Exploring Circuits for Cocaine Seeking Reinstatement
Valentina Martinez Damonte, Lydia G. Bailey, Amit Thakar, Joanna Stralka, Travis E. Brown, and Julie A. Kauer
(see article e1233252025)
Stress can trigger drug-seeking behavior in people with a history of drug use, which has been replicated in rodent models. Julie Kauer's group recently found that acute stress activates kappa opioid receptors (kORs) in the ventral tegmental area (VTA), weakens inhibitory plasticity on dopamine neurons, and triggers reinstatement of cocaine seeking. Herein, Martinez Damonte et al. expand on these findings by looking at where kORs are located in the VTA, what synapses are targeted to disinhibit dopamine neurons, and whether activating kORs can trigger cocaine seeking.
Using light to trigger plasticity at distinct inhibitory synapses in the VTA of mice, the authors found that plasticity at nucleus accumbens (NAc)-to-VTA synapses was weakened by acute stress. Genetically deleting kOR from NAc neurons—not VTA dopamine neurons—prevented this stress sensitivity. Chemically activating NAc neurons with DREADD recapitulated light-activated plasticity as well as the stress sensitivity effect at NAc-VTA synapses. Without acute stress, applying a kOR agonist directly into the VTA of male rats promoted cocaine reinstatement to a similar extent as stress alone. According to the authors, this work suggests that stress may target kORs at inhibitory synapses from the NAc to the VTA to drive cocaine addiction-related behavior. This work also provides insight on the interplay between opioid, GABA, and dopamine signaling.
Representative confocal images of VTA and NAc sections from mice with kORs deleted from their dopamine neurons. Color representations depicted in images. See Martinez Damonte et al. for more information.
Using Zebrafish to Explore Genes Involved in Alcoholism
Joshua Raine, Caroline Kibat, Tirtha Das Banerjee, Antonia Monteiro, and Ajay S. Mathuru
(see article e0304252025)
An emerging treatment development strategy for alcohol use disorders is to focus on the genetic underpinnings to create more personalized treatments. Zebrafish are a cost-effective animal model for probing disease-related genes, but do they even voluntarily seek alcohol? Raine et al. developed a way to give juvenile zebrafish a choice to self-administer alcohol that revealed a biphasic response, with the fish transitioning from attraction to aversion within the span of minutes. Furthermore, lower concentrations of alcohol reduced zebrafish anxiety-like behavior, while higher concentrations led to more sedative effects. The authors explored how a gene (chrna3) influenced sensitivity to alcohol and found that chrna3 mutants showed reduced avoidance to alcohol and self-administered it for longer periods of time. Raine and colleagues also identified neurotransmitter signaling differences in chrna3 mutant brains. According to the authors, their findings point to a potential role of chrna3 in alcohol consumption and the development of alcoholism. Beyond that, the alcohol self-administration model the authors developed may offer a new way for researchers to probe the roles of other genes in alcoholism.
Footnotes
This Week in The Journal was written by Paige McKeon
