Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

Abstract

The striatum contains a high density of histamine H 3 receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H 3 and dopamine D 1 receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H 3 and dopamine D 2 receptors. In the present study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H 3 and D 1 and also between H 3 and dopamine D 2 receptors. The selective H 3 receptor agonist imetit inhibited, while the H 3 receptor antagonist thioperamide potentiated locomotor activation induced by either the D 1 receptor agonist SKF 38393 or the D 2 receptor agonist quinpirole. High scores of locomotor activity were obtained with H 3 receptor blockade plus D 1 and D 2 receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H 3 -D 2 receptor interaction at the membrane level. In agonist/antagonist competition experiments stimulation of H 3 receptors with several H 3 receptor agonists significantly decreased the affinity of D 2 receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in cotransfected HEK-293 cells, H 3 (but not H 4 ) receptors were found to form heteromers with D 2 receptors. The present study demonstrates an important role of postsynaptic H 3 receptors in the modulation of dopaminergic transmission by means of a negative modulation of D 2 receptor function.

Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

“…Especially because of the lack of CPP in H3R KO mice one would expect to find diminished dopamine release evoked by alcohol in nucleus accumbens of H3R KO mice. The H3R gene deletion might have also disrupted the suggested interaction of postsynaptic H3Rs with dopaminergic receptors in striatal GABAergic cells (Ferrada et al, 2008(Ferrada et al, , 2009Moreno et al, 2011) leading to different responses to alcohol in H3R and WT mice. Since only male mice were available for this study, the further studies should also involve females, because there may be sex differences in the observed behaviors.…”

“…H3R was found to be highly expressed in the striatum on GABAergic cell bodies of the medium spiny neurons. Interestingly, these postsynaptic H3Rs are able to form functional heterodimers with dopamine D1 and D2 receptors in vitro and in vivo which integrate histamine-and dopamine-related signals (Ferrada et al, 2008(Ferrada et al, , 2009Moreno et al, 2011). Further, H3R receptors display high constitutive activity, which adds to the complex functional role of this receptor type (Arrang et al, 2007).…”

Histaminergic modulation in Tourette syndrome

“…Histamine acts through four receptors (H1-H4) and actively regulates arousal, feeding, learning and memory processes [56,57]. H1 and H2 receptors are expressed throughout the central nervous system, H3 receptors are limited to the brain, and H4 receptors are primarily located in the immune system, with limited action on the brain [58,59]. 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.…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…The histamine H3 receptor (H3R) has also been shown by BRET to form a heteromeric complex with the D1R and D2R in cells (Ferrada et al, 2008;Ferrada et al, 2009) and to coimmunoprecipitate with the D1R or D2R in the striatum (Moreno et al, 2011). At a functional level, it was demonstrated that H3R-induced activation of ERK phosphorylation occurred only in striatal slices of mice expressing the D1R but not in mice gene-deleted for the D1R.…”

“…Although traditionally G protein-coupled receptors (GPCRs), such as the dopamine receptors, have been depicted as monomeric entities, it is now widely accepted that GPCRs exist as oligomeric complexes (George et al, 2002;Milligan, 2004;Terrillon and Bouvier, 2004), and homomerization has been repeatedly shown to have a critical involvement in important cellular processes, such as receptor translocation to the plasma membrane (Hague et al, 2004;Karpa et al, 2000;Kong et al, 2006;López-Giménez et al, 2007;Salahpour et al, 2004;White et al, 1998). In addition, the discovery that dopamine receptors could form heteromeric complexes (Baragli et al, 2007;Ferrada et al, 2008Ferrada et al, , 2009Ginés et al, 2000;Hillion et al, 2002;Lee et al, 2004;Marcellino et al, 2008a;Marcellino et al, 2008b;Scarselli et al, 2001;Torvinen et al, 2005) has opened up novel avenues of research for drug discovery, as many of these receptor heteromers may exhibit discrete distributions in brain with pharmacological and functional properties distinct from their constituent receptors. For example, the dopamine D1-D2 receptor heteromer was first identified in rat striatum and shown to couple to the Gq/11 protein, a finding that effectively linked dopamine directly to calcium signaling in brain (Rashid et al, 2007a).…”