fisiologia , Humanos , Abuso de Maconha/fisiopatologia , Abuso de Maconha/psicologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Síndrome de Abstinência a Substâncias/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Motivational and attentional processes energize action sequences to facilitate evolutionary competition and promote behavioral fitness. Decades of neuropharmacology, electrophysiology and electrochemistry research indicate that the mesocorticolimbic DA pathway modulates both motivation and attention. More recently, it was realized that mesocorticolimbic DA function is tightly regulated by the brain's endocannabinoid system and greatly influenced by exogenous cannabinoids-which have been harnessed by humanity for medicinal, ritualistic, and recreational uses for 12,000 years. Exogenous cannabinoids, like the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol, produce their effects by acting at binding sites for naturally occurring endocannabinoids. The brain's endocannabinoid system consists of two G-protein coupled receptors, endogenous lipid ligands for these receptor targets, and several synthetic and metabolic enzymes involved in their production and degradation. Emerging evidence indicates that the endocannabinoid 2-arachidonoylglycerol is necessary to observe concurrent increases in DA release and motivated behavior. And the historical pharmacology literature indicates a role for cannabinoid signaling in both motivational and attentional processes. While both types of behaviors have been scrutinized under manipulation by either DA or cannabinoid agents, there is considerably less insight into prospective interactions between these two important signaling systems. This review attempts to summate the relevance of cannabinoid modulation of DA release during operant tasks designed to investigate either motivational or attentional control of behavior. We first describe how cannabinoids influence DA release and goal-directed action under a variety of reinforcement contingencies. Then we consider the role that endocannabinoids might play in switching an animal's motivation from a goal-directed action to the search for an alternative outcome, in addition to the formation of long-term habits. Finally, dissociable features of attentional behavior using both the 5-choice serial reaction time task and the attentional set-shifting task are discussed along with their distinct influences by DA and cannabinoids. We end with discussing potential targets for further research regarding DA-cannabinoid interactions within key substrates involved in motivation and attention.
RESUMO
Endocannabinoids (eCBs) are neuromodulators that influence a wide range of neural systems and behaviors. In the current review, we describe our recent research showing how eCBs, particularly 2-arachidonoylglycerol (2-AG), concurrently shape mesolimbic dopamine (DA) release and associated behavior. We will restrict our discussion by emphasizing three distinct behaviors: reward seeking, interval timing, and active avoidance. During reward seeking we find that 2-AG is necessary to observe cue-evoked DA release events that are thought to represent the value of a rewarding outcome. We then describe data showing that 2-AG modulates unique patterns of DA release and behavior observed under conditions of periodic reinforcement. These data are discussed within the context of interval timing and adjunctive behavior. eCB modulation of DA release is also implicated in defensive behavior, including the avoidance of harm. As in reward seeking, our data suggest that the concentration of DA that is evoked by a warning signal can represent the value of an avoidance outcome. And, disrupting eCB signaling concomitantly reduces the concentration of the avoidance value signal and active avoidance. Disruptions in reward seeking, interval timing, and defensive behavior are commonly observed in a variety of movement disorders (e.g., Parkinson's and Huntington's disease) and disorders of motivation (e.g., addiction). We believe our data on eCB-DA interactions have implications for the development of novel pharmacotherapies to treat these disorders. Thus, we conclude by discussing how eCB pharmacology might be harnessed to treat disorders of movement and motivation.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Dopamina/metabolismo , Endocanabinoides/farmacologia , Motivação/efeitos dos fármacos , Reforço Psicológico , Recompensa , Analgésicos/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Aprendizagem da Esquiva/fisiologia , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/metabolismo , Glicerídeos/farmacologia , Humanos , Morfolinas/farmacologia , Motivação/fisiologia , Naftalenos/farmacologiaRESUMO
Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance. Because the endogenous cannabinoid and opioid systems exhibit considerable cross-talk and cross-tolerance frequently develops following repeated exposure to either opioids or cannabinoids, there is interest in investigating whether a history of synthetic cannabinoid exposure influences the ability of heroin to increase DA release. To test the effects of chronic cannabinoid exposure on cannabinoid- and heroin-evoked DA release, male adult rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2; WIN) using an intravenous (IV) dose escalation regimen (0.2-0.8 mg/kg IV over 9 treatments). As predicted, WIN-treated rats showed a rightward shift in the dose-response relationship across all behavioral/physiological measures when compared to vehicle-treated controls. Then, using fast-scan cyclic voltammetry to measure changes in the frequency of transient DA events in the nucleus accumbens shell of awake and freely-moving rats, it was observed that the DA releasing effects of both WIN and heroin were significantly reduced in male rats with a pharmacological history of cannabinoid exposure. These results demonstrate that repeated exposure to the synthetic cannabinoid WIN can produce tolerance to its DA releasing effects and cross-tolerance to the DA releasing effects of heroin.
Assuntos
Analgésicos Opioides/farmacologia , Benzoxazinas/farmacologia , Canabinoides/administração & dosagem , Dopamina/metabolismo , Tolerância a Medicamentos/fisiologia , Heroína/farmacologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Fatores Etários , Analgésicos , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Long-EvansRESUMO
Recent evidence suggests that the hypocretin-orexin system participates in the regulation of reinforcement processes. The current studies examined the extent to which hypocretin neurotransmission regulates behavioral and neurochemical responses to cocaine, and behavioral responses to food reinforcement. These studies used a combination of fixed ratio, discrete trials, progressive ratio and threshold self-administration procedures to assess whether the hypocretin 1 receptor antagonist, SB-334867, reduces cocaine self-administration in rats. Progressive ratio sucrose self-administration procedures were also used to assess the extent to which SB-334867 reduces responding to a natural reinforcer in food-restricted and food-sated rats. Additionally, these studies used microdialysis and in vivo voltammetry in rats to examine whether SB-334867 attenuates the effects of cocaine on dopamine signaling within the nucleus accumbens core. Furthermore, in vitro voltammetry was used to examine whether hypocretin knockout mice display attenuated dopamine responses to cocaine. Results indicate that when SB-334867 was administered peripherally or within the ventral tegmental area, it reduced the motivation to self-administer cocaine and attenuated cocaine-induced enhancement of dopamine signaling. SB-334867 also reduced the motivation to self-administer sucrose in food-sated but not food-restricted rats. Finally, hypocretin knockout mice displayed altered baseline dopamine signaling and reduced dopamine responses to cocaine. Combined, these studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system. Additionally, the current observations suggest that the hypocretin system may provide a target for pharmacotherapies to treat cocaine addiction.
Assuntos
Cocaína , Dopamina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema Límbico/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Neuropeptídeos/metabolismo , Autoadministração , Animais , Benzoxazóis/metabolismo , Cocaína/administração & dosagem , Cocaína/farmacologia , Eletroquímica , Sistema Límbico/anatomia & histologia , Sistema Límbico/metabolismo , Masculino , Mesencéfalo/anatomia & histologia , Mesencéfalo/metabolismo , Camundongos , Microdiálise , Naftiridinas , Receptores de Orexina , Orexinas , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transdução de Sinais/fisiologia , Ureia/análogos & derivados , Ureia/metabolismoRESUMO
AIMS: The United States of America is currently in an opioid epidemic. Heroin remains the most lethal opioid option with its death rate increasing by over 500% in the last decade. The rewarding and reinforcing effects of heroin are thought to be mediated by its ability to increase dopamine concentration in the nucleus accumbens shell. By activating Gi/o-coupled µ-opioid receptors, opioids are thought to indirectly excite midbrain dopamine neurons by removing an inhibitory GABAergic tone. The partial µ-opioid receptor agonist buprenorphine is a substitution-based therapy for heroin dependence that is thought to produce a steady-state level of µ-opioid receptor activation. But it remains unclear how buprenorphine alters dopamine release relative to heroin and how buprenorphine alters the dopamine-releasing effects of heroin. Because buprenorphine is a partial agonist at the µ-opioid receptor and heroin is a full agonist, we predicted that buprenorphine would function as a weak dopamine releaser relative to heroin, while functioning as a competitive antagonist if administered in advance of heroin. METHODS: We performed fast-scan cyclic voltammetry in awake and behaving rats to measure how heroin, buprenorphine HCl, and their combination affect transient dopamine release events in the nucleus accumbens shell. We also performed a complimentary pharmacokinetic analysis comparing opioid plasma levels at time points correlated to our neurochemical findings. RESULTS: Both buprenorphine and heroin produced changes in the frequency of transient dopamine release events, although the effect of buprenorphine was weak and only observed at a low dose. In comparison with vehicle, the frequency of dopamine release events maximally increased by ~25% following buprenorphine treatment and by ~60% following heroin treatment. Distinct neuropharmacological effects were observed in the high-dose range. The frequency of dopamine release events increased linearly with heroin dose but