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.