Histamine H3 receptors, the complex interaction with dopamine and its implications for addiction

Histamine H-3 receptors are best known as presynaptic receptors inhibiting the release of histamine, as well as other neurotransmitters including acetylcholine and dopamine. However, in the dorsal and ventral striatum, the vast majority of H-3 receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D-1 and D-2) receptors and it has been shown that H-3 receptors form heterodimers with both D-1 and D-2 receptors. Thus, the anatomical localization of H-3 receptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission. Dopamine, especially within the striatal complex, plays a crucial role in the development of addiction, both in the initial reinforcing effects of drugs of abuse, as well as in maintenance, relapse and reinstatement of drug taking behaviour. It is, therefore, conceivable that H-3 receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H-3 receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research.