December 2013 Biol. Pharm. Bull. 36(12) 1871–1882 (2013) 1871 Review

Neuropharmacologic Studies on the Brain Serotonin1A Receptor Using the Selective 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 (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 modulate the release of amine through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and 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 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 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 -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, , 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 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, .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), 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 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 (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. The presynaptic 5-HT1A receptor has higher affinities for ligands than the postsynaptic 5-HT1A receptor. December 2013 1873 decrease in cortical 5-HT release, a presynaptic 5-HT1A recep- terase inhibitors and ACh receptor agonists have the thera- 80) tor-mediated response, but not the 5-HT1A receptor agonist- peutic potential to improve such deficits. We have recently induced increase in the DA release, a postsynaptic 5-HT1A reported that galantamine, but not donepezil, improved social receptor-mediated response74) (Fig. 2). Using WAY100635, we isolation-induced prepulse inhibition disruption in mice81–84) demonstrated that presynaptic 5-HT1A receptors play a key (Fig. 3). To determine whether the isolation-induced prepulse role in the hypothermic (unpublished) and anxiolytic effects of inhibition deficits may be due to dysfunction of the choliner- osemozotan in mice.62) gic system in isolation-reared mice, we examined the effect of isolation rearing on brain cholinergic functions.84) There 4. ANIMAL MODELS were no significant differences in the choline acetyltransfer- ase and acetylcholinesterase activities and basal extracellular

To clarify the role of the 5-HT1A receptor as a potential tar- ACh levels between group- and isolation-reared mice. How- get for the treatment of psychiatric disorders, we studied the ever, by measuring the cholinergic receptor agonist-induced effects of osemozotan in mouse models such as isolation rear- behavioral responses, we found that the muscarinic receptor ing, chronic corticosterone treatment, and psychostimulant-in- function is reduced in isolation-reared mice. These observa- duced behavioral sensitization. These models appear to reflect tions suggest that muscarinic, especially M1, but not nicotinic, the conditions of patients with schizophrenia, treatment-resis- receptor function is reduced in isolation-reared mice. The tant depression, and drug dependence, respectively. proposed mechanism for the effect of galantamine on isolation 4.1. Neurochemical Basis of Isolation Rearing-Induced rearing-induced prepulse inhibition deficits is summarized in Abnormal Behaviors Isolation-reared rodents show ab- Fig. 3. In addition to the muscarinic effect, galantamine has a normal behaviors in adulthood such as hyperlocomotion, nicotinic effect that increases hippocampal insulin-like growth aggressive behaviors, deficits of prepulse inhibition, cogni- factor 2 expression.85) We also found that the binding of the tive impairments, decreased social contact, depression- and metabotropic glutamate 2/3 receptor antagonist [3H] LY341495 anxiety-like behaviors, and reduced pain sensitivity, as in the prefrontal cortex, cerebral cortical layers I–III, and hip- mentioned above. The results of previous studies indicated pocampus was significantly increased by rearing in social iso- that the functions of neurons are altered in lation and that the antagonists decreased the immobility time isolation-reared animals, although measurements of tissue and of isolation-reared mice in the forced swim test.86) These ob- extracellular levels in selected brain regions servations suggest that the glutamate system is also involved have produced inconsistent results.43,75) Furthermore, studies in depression-like behavior in the isolation-rearing model. using in vivo microdialysis provide more direct information on 4.2. Effect of Osemozotan on Abnormal Behaviors in monoaminergic neuronal activity in selected brain regions of Isolation-Reared Mice Postmortem studies showed that isolation-reared rats. Isolation rearing increases basal levels of 5-HT1A receptors are increased in the prefrontal cortex of extracellular DA in the nucleus accumbens of rats76) and in the schizophrenic patients.87,88) Microdialysis studies found that 66) prefrontal cortex of mice, although inconsistent results were 5-HT1A receptor agonists increase DA release in the frontal also reported in rats.77,78) In addition, isolation rearing en- hances DA release induced by footshock, contextual stimulus, and in rats.76–78) We found that isolation rear- ing specifically affects dopaminergic neurons in the frontal cortex in mice.79) That is, isolation rearing causes a selective enhancement of mesocortical dopaminergic activity, resulting in an imbalance between the monoaminergic neurotransmit- ter systems. This neurochemical change may contribute to isolation-induced abnormal behavior such as high spontaneous locomotor activity or aggressive behavior. We also showed that isolation rearing not only enhances mesocortical dopa- minergic activity but also reduces the response of dopaminer- gic, but not adrenergic and serotonergic, neurons to 5-HT1A receptor activation. In other words, the administration of

