Histamine H3 receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa-derived extracellular dopamine in dopamine-denervated rat striatum

Abstract

To explore a recently established association between histaminergic and dopaminergic neuronal phenotypic systems in brain, we determined the effect of the respective histaminergic H(3) receptor agonist and antagonist/inverse agonist, imetit and thioperamide, on L-DOPA - derived tissue and extracellular DA and metabolite levels in the striatum of 6-hydroxydopamine (6-OHDA) - lesioned rats (i.e., parkinsonian rats). We also examined the influence of histamine H(3) ligands on L-DOPA evoked behavioral responses (locomotor activity, number of rearings, stereotyped behavior and motor coordination). Using HPLC/ED and in vivo microdialysis technique imetit (5 mg/kg, i.p.) but not thioperamide (5 mg/kg, i.p.) was shown to attenuate an L-DOPA-evoked (15 mg/kg, i.p.; carbidopa, 30 min pretreatment) increase in extracellular DA in the neostriatum of 6-OHDA-lesioned rats. However, both imetit and thioperamide increased microdialysate levels of DOPAC and HVA, probably by enhancing intraneuronal DA utilization. As indicated by neurochemical analysis of the striatum imetit produced a decrease in tissue DA content. These findings support the hypothesis that central H(3) histaminergic receptors have a modulatory role in the storage, metabolism and release of DA derived from exogenous L-DOPA challenge. Furthermore, evidence from behavioral studies indicate that histamine H3 receptor blockade markedly improved motor coordination. Conversely, histamine H(3) receptor stimulation, being without effect on motor coordination, enhanced vertical activity in rats. From the above we conclude that the histamine H(3) agonism may augment motor dyskinesia in Parkinson's disease (PD) patients and presumably worsen L-DOPA therapy. Consequently, the histaminergic system represents a viable target for modulating the effectiveness of L-DOPA therapy in Parkinson's disease.

Histaminergic Activity in a Rodent Model of Parkinson’s Disease

“…As indicated by biochemical analysis, basal the histamine level was greatly altered in 6-OHDA-lesioned rats. It is noteworthy that in our recently published findings, thioperamide improved motor coordination in the rota-rod test in 6-OHDA rats and at the same time did not alter DA exocytosis in the striatum after L-DOPA (15 mg/kg IP) treatment (Nowak et al 2008a), while imetit did. In summary, the histamine H 3 receptor may represent a viable target for attenuation of motor disability in Parkinson's disease, either through direct action or via its ability to modulate the release of other neurotransmitters such as serotonin.…”

Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study

“…This finding is consistent with previous observations. It was reported that thioperamide potentiated L-dopa-and methamphetamineinduced DA release in striatum and nucleus accumbens, respectively (Munzar et al 2004;Nowak et al 2008). Other antagonists of H 3 receptors, ABT-239 and GSK189254, increased DA levels in PFC and cingulate cortex, respectively (Fox et al 2005;Medhurst et al 2007).…”

Acute l-DOPA Effect on Hydroxyl Radical- and DOPAC-Levels in Striatal Microdialysates of Parkinsonian Rats

“…These findings are in line with our previous studies in which we showed that the baseline striatal extraneuronal (i.e., microdialysate) level of DA in 6-OHDA-lesioned rats varied between 3.2 and 3.6 pg/20 ll and that L-DOPA acutely produced a gradual increase in the microdialysate DA concentration, up to 160 pg/20 ll at 180 min, with a concomitant rise in DOPAC levels (from *0.65-0.75 ng/20 ll to *25 ng/20 ll) (Nowak et al 2008). Additionally, L-DOPA-derived DA in the in vivo microdialysates is several-fold higher in DA-denervated versus intact striatum (Kostrzewa et al 2005).…”