December 2013 Biol. Pharm. Bull. 36(12) 1871–1882 (2013) 1871 Review Neuropharmacologic Studies on the Brain Serotonin1A Receptor Using the Selective Agonist Osemozotan Toshio Matsudaa,b a Laboratory of Medicinal Pharmacology, Osaka University Graduate School of Pharmaceutical Sciences; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan: and b Kanazawa University, Hamamatsu University School of Medicine, Chiba University, University of Fukui, Osaka Univeristy United Graduate School of Child Development; 2–2 Yamada-oka, Suita, Osaka 565–0871, Japan. Received August 13, 2013 Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuro- psychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodula- tory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and antidepressant effects and improves abnormal behaviors such as aggressive behavior and deficits of prepulse inhibition in isolation-reared mice. We also demonstrated that spinal 5-HT1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced ab- normal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encoun- ter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan at- tenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT1A receptor and other receptors. This review summarizes the neuropharmacology of the 5-HT1A receptor, focusing on our studies using osemozotan, and suggests that the 5-HT1A receptor may be a target molecule for the treatment of psychiatric disorders, pain, and drug depen- dence. Key words serotonin1A receptor; osemozotan; isolation rearing; depression; anxiety; aggression 1. INTRODUCTION Among the 14 known serotonin (5-HT) receptor subtypes, the 5-HT1A receptor has received a great deal of attention mainly because it is implicated in anxiety and depression.1–4) 5-HT1A receptors are located both pre- and postsynaptically. Presynaptic 5-HT1A receptors (as somadendritic 5-HT1A au- toreceptors) are present on serotonergic neurons in the dorsal Fig. 1. Chemical Structure of Osemozotan (5-[3-{(2S)-(1,4-benzodiox- and medial raphe nuclei, and postsynaptic 5-HT1A receptors an-2-ylmethyl)amino}propoxy]-1,3-benzodioxol Hydrochloride) are found at high density in the limbic regions and in the frontal and entorhinal cortices.5,6) They couple negatively via G-proteins to adenylate cyclase in the hippocampal tissue useful to study the pathological role of the 5-HT1A receptor. 7,8) and cell lines stably expressing the cloned 5-HT1A receptor, Using this psychiatric disorder model, we studied the neuro- and their activation causes neuronal hyperpolarization, an pharmacological effects of osemozotan. effect mediated through the G-protein-coupled opening of the Selective 5-HT reuptake inhibitors (SSRIs) are widely used + 9,10) K channels. The effects of 5-HT1A receptor agonists on as first-line treatment of depression, but about 30–50% of pa- animal behaviors have been extensively studied, since the ago- tients do not initially respond to SSRIs.33,34) Clinical reports nists show antidepressant-like and anxiolytic-like effects.1–4) show that combination therapy with an SSRI and antipsy- We developed the novel 5-HT1A receptor agonist (S)-5-[3-[(1,4- chotic drug is effective in patients with treatment-resistant benzodioxan-2-ylmethyl) amino] propoxy]-1,3-benzodioxole depression,35–38) but the neurochemical basis for the effective- HCl (MKC-242, called osemozotan)11,12) (Fig. 1). ness of combination therapy is not known. It is likely that the Rearing rats or mice in social isolation produces behavioral antidepressant-like effect of SSRIs is mediated by the activa- 13–17) 18–21) changes such as hyperactivity, anxiety-like behavior, tion of the 5-HT1A receptor, since SSRIs increase extracellular 22,23) 24) depression, aggression, deficits of prepulse inhibi- levels of 5-HT, which interacts with the 5-HT1A receptor. On tion,25–27) and reduced pain sensitivity to noxious stimuli.28–30) the other hand, fluvoxamine, an SSRI, has an affinity for the 39) 40) These findings suggest that isolation-reared animals reflect σ1 receptor, which may be involved in cognitive function. certain aspects of human psychopathologies such as anxiety, First, we studied the effects of combined fluvoxamine and the 31,32) depression, and schizophrenia. Therefore, this model is dopamine (DA)-D2 antagonist sulpiride on brain monoamine release and second, the involvement of the σ1 receptor in the The author declares no conflict of interest. effects of fluvoxamine. Subsequent studies using osemozotan e-mail: [email protected] © 2013 The Pharmaceutical Society of Japan 1872 Vol. 36, No. 12 showed that prefrontal DA release is enhanced by functional receptors. It should be noted that the regulation of DA release interaction of 5-HT1A and DA-D2 or