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 H3 receptor (H3R) is an autoreceptor and also an heteroreceptor. H3Rs 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 H3R 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 H3R agonists and antagonists on animal models of alcohol, nicotine and psychostimulant use. At present, the effects of H3R 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 H3R ligands on two-bottle choice and memory tasks, respectively, have also been investigated. The results of these studies are inconsistent. For alcohol, H3R antagonists generally decreased the reward-related properties of ethanol, which suggests that H3R antagonists may be effective as a treatment option for alcohol use disorder. However, the effects of H3R antagonists on nicotine and psychostimulant motivation and reward are less clear. H3R 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 H3R antagonists are a viable therapeutic option. The fact that different drugs of abuse have different brain targets may explain the differential effects of H3R ligands.