RESUMEN
Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.
Asunto(s)
Consumo de Bebidas Alcohólicas , Alcoholismo , Núcleo Accumbens , Receptores Opioides kappa , Síndrome de Abstinencia a Sustancias , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Masculino , Alcoholismo/tratamiento farmacológico , Alcoholismo/psicología , Alcoholismo/metabolismo , Ratas , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/psicología , Etanol/administración & dosificación , Etanol/farmacología , Autoadministración , Antagonistas de Narcóticos/farmacología , Pirrolidinas/farmacología , Pirrolidinas/administración & dosificación , Conducta Animal/efectos de los fármacosRESUMEN
The dynorphin (DYN)/kappa-opioid receptor (KOR) system is involved in dysphoria and negative emotional states. Dysregulation of KOR function promotes maladaptive behavioral regulation during withdrawal associated with alcohol dependence. Mesolimbic dopaminergic (DA) projections from the ventral tegmental area (VTA) innervate the extended amygdala circuitry and presynaptic KORs attenuate DA in these regions leading to an excessive alcohol consumption and negative affective-like behavior, whereas mesocortical KOR-regulated DA projections have been implicated in executive function and decision-making. Thus, the neuroadaptations occurring in DYN/KOR systems are important aspects to consider for the development of personalized therapeutic solutions. Herein, we study the contribution of the VTA DA neuron Oprk1 (KOR gene) in excessive alcohol consumption, negative emotional state, and executive function. To do so, Oprk1 mRNA expression and KOR function were characterized to confirm alcohol dependence-induced dysregulation in the VTA. Then, a transgenic Cre-Lox rat model (male and female TH::Cre rats) was used to allow for conditional and inducible overexpression of Oprk1 in VTA DA neurons. The effect of this overexpression was evaluated on operant alcohol self-administration, negative emotional states, and executive function. We found that VTA Oprk1 overexpression recapitulates some phenotypes of alcohol dependence including escalated alcohol self-administration and depressive-like behavior. However, working memory performance was not impacted following VTA Oprk1 overexpression in TH::Cre rats. This supports the hypothesis that dysregulated KOR signaling within the mesolimbic DA system is an important contributor to symptoms of alcohol dependence and shows that understanding Oprk1-mediated contributions to alcohol use disorder (AUD) should be an important future goal.
Asunto(s)
Alcoholismo , Ratas , Masculino , Femenino , Animales , Alcoholismo/metabolismo , Área Tegmental Ventral/metabolismo , Receptores Opioides kappa/metabolismo , Dinorfinas/metabolismo , Etanol , Dopamina/metabolismo , FenotipoRESUMEN
In insects the tactile sense is important for near-range orientation and is involved in various behaviors. Nocturnal insects, such as the stick insect Carausius morosus, continuously explore their surroundings by actively moving their antennae when walking. Upon antennal contact with objects, stick insects show a targeted front-leg movement. As this reaction occurs within 40 ms, descending transfer of information from the brain to the thorax needs to be fast. So far, a number of descending interneurons have been described that may be involved in this reach-to-grasp behavior. One of these is the contralateral ON-type velocity-sensitive neuron (cONv). cONv was found to encode antennal joint-angle velocity during passive movement. Here, we characterize the transient response properties of cONv, including its dependence on joint angle range and direction. As antennal hair field afferent terminals were shown to arborize close to cONv dendrites, we test whether antennal hair fields contribute to the joint-angle velocity encoding of cONv. To do so, we conducted bilateral extracellular recordings of both cONv interneurons per animal before and after hair field ablations. Our results show that cONv responses are highly transient, with velocity-dependent differences in delay and response magnitude. As yet, the steady state activity level was maintained until the stop of antennal movement, irrespective of movement velocity. Hair field ablation caused a moderate but significant reduction of movement-induced cONv firing rate by up to 40%. We conclude that antennal proprioceptive hair fields contribute to the velocity-tuning of cONv, though further antennal mechanoreceptors must be involved, too.NEW & NOTEWORTHY Active tactile exploration and tactually induced behaviors are important for many animals. They require descending information transfer about tactile sensor movement to thoracic networks. Here, we investigate response properties and afferent input to the identified descending interneuron cONv in stick insects. cONv may be involved in tactually induced reach-to-grasp movements. We show that cONv response delay, transient and steady state are velocity-dependent and that antennal proprioceptive hair fields contribute to the velocity encoding of cONv.
Asunto(s)
Antenas de Artrópodos/fisiología , Interneuronas/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Antenas de Artrópodos/citología , Antenas de Artrópodos/inervación , Ganglios de Invertebrados/citología , Ganglios de Invertebrados/fisiología , Insectos , Movimiento , Tacto , Percepción del TactoRESUMEN
In the absence of any obvious input, sensory neurons and interneurons can display resting or spontaneous activity. This is often regarded as noise and removed through trial averaging, although it may reflect history-dependent modulation of tuning or fidelity and, thus, be of functional relevance to downstream interneurons. We investigated the history dependence of spontaneous activity in a pair of identified, bimodal descending interneurons of the stick insect, called contralateral ON-type velocity-sensitive interneurons (cONv). The bilateral pair of cONv conveys antennal mechanosensory information to the thoracic ganglia, where it arborizes in regions containing locomotor networks. Each cONv encodes the movement velocity of the contralateral antenna, but also substrate vibration as induced by discrete tapping events. Moreover, cONv display highly fluctuating spontaneous activity that can reach rates similar to those during antennal movement at moderate velocities. Hence, cONv offer a unique opportunity to study history-dependent effects on spontaneous activity and, thus, encoding fidelity in two modalities. In this work, we studied unimodal and cross-modal effects as well as unilateral and bilateral effects, using bilateral recordings of both cONv neurons, while moving one antenna and/or delivering taps to induce substrate vibration. Tapping could reduce spontaneous activity of both neurons, whereas antennal movement reduced spontaneous activity of the contralateral cONv neuron only. Combination of both modalities showed a cooperative effect for some parameter constellations, suggesting bimodal enhancement. Since both stimulus modalities could cause a reduction of spontaneous activity at stimulus intensities occurring during natural locomotion, we conclude that this should enhance neuronal response fidelity during locomotion.NEW & NOTEWORTHY The spontaneous activity in a pair of identified, descending insect interneurons is reduced depending on stimulus history. At rest, spontaneous activity levels are correlated in both interneurons, indicating a common drive from background activity. Whereas taps on the substrate affect both interneurons, antennal movement affects the contralateral interneuron only. Cross-modal interaction occurs, too. Since spontaneous activity is reduced at stimulus intensities encountered during natural locomotion, the mechanism could enhance neuronal response fidelity during locomotion.