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

Abstract

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. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit

Histaminergic modulation in Tourette syndrome

“…Specifically, H3 receptors are found in high concentrations throughout the cortex, hippocampus and striatum [54], the latter of which has been strongly associated with TS pathophysiology. Moreover, H3 receptors in the striatum have been shown to have significant roles in modulating dopaminergic neurotransmission [59,60], thus further supporting their possible role in TS [61]. Specifically, histamine neurotransmission appears to reduce the concentration of dopamine in the striatum by acting at H3 heteroreceptors on dopaminergic afferents.…”

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

“…H3R is coupled to G␣ i and thereby can reduce cAMP-mediated signaling, at least in some cells (7,30,31). This could oppose the effects of D1R activation on the cAMP/PKA/DARPP-32 signaling pathway.…”

The other side of the histamine H3 receptor

“…A large proportion of H3Rs are located presynaptically on both histaminergic and non-histaminergic neurons. Without exception, stimulation of these presynaptic H3Rs inhibits the release of a neurotransmitter, including histamine, dopamine, acetylcholine, and glutamate [71]. A recent study has shown that the H3R located on histaminergic terminals is most likely a short isoform [H 3(431) ].…”

“…Several studies have now shown that large regional differences exist in the influence of H3R on neurotransmitter release. For instance, whereas in the prefrontal cortex H3R antagonists/inverse agonists enhance dopamine and histamine release, they have no such effect in the dorsal striatum (for an overview see [71]). …”

“…However, H3R antagonists have been evaluated in several models of drug use, including self-administration and conditioned place preference [71]. These studies show support for a therapeutic role for H3R antagonists in alcohol addiction, whereas the literature on psychostimulants is much less clear (Table 1).…”