biphasically with buprenorphine dose. We also found that buprenorphine pretreatment occluded the dopamine-releasing effects of heroin, but plasma levels of buprenorphine had returned to baseline at this time point. CONCLUSION: These findings support the notion that low-dose buprenorphine is a weak dopamine releaser relative to heroin and that buprenorphine pretreatment can block the dopamine-releasing effects of heroin. The finding that high-dose buprenorphine fails to increase dopamine release might explain its relatively low abuse potential among opioid-dependent populations. Because high-dose buprenorphine decreased dopamine release before occluding heroin-evoked dopamine release, and buprenorphine was no longer detected in plasma, we conclude that the mechanisms through which buprenorphine blocks heroin-evoked dopamine release involve multifaceted pharmacokinetic and pharmacodynamic interactions.
Assuntos
Analgésicos Opioides/administração & dosagem , Buprenorfina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Dopamina/metabolismo , Heroína/administração & dosagem , Núcleo Accumbens/metabolismo , Administração Intravenosa , Animais , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismoRESUMO
RATIONALE AND OBJECTIVE: Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. MATERIALS AND METHODS: Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. RESULTS: Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. CONCLUSIONS: Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Esquema de Reforço , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
The mesocorticolimbic dopamine pathway is generally considered to be a reward pathway. While shortsighted, there is a strong basis for this view of dopamine function. Here, we first describe the role of phasic dopamine release events in reward seeking. We then explain why these release events are being reconsidered as value signals and how we applied behavioral economics to confirm they play a causal role in the valuation of reward. Just because dopamine release can function as a dopamine reward value signal however, does not imply that dopamine is solely a reward molecule. Rather, mesocorticolimbic dopamine appears to mediate many adaptive behaviors, including: reward seeking, avoidance, escape and fear-associated conditioned freezing. While more studies are needed before a consensus is reached on when, where and how dopamine mediates aversively-motivated behavior, its involvement is almost irrefutable. Thus, we next describe the role dopamine plays in these ethologically-relevant defensive behaviors. We conclude by describing our recent behavioral economics results that reveal a causal role for dopamine in the valuation of avoidance.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Dopamina/metabolismo , Dopamina/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Economia Comportamental , Modelos Animais , Motivação/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , RecompensaRESUMO
Benzodiazepines make up a class of psychoactive drugs that act as allosteric co-activators of the inhibitory GABAA receptor. These drugs are useful for the treatment of several psychiatric disorders but also hold considerable abuse liability. Despite the common use and misuse of benzodiazepines, the mechanisms through which these drugs exert their reinforcing effects remain incompletely understood. Transient phasic increases in dopamine levels are believed to play an important role in defining the reinforcing properties of drugs of abuse, and we recently demonstrated that systemic administration of benzodiazepines increased the frequency of these events but concomitantly reduced their amplitude. This observation provides insight into the pharmacological effects of benzodiazepines on dopamine signaling, but the processes through which benzodiazepines drive changes in phasic dopamine signals remain unclear. In these studies, we investigated the mechanisms through which benzodiazepines may reduce the phasic dopamine transient amplitude. We tested the effect of the benzodiazepine diazepam and the GABAA agonist muscimol on evoked dopamine release from nucleus accumbens brain slices using fast scan cyclic voltammetry. We found that both diazepam and muscimol reduce dopamine release and that reductions in dopamine release following GABAA receptor activation can be blocked by co-application of a GABAB receptor antagonist. These results suggest that activation of GABAA receptors in the nucleus accumbens decreases dopamine release by disinhibition of local GABA signaling and subsequent activation of GABAB receptors. Overall, this work provides a putative mechanism through which benzodiazepines reduce the amplitude of phasic dopamine release in vivo.
