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

Histamine H₃ 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 H₃ receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D₁ and D₂) receptors and it has been shown that H₃ receptors form heterodimers with both D₁ and D₂ receptors. Thus, the anatomical localization of H₃ 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 H₃ receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H₃ receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research.