Comparison of the Effects of Deramciclane, Ritanserin and Buspirone on Extracellular Dopamine and Its Metabolites in Striatum and Nucleus Accumbens of Freely Moving Rats

Abstract

Abstract:In the present study, we assessed the effect of single graded doses of a putative anxiolytic compound, the 5-HT 2A/C antagonist, deramciclane fumarate (EGIS-3886), on the dopamine efflux and metabolism in nucleus accumbens and striatum and thus evaluated the dose window for deramciclane to cause adverse effects related to the brain dopaminergic system. Dual probe in vivo microdialysis in freely moving rats was used to compare the effects of graded doses of deramciclane fumarate (3, 10 and 30 mg/kg), 5-HT 2A/C antagonist ritanserin (1 mg/kg) and a partial 5-HT 1A agonist buspirone hydrochloride (5 mg/kg) on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens and striatum assayed by high performance liquid chromatography with electrochemical detection. The indirect dopamine agonist, D-amphetamine sulfate (2 mg/kg), was used as a positive control. Ritanserin, buspirone and deramciclane 3 and 10 mg/kg had no significant effects on the extracellular dopamine levels in either brain area but deramciclane 30 mg/kg significantly increased accumbal dopamine as well as DOPAC and HVA in both brain areas. As expected, the positive control D-amphetamine significantly increased both striatal and accumbal dopamine levels. The effects of buspirone or the highest deramciclane dose and D-amphetamine on DOPAC and HVA levels were opposite; buspirone and deramciclane increased while D-amphetamine decreased the metabolite levels in both brain areas. The results indicate that a single high dose of deramciclane has the neuroleptic-or buspirone-like effect, particularly in mesolimbic regions. There is at least a 5-fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat.The major serotonergic pathway originating from the raphe nuclei of the brainstem and projecting to the forebrain, including limbic and nigrostriatal systems, is believed to play a role in anxiety [1,2]. The results of early studies based on lesions of serotonergic system and 5-hydroxytryptamine (5-HT) ligands are conflicting, but the development of rather subtype-selective 5-HT receptor antagonists and agonists has enabled more precise functional studies in that field [3 -8].In general, 5-HT 2 receptors have been identified as mediators of anxiolytic-like drug effects [9,10]. 1-(3-Chlorophenyl)piperazine (mCPP), which is predominantly a 5-HT 2C receptor agonist, has been shown to induce anxiety and panic attacks both in animal models and in man [11,12]. In contrast, 5-HT 2C antagonists, like ritanserin, have shown anxiolytic activity in animal models and also in man [12][13][14][15][16][17]. Ritanserin displays high affinity for 5-HT 2A and 5-HT 2C receptors [14,18] and its affinity for 5-HT 1A , dopaminergic D 2 , and adrenergic α 1 and α 2 receptors is 1/100 or less of that for 5-HT 2 receptors [19]. However, none of the 5-HT 2 antagonists has been launched for clinical use as an anxiolytic drug.The partial 5-HT 1A agonist buspirone is the only notable non-benz...

Combined ipsilateral limb use score as an index of motor deficits and neurorestoration in parkinsonian rats

“…The tissue samples were frozen and stored at −70° C until being analyzed. DA levels in both striata were analyzed by a high performance liquid chromatography (HPLC) method with electrochemical detection (ECD) as previously described (Kääriäinen et al, ). The following modifications were made to adapt the method for tissue homogenate matrix.…”

Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans

“…It could also be speculated that because of the higher affinity of endogenous DA for the DRD 3 (vs DRD 2 ), increases in DA would have interfered with buspirone in ƒD 3 more so than in ƒD 2 . However, several studies reported no significant effects of buspirone on DA release using microdialysis in striatal areas in rats (Kaariainen et al, 2008;Liu et al, 2004). In addition, the elevation of DA induced by acute antipsychotics is in the range of 100% (Ichikawa and Meltzer, 1991), and therefore it is unlikely that potential elevation of DA induced by buspirone would lead to significant occupancy of receptors as assessed by PET (Martinez and Narendran, 2010).…”

Therapeutic doses of buspirone block D3 receptors in the living primate brain

“…The attribution of buspirone-induced changes in (Rabiner et al, 2009), and (2) buspirone increases extracellular dopamine, which may differentially affect the binding of the two radiotracers (Gobert et al, 1999;Kaariainen et al, 2008 (Rabiner et al, 2009), which we attribute to both a small degree of D 2 R binding but also competition from endogenous dopamine released by buspirone (Gobert et al, 1999;Kaariainen et al, 2008). We also cannot exclude underestimation of D 3 R occupancy due to the presence of D 3 R in CB (Ginovart et al, 2007;Rabiner et al, 2009), which could affect occupancy measures when using [ 11 C]PHNO (Searle et al, 2013).…”