Assuntos
Dopamina/metabolismo , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores de GABA-A/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Diazepam/farmacologia , Moduladores GABAérgicos/farmacologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-DawleyRESUMO
Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10â¯mg/kg) either 30â¯min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Serotoninérgicos/farmacologia , Animais , Sinais (Psicologia) , Medo , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Long-EvansRESUMO
Investigators who study drug addiction are fortunate to have access to excellent animal models. Such models will be invaluable in the assessment of factors involved in the progression of drug addiction. The relevance of these findings, however, will depend on the general understanding of how each model is related to drug addiction. The present review focuses on several procedures that were designed to model the addiction process and questions whether these models are tapping into the same underlying process or whether each is addressing a unique feature. Furthermore, various factors (e.g., rate of drug onset, dose magnitude, early drug history, periods of abstinence) influencing the progression of these addiction-like changes in behavior are discussed.
RESUMO
While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid.
Assuntos
Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Dopamina/metabolismo , Economia Comportamental , Motivação/fisiologia , Núcleo Accumbens/metabolismo , Reforço Psicológico , Recompensa , Animais , Técnicas Eletroquímicas , Masculino , Optogenética , Ratos , Ratos Long-EvansRESUMO
Phasic dopamine (DA) release accompanies approach toward appetitive cues. However, a role for DA in the active avoidance of negative events remains undetermined. Warning signals informing footshock avoidance are associated with accumbal DA release, whereas depression of DA is observed with unavoidable footshock. Here, we reveal a causal role of phasic DA in active avoidance learning; specifically, optogenetic activation of DA neurons facilitates avoidance, whereas optical inhibition of these cells attenuates it. Furthermore, stimulation of DA neurons during presentation of a fear-conditioned cue accelerates the extinction of a passive defensive behavior (i.e., freezing). Dopaminergic control of avoidance requires endocannabinoids (eCBs), as perturbing eCB signaling in the midbrain disrupts avoidance, which is rescued by optical stimulation of DA neurons. Interestingly, once the avoidance task is learned, neither DA nor eCB manipulations affect performance, suggesting that once acquisition occurs, expression of this behavior is subserved by other anatomical frameworks. Our findings establish an instrumental role for DA release in learning active responses to aversive stimuli and its control by eCB signaling.
Assuntos
Aprendizagem da Esquiva/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/farmacologia , Núcleo Accumbens/fisiologia , Animais , Sinais (Psicologia) , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Medo/fisiologia , Masculino , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Optogenética , Ratos , Ratos Long-Evans , RecompensaRESUMO
RATIONALE: Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in the brain. However, many questions remain about the effects of alcohol on the delicate equilibrium between such neurochemical processes as DA release and uptake. Dysregulation of these processes in the mesolimbic and nigrostriatal systems after chronic alcohol ingestion could be a neuroadaptation contributing to dependence. OBJECTIVES: In the present study, we have employed an alcohol vapor inhalation model to characterize the effects of chronic alcohol exposure on DA dynamics in rat nucleus accumbens (NAc) and caudate putamen (CP) using fast-scan cyclic voltammetry (FSCV) in brain slices. This method provides a unique view of real-time, spatially resolved changes in DA concentration. RESULTS: We found that chronic alcohol exposure enhanced DA uptake rates in rat NAc and CP. These changes would have the effect of down-regulating extracellular DA levels, presumably a compensatory effect related to increased DA release by repeated alcohol exposure. The sensitivity of terminal release-regulating DA autoreceptors was not different in alcohol-exposed rats compared with alcohol-naïve animals. CONCLUSIONS: The DA uptake changes after chronic alcohol exposure documented here using FSCV may be associated with a compensatory response of the DA system aimed at decreasing DA signaling. Alterations in autoreceptor function may require relatively long lasting alcohol exposure.