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Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.
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Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death1. Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.
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BACKGROUND: Much of the existing animal literature on the devaluation task suggests that prior repeated exposure to drugs of abuse during adulthood can impair goal-directed action, but the literature on human drug users is mixed. Also, the initiation of drug use often occurs during adolescence, but examinations of the effects of drug exposure during adolescence on behavior in the devaluation task are lacking. METHODS: We examined whether repeated exposure during adolescence to amphetamine (3 mg/kg injections every-other day from post-natal day 27-45) or ketamine (twice daily 30 mg/kg injections from post-natal day 35-44) would impair behavior in a devaluation test when tested drug-free in adulthood. Rats were trained to press a left lever with a steady cue-light above it for one reinforcer and a right lever with a flashing cue-light above it for a different reinforcer. We tested whether any impairments in goal-directed action could be overcome by compensation between strategies by giving rats information based on lever-location and cue-lights during the test that was either congruent (allowing compensation) or incongruent (preventing compensation between strategies) with the configurations during training. RESULTS: Our results provided no evidence for impairment of goal-directed action during adulthood after adolescent amphetamine or ketamine exposure. CONCLUSIONS: We discuss possible reasons for this discrepancy with the prior literature, including (1) the age of exposure and (2) the pattern in the previous literature that most previous demonstrations of drug exposure impairing devaluation in laboratory animals may be attributed to either drug-associated cues present in the testing environment and/or accelerated habit learning in tasks that predispose laboratory animals towards habit formation with extended training (with training procedures that should resist the formation of habits in the current experiment). However, additional research is needed to examine the effects of these factors, as well a potential role for the particular doses and washout periods to determine the cause of our finding of no devaluation impairment after drug exposure.
Asunto(s)
Anfetamina , Ketamina , Animales , Ketamina/farmacología , Ketamina/administración & dosificación , Anfetamina/farmacología , Anfetamina/administración & dosificación , Masculino , Ratas , Condicionamiento Operante/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Ratas Long-Evans , Conducta Animal/efectos de los fármacos , Factores de Edad , Señales (Psicología)RESUMEN
People often falsely believe that individuals from low socioeconomic status (SES) backgrounds are less harmed than those from higher SES backgrounds by a wide range of negative events. We report three studies (total N = 1,625) that provide evidence that this "thick skin bias" emerges at least in part because people overgeneralize otherwise accurate intuitions about adaptation. Across studies, participants accurately intuited that people adapt to psychophysical experiences (e.g., brightness, weight, and volume) but also inaccurately intuited that people similarly adapt to life hardships that actually tend to exacerbate the harm of future negative events. Experimentally decreasing the salience of psychophysical adaptation intuitions reduced the thick skin bias, suggesting a causal link between these adaptation intuitions and the belief that people in poverty are less vulnerable to harm and underlining the importance of studying how biased beliefs about the effects of poverty may perpetuate inequality.