5-HT1A agonists activates brain adrenergic and serotonergic, but not dopaminergic, neurons in isolation-reared mice. This observation suggests that the administration of 5-HT1A recep- tor agonists improves the impaired balance of mesocortical monoaminergic neurotransmitter systems in isolation-reared mice. It is likely that an imbalance between monoaminergic Fig. 3. Proposed Mechanism of the Effect of Galatanamine on Isolation neurotransmitter systems may be the neurochemical basis for Rearing-Induced Deficits of Prepulse Inhibition in Mice isolation-induced abnormal behavior, and counteracting this Galantamine-induced increase in ACh levels is inhibited by the DA-D1 receptor antagonist SCH23390. Galantamine improves prepulse inhibition deficits in social imbalance by 5-HT1A receptor activation partly contributes to isolation-reared mice in an M1 receptor-dependent manner, since the muscarinic the attenuation of isolation-induced abnormal behavior. receptor antagonist scopolamine and the specific M1 muscarinic receptor antago- In contrast to the DA and NA systems, there is little infor- nist telenzepine antagonize the effect of galantamine, and the muscarinic receptor agonist oxtremorine and the M1 muscarinic receptor agonist N- mation on the cholinergic system in isolation-reared rodents.50) improve isolation rearing-induced prepulse inhibition deficits. Rearing in isolation decreases muscarinic, especially M1, receptor function and the reduced muscarinic A disruption of cerebral cholinergic pathways may contribute receptor function may be involved in prepulse inhibition deficits in isolation-reared to the cognitive deficits of schizophrenia, and - mice. 1874 Vol. 36, No. 12

Fig. 4. Prefrontal DA and 5-HT Responses to Encounter Stimulation in Isolation-Reared Mice Male isolation-reared mice show enhanced encounter-induced increases in c-Fos expression in the prefrontal cortex (PFC), dorsal raphe nucleus (DRN), and ventral tegmental area (VTA). Microdialysis study also shows that encounter stimulation increases prefrontal DA and 5-HT release in isolation-reared mice. The increased prefrontal 5-HT levels are blocked by , osemozotan, and LY379268, whereas increased prefrontal DA levels are only blocked by diazepam and LY379268. The pharmacologic approach suggests that psychologic stress specifically activates the prefrontal DA and 5-HT systems, and the 5-HT system plays a key role in the induction of abnormal behaviors in male isolation-reared mice. cortex in rats61,89) and mice.79) In addition, atypical neurolep- changes were observed both during and after the encounters, 90,91) tics have affinity for 5-HT1A receptors, and and it is likely that the changes are related to both psychologi- increases ACh release in a 5-HT1A receptor-mediated mecha- cal and physical stress. 92) nism. These observations suggest that 5-HT1A receptors are We have recently tried to identify the primary neurochemi- implicated in the pathophysiology of schizophrenia. In this cal changes for induction of abnormal behaviors in isolation- regard, we showed that osemozotan reversed prepulse inhibi- reared mice101) (Fig. 4). This study used a cage that was di- tion deficits in isolation-reared mice.93) We also observed that vided into two compartments (large and small) by a mesh par- the effect of osemozotan on prepulse inhibition deficits was tition, and we examined the effects of intruder encounters on blocked by a low dose of WAY100635, suggesting the involv- c-Fos expression and the levels of DA and 5-HT in the brain ment of presynaptic 5-HT1A receptors, since the presynaptic regions of resident mice reared in a group or in isolation. 5-HT1A receptors are more sensitive to WAY100635 than the We found that the encounter stimulation increased prefrontal postsynaptic 5-HT1A receptors. Activation of the presynap- c-Fos expression, DA levels, and 5-HT levels in male isola- tic 5-HT1A receptors results in a reduction in the firing rate tion-reared mice, while it did not affect the c-Fos expression, of serotonergic neurons and suppression of 5-HT synthesis, DA, or 5-HT levels in group-reared mice. The important find- 5-HT turnover, and 5-HT release in the projection areas.2) ing was that encounter-induced increases in c-Fos expression This causes a reduction in signaling via all subtypes of 5-HT in the dorsal raphe nucleus and ventral tegmental area, but receptor at the target cells. Therefore, presynaptic 5-HT1A not nucleus accumbens shell, are much greater in isolation- receptor activation may improve isolation rearing-induced reared than group-reared mice. Furthermore, osemozotan, the changes in brain dopaminergic neurons,61,79) which play a role metabotropic glutamate 2/3 receptor agonist MGS0028, and in prepulse inhibition deficits.11) the γ-aminobutyric acid-A receptor agonist diazepam attenuat- 65,66,93,102) 5-HT1A receptor agonists reduce not only prepulse inhibi- ed isolation-induced abnormal behaviors and encoun- tion deficits but also aggressive behavior in isolation-reared ter-induced hyperactivity, c-Fos expression in the prefrontal rodents,71,72,93–98) although the exact mechanism is not known. cortex and dorsal raphe nucleus, and increases in prefrontal Since aggressive behaviors and social interaction deficits in 5-HT levels.100) These findings suggest that the prefrontal DA isolation-reared rodents are induced by exposure to an intrud- and 5-HT systems are activated by encounter stimulation in er, it is likely that an encounter with an intruder may produce isolation-reared mice, and the encounter-induced activation neurobiological changes for the induction of abnormal behav- of 5-HT system triggers the induction of some abnormal be- iors. In resident-intruder tests, van Erp and Miczek99) reported haviors in male isolation-reared mice (Fig. 4). Although those that encounters with the intruder increased prefrontal and results suggested that the glutamate system is also involved in accumbal DA and decreased cortical 5-HT levels in the resi- the abnormal behavior of isolation-reared mice, it should be dent aggressive rats. Anstrom et al.,100) using fast-scan cyclic noted that metabotropic glutamate 2/3 receptor agonists at- voltammetry and multiunit recording techniques, reported that tenuate hyperactivity, while the receptor antagonists attenuate an aggressive encounter increases phasic DA transmission in depression-like behavior in isolation-reared mice. the mesolimbic pathway in defeated rats. These neurochemical 4.3. Isolation Rearing-Induced Hypoalgesia Previ - December 2013 1875

Fig. 5. Involvement of the Prefrontal DA System in Chronic Corticosterone Administration-Induced and Isolation Rearing-Induced Depressive-Like Behaviors in Mice Chronic corticosterone administration and isolation rearing cause depression-like behavior in mice, and the glucocorticoid receptor (GR) antagonist RU-43044 attenu- ates the abnormal behavior. Moreover, chronic corticosterone administration and isolation rearing enhance dopaminergic neurotransmission in the prefrontal cortex, and RU-43044 reverses this enhanced neurotransmission. It is likely that the prefrontal DA system plays a key role in glucocorticoid responses. ous studies showed that the 5-HT1A receptor is involved in nist RU-43044 reversed the increased immobility time in the the antinociceptive effect of the 5-HT-NA forced swim test.110) The role of the glucocorticoid receptor venlafaxine103) and the antiallodynic effect of the was reported clinically with mifepristone for the treatment 104) 115–117) . Furthermore, F13640 (befiradol), a novel 5-HT1A of psychotic depression. Consistent with the results of receptor agonist, shows analgesic activity in animal models behavioral studies, chronic corticosterone administration and and is currently developed for human use.105,106) These results isolation rearing enhanced dopaminergic neurotransmission support the utility of 5-HT1A receptor activation as an antino- in the prefrontal cortex, and this enhanced neurotransmission ciceptive strategy. Along this line, isolation rearing from post- was reversed by RU-43044110) (Fig. 5). These findings sug- weaning reduces pain sensitivity to noxious thermal stimuli in gest that the prefrontal dopaminergic system is responsible rodents.26–28,107) We have recently demonstrated that isolation for the antidepressant effect of RU-43044. This suggestion is rearing causes activation of the anterior cingulate cortex, peri- in agreement with the recent finding that glucocorticoid acts aqueductal gray matter, and rostral ventromedial medulla in locally within the prefrontal cortex to modulate mesocorti- mice, and that spinal 5-HT1A receptors are involved in isola- cal DA efflux by potentiation of the glutamatergic drive onto tion rearing-induced hypoalgesia in -induced noci- DA neurons in the ventral tegmental area.118) Concerning 108) ception. The intrathecal injection of WAY100635 attenuated the involvement of the 5-HT1A receptor in the corticosterone isolation rearing-induced hypoalgesia in capsaicin-induced model, Czyrak et al. demonstrated that chronic corticosterone nociception, and osemozotan caused analgesia in group-reared administration decreased the 5-HT1A receptor binding in the mice after capsaicin-induced nociception. These findings sug- ventral hippocampus and entorhinal cortex.119) Furthermore, gest that spinal 5-HT1A receptor activation via the descend- Saphier et al. reported that 5-HT1A agonists attenuated the ing serotonergic inhibitory pathway contributes to isolation adrenocortical responses to acoustic stimulation, conditioned rearing-induced hypoalgesia. fear, interleukin-1α and administration.120) Recently, 4.4. Corticosterone Model There are many studies on we have found that chronic corticosterone-treated mice could the effects of in normal animals, but a more be used as an animal model of treatment-resistant depression relevant study is to evaluate the effects of the drugs in para- and that mGlu2/3 receptor antagonists had an antidepressant- digms designed to mimic symptoms of human depression.109) like effect in this model.121) This study also suggested that As shown above, mice reared in isolation show increased the prefrontal dopaminergic system is involved in the anti- spontaneous locomotor activity, aggressive behavior, anxiety depressant-like effect of mGlu2/3 receptor antagonists in the behavior, and deficits in prepulse inhibition.17,65,67,81,93) We depression model. We also found that prefrontal dopaminergic also found that isolation rearing increased immobility time in neurotransmission is involved in glucocorticoid receptor- the forced swim test in mice.110) Animal models of repeated mediated modulation of methamphetamine (METH)-induced stress exposure simulate the presumed etiology of depression, hyperactivity.122) and this stress may be produced by exogenous corticosterone 4.5. Psychostimulant-Induced Behavioral Sensitiza- administration.111–114) Thus, chronic corticosterone administra- tion METH is a central nervous system stimulant, and tion, like isolation rearing,110) provides a reliable rodent model its prolonged use results in dependence and psychosis that of depression for studies on the neurobiological mechanisms are indistinguishable from paranoid-type schizophrenia.123) of depression or antidepressant-like effects. We found that Repeated administration of METH causes a long-lasting, chronic corticosterone administration and isolation rearing augmented locomotor response, called behavioral sensitiza- increased immobility time in the forced swim and tail suspen- tion,124,125) which is one of the animal models of METH de- sion tests in mice, and that the glucocorticoid receptor antago- pendence and psychosis. The mesocorticolimbic DA system is 1876 Vol. 36, No. 12

Fig. 6. Effect of Chronic METH Administration on Prefrontal Serotonergic Neurons and Locomotor Activity

Chronic METH administration causes behavioral sensitization and an increase in prefrontal 5-HT release. The 5-HT1A agonist osemozotan inhibits prefrontal 5-HT release and improves METH-induced behavioral sensitization. The 5-HT1A receptor is involved in METH-induced behavioral sensitization, and this receptor is a potential target for the treatment of METH dependence. widely recognized to play an essential role in sensitization to 5. MODULATION OF PREFRONTAL DA RELEASE METH, for which the release and reuptake inhibition of DA BY INTERACTION OF THE 5-HT1A AND OTHER are a primary mechanism mediating the behavioral effects of RECEPTORS the drug, although the behavioral effects of repeated METH administration have also been suggested to be modulated Clinical studies showed that combined therapy with an by other systems including 5-HT.126,127) However, the neuro- SSRI and antipsychotic drug is effective in patients with chemical mechanisms by which 5-HT receptor ligands affect treatment-resistant depression.35–38) We found that the combi- the psychostimulant-induced behavioral effects are unknown. nation of sulpiride and fluvoxamine caused a marked increase We found that repeated METH administration causes not in extracellular DA levels in the prefrontal cortex, while only behavioral sensitization but also enhances a METH sulpiride did not affect the fluvoxamine-induced increases in challenge-induced increase in the extracellular 5-HT levels the 5-HT and NA levels.137) This combined effect of sulpiride in the prefrontal cortex, and that these effects are reversed by and fluvoxamine was blocked by a low dose of WAY100635, a 128) osemozotan (Fig. 6). We also found that , a 5-HT2 5-HT1A receptor antagonist, but not by local application of the receptor antagonist, attenuated METH-induced behavioral antagonist. On the other hand, local application of sulpiride sensitization.129) METH-induced behavioral sensitization in in the cortex, like systemic sulpiride, with systemic fluvox- mice is an animal model for psychostimulant-induced psy- amine increased extracellular levels of DA. These findings chosis and schizophrenia in terms of paranoid psychotic state suggest that a combination of prefrontal DA-D2/D3 blockade 124,130) and relapse liability. Therefore, the results of our study and 5-HT1A receptor activation via 5-HT transporter inhibition imply that 5-HT1A receptor agonists may have a therapeutic in regions other than the cortex increases prefrontal DA re- value for the treatment of METH abuse or psychosis.131) In this lease (Fig. 7). In agreement with the neurochemical effect, the relation, we also found that attenuates acute METH- coadministration of sulpiride and fluvoxamine had an antide- induced hyperactivity and chronic METH-induced behavioral pressant-like effect under the conditions that each drug alone sensitization via modulation of the prefrontal release of DA had no effect.138) Antipsychotic drugs increase prefrontal ACh 132) 139) and 5-HT, respectively. This result suggests that a 5-HT1A release, but this effect is not enhanced by fluvoxamine. 39) receptor-mediated mechanism is involved in the effect of lith- Fluvoxamine has the highest affinity for the σ1 receptors ium on chronic METH-induced behavioral sensitization. The and shows agonistic activity toward the receptors.140–143) A 11 5-HT1A receptor is also involved in cocaine-induced behav- positron emission tomography study using [ C] SA4503, a 133,134) ioral sensitization. With respect to the role of the 5-HT selective σ1 receptor agonist, indicated that high occupancy system in METH-induced hyperactivity, we found that the of σ1 receptors occurs in the brain following the administra- activation of prefrontal mGlu2/3 receptors inhibits the psycho- tion of therapeutic doses of fluvoxamine to healthy male 144) motor stimulant effect of METH in mice, and this effect may volunteers. This suggests that σ1 receptors are involved in 135) be mediated by the prefrontal 5-HT system. This finding the clinical effects of fluvoxamine. σ1 Receptors have a neu- suggests that prefrontal mGlu2/3 receptors are functionally romodulatory role on the neurotransmitter system, including coupled with the serotonergic system. Our recent study has the serotonergic, noradrenergic, dopaminergic, glutamatergic, shown that the mGlu2/3 receptor agonist MGS0028 improves and cholinergic systems, and are related to depression.145–151) abnormal behaviors in pituitary adenylate cyclase activating Previous studies using in vivo microdialysis showed that flu- polypeptide-knockout mice, an experimental model of psychi- voxamine causes a transient increase in the extracellular levels atric disorders.136) of DA and/or NA in the prefrontal cortex,137,152,153) but it is not

known whether σ1 receptors are involved in the neurochemical effect of fluvoxamine.

To investigate the involvement of σ1 receptors in the neu- December 2013 1877

6. CONCLUSION

Progress in the pharmacology of 5-HT1A receptors was made by the identification of a selective 5-HT1A receptor agonist and the finding that the 5-HT1A receptor agonist aza- pirone compounds have anxiolytic and antidepressant effects

in clinical cases. We developed the novel 5-HT1A receptor agonist osemozotan and studied the functional roles of the

receptor in the brain using this compound. 5-HT1A receptors are localized presynaptically or postsynaptically, and their activation affects not only 5-HT release but also DA, NA, and ACh release in the brain. That is, the brain 5-HT system affects other transmitter systems. In this relation, we found that the 5-HT system is also coupled with the glutamate system. Osemozotan improved most abnormal behaviors of Fig. 7. Neurochemical Basis for Combination Therapy with SSRIs and psychiatric disorder models such as isolation rearing, chronic Antipsychotic Drugs corticosterone administration, and chronic psychomotor SSRIs increase extracellular levels of 5-HT, which interacts with the 5-HT1A receptor in brain regions other than the prefrontal cortex, probably the raphe stimulant models. It should be noted that abnormal behaviors nucleus. An antipsychotic drug blocks the DA-D2 receptor. Combined activation of of isolation-reared mice are triggered by transient activation of the 5-HT1A receptor and inhibition of the DA-D2 receptor increases prefrontal DA release, resulting in enhancement of the antidepressant-like effects of SSRIs. the raphe-prefrontal 5-HT system. Studies in animal models suggested that the 5-HT1A receptor is a potential target for the treatment of anxiety, depression, pain, and drug dependence. Studies on fluvoxamine also showed that prefrontal DA release

is regulated by a functional interaction between 5-HT1A and DA-D2 or σ1 receptors. Further studies are required to clarify the pharmacologic significance of the novel regulation mecha- nisms of the DA system.

Acknowledgments I would like to express many thanks to my supervisor, Professor Akemichi Baba (President of Hyogo University of Health Sciences), for his invaluable guid- ance and suggestions. I also thank Drs. Hitoshi Hashimoto, Kazuhiro Takuma, Norito Shintani, and Yukio Ago of Osaka University Graduate School of Pharmaceutical Sciences; Dr. Yutaka Koyama of the Faculty of Pharmacy, Osaka Ohtani Fig. 8. Enhancement of Prefrontal DA Levels by Combined Activation University; and Drs. Michikazu Abe, Kenichi Saito, Mitsuo of 5-HT1A and σ1 Receptors in the Absence of Neurosteroids Egawa and Akihiro Tobe of Mitsubishi Tanabe Pharma Co. Fluvoxamine inhibits the serotonin transporter (SERT) and activates the σ1 re- for their kind support; as well as all graduate students who ceptor. Under the conditions of lower levels of circulating neurosteroids, combined activation of the 5-HT1A receptor and σ1 receptor enhances prefrontal DA release. were involved in the studies for their creative work. This work The 5-HT1A receptor involved in the interaction is localized in brain regions other was supported in part by Grants-in-Aid for Scientific Research than the prefrontal cortex, and the σ receptor is localized in the prefrontal cortex. 1 from the Japan Society for the Promotion of Science. rochemical effects of fluvoxamine, endocrine manipulations REFERENCES were performed.152) Mice were adrenalectomized and castrated to remove the peripheral sources of neuroactive steroids, 1) De Vry J. 5-HT1A receptor agonists: recent developments and con- 154,155) troversial issues. Psychopharmacology (Berl.), 121, 1–26 (1995). which are endogenous ligands for σ1 receptors. Adrenal- ectomy/castration potentiated fluvoxamine-induced increases 2) Barnes NM, Sharp T. A review of central 5-HT receptors and their in the extracellular levels of DA, but not of NA and 5-HT, and function. Neuropharmacology, 38, 1083–1152 (1999). 3) Blier P, Ward NM. Is there a role for 5-HT agonists in the treat- this effect was blocked by BD1047, a σ receptor antagonist.156) 1A 1 ment of depression? Biol. Psychiatry, 53, 193–203 (2003). Moreover, we found that the enhancement of prefrontal do- 4) Lucki I, Singh A, Kreiss DS. Antidepressant-like behavioral paminergic neurotransmission by fluvoxamine is mediated effects of serotonin receptor agonists. Neurosci. Biobehav. Rev., by the activation of 5-HT1A and σ1 receptor activation under 18, 85–95 (1994). 157) circulating neuroactive steroid-deficient conditions (Fig. 8). 5) Pazos A, Palacios JM. Quantitative autoradiographic mapping of It is likely that fluvoxamine exerts its beneficial effect via σ1 serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain receptor-mediated enhancement of prefrontal dopaminergic Res., 346, 205–230 (1985). neurotransmission under neurosteroid-deficient conditions. 6) Vergé D, Daval G, Marcinkiewicz M, Patey A, El Mestikawy S, SSRIs increase extracellular levels of 5-HT, which interacts Gozlan H, Hamon M. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxy- with the receptor subtypes including the 5-HT1A receptor. The two studies on fluvoxamine described above provide novel tryptamine-treated rats. J. Neurosci., 6, 3474–3482 (1986). 7) Saudou F, Hen R. 5-Hydroxytryptamine receptor subtypes in ver- regulation mechanisms of the prefrontal DA release through tebrates and invertebrates. Neurochem. Int., 25, 503–532 (1994). the interaction of 5-HT1A and other receptors. 1878 Vol. 36, No. 12

8) Albert PR, Lembo P, Storring JM, Charest A, Saucier C. The rearing of rats produces a deficit in prepulse inhibition of acous-

