Next-generation vaccines for substance use disorders

Substance use disorders(SUDs)impact an estimated 300 million people worldwide,significantly impairing both health and social functioning.These disorders are marked by an inability to regulate substance use,despite the harmful consequences.Addiction affects various neurotransmitter systems,including dopamine,serotonin,γ-aminobutyric acid(GABA),and glutamate,each of which plays a role in the reward,stress,and self-control pathways of the brain(Koob&Volkow,2016).While significant advances have been made in neuroscience,our understanding of how these neurotransmitter systems interact and contribute to addiction is still evolving.This knowledge gap represents a significant challenge in the formulation of effective treatments for SUDs.At present,the US Food and Drug Administration(FDA)has approved pharmacological treatments for alcohol,nicotine,and opioid use disorders(Vasiliu,2022);however,no such treatments have been authorized for SUDs in general,or specifically for stimulant use disorders,such as cocaine and methamphetamine addiction.Notably,the FDA has not approved any new drugs for SUD treatment in the past 40 years.

Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling

Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs.Nicotine attenuates the neuroinflammation induced by microglial activation.However,the molecular target(s)underlying anti-inflammatory action of nicotine has not been fully understood.Considering the psychoactive substances morphine,cocaine,and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4(TLR4),here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2(MD2).