Therapeutic Potential of Histamine H3 Receptors in Substance Use Disorders.

Substance use disorders are a leading cause of morbidity and mortality, and available pharmacological treatments are of modest efficacy. Histamine is a biogenic amine with four types of receptors. The histamine H receptor (HR) is an autoreceptor and also an heteroreceptor. HRs are highly expressed in the basal ganglia, hippocampus and cortex, and regulate a number of neurotransmitters including acetylcholine, norepinephrine, GABA and dopamine. Its function and localization suggest that the HR may be relevant to a number of psychiatric disorders and could represent a potential therapeutic target for substance use disorders. The purpose of the present review is to summarize preclinical studies investigating the effects of HR agonists and antagonists on animal models of alcohol, nicotine and psychostimulant use. At present, the effects of HR antagonists such as thioperamide, pitolisant or ciproxifan have been investigated in drug-induced locomotion, conditioned place preference, drug self-administration, reinstatement, sensitization and drug discrimination. For alcohol and nicotine, the effects of HR ligands on two-bottle choice and memory tasks, respectively, have also been investigated. The results of these studies are inconsistent. For alcohol, HR antagonists generally decreased the reward-related properties of ethanol, which suggests that HR antagonists may be effective as a treatment option for alcohol use disorder. However, the effects of HR antagonists on nicotine and psychostimulant motivation and reward are less clear. HR antagonists potentiated the abuse-related properties of nicotine, but only a handful of studies have been conducted. For psychostimulants, evidence is mixed and suggests that more research is needed to establish whether HR antagonists are a viable therapeutic option. The fact that different drugs of abuse have different brain targets may explain the differential effects of HR ligands.