5-HT1A receptor: signaling, desensitization, and gene transcription. tic startle similar to that in schizophrenia. Biol. Psychiatry, 34, Neuropsychopharmacology, 14, 19–25 (1996). 361–372 (1993). 9) Nicoll RA, Malenka RC, Kauer JA. Functional comparison of 26) Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Rob- neurotransmitter receptor subtypes in mammalian central nervous bins TW. Social isolation in the rat produces developmentally spe- system. Physiol. Rev., 70, 513–565 (1990). cific deficits in prepulse inhibition of the acoustic startle response 10) Aghajanian GK. Electrophysiology of serotonin receptor sub- without disrupting latent inhibition. Neuropsychopharmacology, types and signal transduction pathways. Psychopharmacolgy: 10, 61–72 (1994). The Fourth Generation of Progress. (Bloom FR, Kupfer DJ eds.), 27) Bakshi VP, Swerdlow NR, Braff DL, Geyer MA. Reversal of isola- Raven Press, New York, pp. 1451—1459 (1995). tion rearing-induced deficits in prepulse inhibition by seroquel and 11) Matsuda T, Yoshikawa T, Suzuki M, Asano S, Somboonthum P, . Biol. Psychiatry, 43, 436–445 (1998). Takuma K, Nakano Y, Morita T, Nakasu Y, Kim HS, Egawa M, 28) Coudereau JP, Monier C, Bourre JM, Frances H. Effect of isola- Tobe A, Baba A. Novel benzodioxan derivative, 5-(3-[((2S)-1,4- tion on pain threshold and on different effects of . Prog. benzodioxan-2-ylmethyl)amino]propoxy)-1,3-benzodioxole HCl Neuropsychopharmacol. Biol. Psychiatry, 21, 997–1018 (1997). (MKC-242), with a highly potent and selective agonist activity at 29) Tuboly G, Benedek G, Horvath G. Selective disturbance of pain

rat central serotonin1A receptors. Jpn. J. Pharmacol., 69, 357–366 sensitivity after social isolation. Physiol. Behav., 96, 18–22 (2009). (1995). 30) Meng Q, Li N, Han X, Shao F, Wang W. Peri-adolescence isolation 12) Abe M, Tabata R, Saito K, Matsuda T, Baba A, Egawa M. Novel rearing alters social behavior and nociception in rats. Neurosci. benzodioxan derivative, 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)- Lett., 480, 25–29 (2010). amino]propoxy]-1,3-benzodioxole HCl (MKC-242), with anxiolyt- 31) Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Phar- ic-like and antidepressant-like effects in animal models. J. Phar- macological studies of prepulse inhibition models of sensorimotor macol. Exp. Ther., 278, 898–905 (1996). gating deficits in schizophrenia: a decade in review. Psychophar- 13) Einon DF, Morgan MJ. Early isolation produces enduring hyperac- macology (Berl.), 156, 117–154 (2001). tivity in the rat, but no effect upon spontaneous alternation. Q. J. 32) Willner P. The validity of animal models of depression. Psycho- Exp. Psychol., 30, 151–156 (1978). pharmacology (Berl.), 83, 1–16 (1984). 14) Gentsch C, Lichtsteiner M, Feer H. Locomotor activity, defecation 33) Ferrier IN. Treatment of major depression: is improvement score and corticosterone levels during an open-field exposure: a enough? J. Clin. Psychiatry, 60 (Suppl. 6), 10–14 (1999). comparison among individually and group-housed rats, and geneti- 34) Nelson JC. A review of the efficacy of serotonergic and noradren- cally selected rat lines. Physiol. Behav., 27, 183–186 (1981). ergic reuptake inhibitors for treatment of major depression. Biol. 15) Gentsch C, Lichtsteiner M, Feer H. Behavioural comparisons be- Psychiatry, 46, 1301–1308 (1999). tween individually- and group-housed male rats: effects of novel 35) Barbui C, Hotopf M. v. the rest: still the leading environments and diurnal rhythm. Behav. Brain Res., 6, 93–100 antidepressant after 40 years of randomized controlled trials. Br. J. (1982). Psychiatry, 178, 129–144 (2001). 16) Wright IK, Ismail H, Upton N, Marsden CA. Effect of isolation 36) O’Connor M, Silver H. Adding risperidone to selective serotonin rearing on 5-HT agonist-induced responses in the rat. Psychophar- reuptake inhibitor improves chronic depression. J. Clin. Psycho- macology (Berl.), 105, 259–263 (1991). pharmacol., 18, 89–91 (1998), letter. 17) Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, 37) Ostroff RB, Nelson JC. Risperidone augmentation of selective Hedou G, Feldon J, Moran MC, Nelson P. Behavioral, neurochemi- serotonin reuptake inhibitors in major depression. J. Clin. Psychia- cal and endocrinological characterization of the early social isola- try, 60, 256–259 (1999). tion syndrome. Neuroscience, 100, 749–768 (2000). 38) Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs 18) Hall FS, Huang S, Fong GW, Pert A, Linnoila M. Effects of iso- TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman lation-rearing on locomotion, anxiety and responses to ethanol in PD, Meltzer HY. A novel augmentation strategy for treating resis- Fawn Hooded and Wistar rats. Psychopharmacology (Berl.), 139, tant major depression. Am. J. Psychiatry, 158, 131–134 (2001). 203–209 (1998). 39) Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of 19) Ago Y, Takahashi K, Nakamura S, Hashimoto H, Baba A, Ma tsu- selective serotonin reuptake inhibitors with subtypes of σ receptors da T. Anxiety-like and exploratory behaviors of isolation-reared in rat brain. Eur. J. Pharmacol., 307, 117–119 (1996). mice in the staircase test. J. Pharmacol. Sci., 104, 153–158 (2007). 40) Hayashi T, Su TP. σ-1 Receptor ligands: potential in the treatment 20) Maisonnette S, Morato S, Brandao ML. Role of resocialization and of neuropsychiatric disorders. CNS Drugs, 18, 269–284 (2004).