σ1 receptors. This review by 5-HT1A receptor agonists is region specific; stimulation was summarizes the neuropharmacology of the 5-HT1A receptor observed in the hippocampus and cerebral cortex but not in based on studies using the receptor agonist osemozotan. the striatum. Osemozotan showed the pharmacological profile of a 2. NEUROCHEMICAL AND PHARMACOLOGICAL 5-HT1A agonist as described above. That is, systemic ad- EFFECTS OF OSEMOZOTAN ministration of osemozotan inhibited anxiety-like12,62) and depression-like behaviors.12,63,64) Furthermore, it inhibited 65–67) 68) Progress in the pharmacology of 5-HT1A receptors was aggressive and obsessive–compulsive behaviors. These driven by the early identification of a selective 5-HT1A recep- results support the idea that the 5-HT1A receptor is a potential tor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH- target for the treatment of psychiatric disorders. DPAT) and the discovery that the 5-HT1A receptor agonist azapirone compounds were anxiolytic and antidepressant in 3. DIFFERENCE IN AFFINITY FOR LIGANDS BE- 41,42) a clinical setting. A number of compounds were devel- TWEEN PRESYNAPTIC AND POSTSYNAPTIC 5-HT1A oped as 5-HT1A receptor agonists and antagonists, but so far RECEPTORS 43,44) only a few have been clinically effective. 5-HT1A recep- tor agonists not only produce anxiolytic, antidepressant, and There are differences in the G-protein coupling between 45–47) 48,49) hypothermic effects, but also alter feeding behavior, pre- and postsynaptic 5-HT1A receptors. The presynaptic 50–52) 53,54) sexual behavior, and pain modulation. Using the 5-HT1A receptors are considered to play a role in not only the 11) 69,70) selective 5-HT1A receptor agonist osemozotan, we studied anxiolytic effect of 5-HT1A receptor agonists but also the the roles of the 5-HT1A receptor in the brain. Osemozotan augmentation of SSRI therapy by the mixed 5-HT1A receptor/ is about 500-fold to more than 1000-fold more active at the β-adrenoceptor antagonist, pindolol.71–73) For this reason, it 5-HT1A site than at the 5-HT2A, 5-HT1B, 5-HT2C, 5-HT3, α2- is important to study the regulation of pre- and postsynaptic 11) adrenergic, and DA-D1 sites. Furthermore, this compound 5-HT1A receptors to understand not only the action of 5-HT1A 55) interacts in vivo with 5-HT1A receptors in the brain. In vivo receptor agonists but also the antidepressant effect of coad- administration of osemozotan, unlike azapirone compounds, ministering an SSRI and a 5-HT1A receptor antagonist. The does not produce the metabolite 1-(2-pyrimidinyl) piperazine, role of the presynaptic 5-HT1A receptors has been studied by which antagonizes the antidepressant effect of 8-OH-DPAT.12) chemical lesion with the 5-HT neuronal toxin 5,7-dihydroxy- Therefore, it should be noted that osemozotan is a suitable tryptamine or the 5-HT synthesis inhibitor p-chlorophenyl- 5-HT1A receptor agonist for in vivo experiments. The 5-HT1A alanine. Treatment with these drugs decreases 5-HT levels in receptor is expressed both presynaptically as an autoreceptor the brain markedly but not completely. Therefore, the strategy by 5-HT-containing neurons and postsynaptically by a variety cannot exclude the possibility that serotonergic neurons are of other neurons; the effects of 5-HT1A receptor agonists are still present. It is also likely that treatment upregulates post- then mediated by presynaptic or postsynaptic 5-HT1A recep- synaptic 5-HT receptors. Alternatively, local application of tors (Fig. 2). Activation of 5-HT1A receptors affects the release the agonists in discrete regions of the brain such as the dorsal of not only 5-HT but also of other neurotransmitters such as raphe and limbic regions is also used to study the roles of pre- noradrenaline (NA), DA, and acetylcholine (ACh). That is, synaptic and postsynaptic 5-HT1A receptors, respectively. This 5-HT1A receptors have the effect of inhibitory regulation on strategy, however, is difficult in small animals like mice. the release of 5-HT and stimulatory regulation on the release In these circumstances, we found in mice that presynaptic 56,57) 58) of NA, DA, and ACh. The regulation of 5-HT and ACh and postsynaptic 5-HT1A receptors differed in sensitivity to is mediated by presynaptic 5-HT1A receptors, and that of the 5-HT1A receptor antagonist WAY100635; a low dose of 59,60) 61) NA or DA release is mediated by postsynaptic 5-HT1A WAY100635 blocked the 5-HT1A receptor agonist-induced Fig. 2. Neurochemical Profiles of Presynaptic and Postsynaptic 5-HT1A Receptor Activation Activation of the presynaptic 5-HT1A receptor inhibits 5-HT release and facilitates ACh release, while that of the postsynaptic 5-HT1A receptor facilitates the release of NA and DA.