Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization

The dorsal striatum plays an important role in the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using a novel approach that relies on the viral-mediated expression of an engineered GPCR (hM4D), we demonstrated that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons in rats, CNO did not change acute locomotor responses to amphetamine but altered behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behaviors such as sensitization

Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive.

Stressors motivate an array of adaptive responses ranging from \u27fight or flight\u27 to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF\u27s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders

Physician perspective on the implementation of risk mitigation strategies when prescribing opioid medications: a qualitative analysis

Abstract Objective To understand the physician perspective on the barriers and facilitators of implementing nine different opioid risk mitigation strategies (RMS) when prescribing opioid medications. Methods We created and dispersed a cross-sectional online survey through the Qualtrics© data collection platform among a nationwide sample of physicians licensed to practice medicine in the United States who have prescribed an opioid medication within the past year. The responses were analyzed using a deductive thematic analysis approach based on the Consolidated Framework for Implementation Research (CFIR) to ensure a holistic approach to identifying the barriers and facilitators for each RMS assessed. In concordance with this method, the themes and codes for the thematic analysis were defined prior to the analysis. The five domains within the CFIR were used as themes and the 39 nested constructs were treated as the codes. Two members of the research team independently coded the transcripts and discussed points of disagreement until consensus was reached. All analyses were conducted in ATLAS.ti© V7. Results The completion rate for this survey was 85.1% with 273 participant responses eligible for analysis. Intercoder reliability was calculated to be 82%. Deductive thematic analysis yielded 2,077 descriptions of factors affecting implementation of the nine RMS. The most salient code across all RMS was Knowledge and Beliefs about the Intervention, which refers to individuals’ attitudes towards and value placed on the intervention. Patient Needs and Resources, a code referring to the extent to which patient needs are known and prioritized by the organization, also emerged as a salient code. The physicians agreed that the patient perspective on the issue is vital to the uptake of each of the RMS. Conclusions This deductive thematic analysis identified key points for actionable intervention across the nine RMS assessed and established the importance of patient concordance with physicians when deciding on a course of treatment

Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmissio