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Background and purpose: GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. Experimental approach: We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol‐naïve mice to investigate its impact on anxiety‐related behaviour. Key results: The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR‐dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired‐pulse depression of GABAA receptor‐dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol‐treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety‐related behaviour in ethanol‐naïve mice. Conclusions and implications: Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre‐ and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety‐related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

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The author comments on a review of researches which show a low level of precipitated withdrawal with buprenorphine induction to treat opioid use disorder (OUD) in 2025. Topics covered include synthetic fentanyl's involvement in overdose deaths, and the treatment of opioid withdrawal by buprenorphine and methadone. Also noted is the possible successful treatment of OUD when there is a low likelihood of precipitated withdrawal.

Prior to entering the market, health authorities conduct a rigorous evaluation of compiled information for drugs delaying its entry. To address this void expedited pathways are introduced. In this study, both oncology and non-oncology drugs approved through various expedited pathways from the US and Europe have been scrutinized using the USFDA's Novel Drug approvals from 2020 to 2023 and EMA's Human Medicine Highlights 2020 to 2023. Withdrawals if any along with factors causing withdrawal have also been studied. Among all the pathways accelerated approval has high oncological drug approvals and also high withdrawal for drugs approved based on surrogate endpoints. From the study conducted it was observed that intensive evaluation has to be performed both pre and post-approval for drugs approved based on surrogate endpoints as well as on the conduct of their confirmatory trials. [Display omitted] • Expedited pathways are gaining attraction for speeding up medicine approvals. • Notably, the USFDA's accelerated approval process has sparked a surge in oncological drugs. • Rising withdrawals of accelerated approvals reflect reliance on surrogate endpoints and incomplete confirmatory trials. [ABSTRACT FROM AUTHOR]

Conditioned preference paradigms like conditioned colour preference tests (CCP) can be used to investigate addictive drug seeking in zebrafish (Danio rerio), but many aspects of this procedure require further study. Conditioned preference can be tested with either biased or unbiased conditioning methods, each with their own strengths and weaknesses. The present study used unbiased stimuli to test seeking behaviour in ethanol-exposed zebrafish at different durations of drug withdrawal. Zebrafish were exposed to one of two equally preferred colours (red or yellow) while dosed with 0.8 % vol/vol ethanol or with habitat water (controls) for 1 h each day for 21 days. Next, fish experienced withdrawal for either 2-, 4-, or 8-days then were tested in a two-way red and yellow task for 10 min with their movement recorded via motion-tracking software. Fish conditioned to red showed a main effect of ethanol and a significant preference for red compared to yellow at 8-days of withdrawal but not at 2-days or 4-days of withdrawal. Fish conditioned to yellow did not show any colour preference during the 2-, 4-, or 8-days of withdrawal, but did show a main effect of withdrawal duration. This work expands our understanding of CCP paradigms in zebrafish and highlights the capacity of zebrafish to develop an association to red but not yellow under our experimental conditions. • Zebrafish repeatedly exposed to ethanol and the colour red over a period of 21 days spent more time in the colour red at 8-days of withdrawal. • Zebrafish repeatedly exposed to ethanol and the colour yellow over a period of 21 days show no conditioned colour preference. • There were no sex differences in conditioned colour preference. [ABSTRACT FROM AUTHOR]

Prolonged periods of opioid use have been shown to cause neuroadaptations in the brain's reward circuitry, contributing to addictive behaviors and drug dependence. Recently, considerable focus has been placed on the role of the endocannabinoid system (ECS) and its CB receptors in opioid-driven behaviors. However, opioid-induced neuroadaptations to the ECS remain understudied. In this study, we systematically assessed CB1 receptor (CB1R) protein expression within the cortico-mesolimbic-basal ganglia circuit in rats following chronic fentanyl exposure. Male and female Long Evans rats were administered increasing daily doses of fentanyl or saline for 14 days. During naloxone-precipitated withdrawal, fentanyl-treated rats exhibited significantly higher withdrawal symptoms than saline-treated controls. Using Western Blotting, we demonstrated that the fentanyl-treated rats had significantly higher CB1R expression in the insula and significantly lower CB1R expression in the nucleus accumbens and substantia nigra compared to saline-treated rats. No significant differences in CB1R expression were detected between saline and fentanyl-treated rats in the prefrontal cortex, dorsal striatum, medial septum, hypothalamus, amygdala, hippocampus, ventral tegmental area, periaqueductal gray area, pedunculopontine tegmentum, and laterodorsal tegmentum (LDT). These findings suggest that chronic fentanyl exposure leads to region-specific neuroadaptations of CB1R protein expression in motivation- and addiction-associated brain regions. [ABSTRACT FROM AUTHOR]