of 5-HT1A receptor activation on the anxiogenic effects induced 41) Middlemiss DN, Fozard JR. 8-Hydroxy-2-(di-n-propylamino)tetra-

by isolation in the elevated plus-maze test. Physiol. Behav., 54, lin discriminates between subtypes of the 5-HT1 recognition site. 753–758 (1993). Eur. J. Pharmacol., 90, 151–153 (1983).

21) Schreiber R, De Vry J. 5-HT1A receptor ligands in animal models 42) Robinson DS, Rickels K, Feighner J, Fabre LF Jr, Gammans RE, of anxiety, impulsivity and depression: multiple mechanisms of Shrotriya RC, Alms DR, Andary JJ, Messina ME. Clinical effects

action? Prog. Neuropsychopharmacol. Biol. Psychiatry, 17, 87–104 of the 5-HT1A partial agonists in depression: a composite analysis (1993). of in the treatment of depression. J. Clin. Psychophar- 22) Hilakivi LA, Ota M, Lister RG. Effect of isolation on brain macol., 10 (Suppl.), 67S–76S (1990). monoamines and the behavior of mice in tests of exploration, lo- 43) Fone KC, Porkess MV. Behavioural and neurochemical effects of comotion, anxiety and behavioral ‘despair.’ Pharmacol. Biochem. post-weaning social isolation in rodents—relevance to develop- Behav., 33, 371–374 (1989). mental neuropsychiatric disorders. Neurosci. Biobehav. Rev., 32, 23) Heritch AJ, Henderson K, Westfall TC. Effects of social isolation 1087–1102 (2008). on brain catecholamines and forced swimming in rats: prevention 44) Lacivita E, Di Pilato P, De Giorgio P, Colabufo NA, Berardi F,

by antidepressant treatment. J. Psychiatr. Res., 24, 251–258 (1990). Perrone R, Leopoldo M. The therapeutic potential of 5-HT1A 24) Potegal M, Einon D. Aggressive behaviors in adult rats deprived of receptors: a patent review. Expert Opin. Ther. Pat., 22, 887–902 playfighting experience as juveniles. Dev. Psychobiol., 22, 159–172 (2012). (1989). 45) Matsuda T, Kanda T, Seong YH, Baba A, Iwata H. p-Chloro- 25) Geyer MA, Wilkinson LS, Humby T, Robbins TW. Isolation phenylalanine attenuates the pituitary-adrenocortical response December 2013 1879

to 5-HT1A receptor agonists in mice. Eur. J. Pharmacol., 181, 63) Matsuda T, Somboonthum P, Suzuki M, Asano S, Baba A. Anti-

295–297 (1990). depressant-like effect by postsynaptic 5-HT1A receptor activation 46) Bill DJ, Knight M, Forster EA, Fletcher A. Direct evidence for an in mice. Eur. J. Pharmacol., 280, 235–238 (1995). important species difference in the mechanism of 8-OH-DPAT- 64) Abe M, Saito K. Reduction of wrap restraint stress-induced def-

induced hypothermia. Br. J. Pharmacol., 103, 1857–1864 (1991). ecation by MKC-242, a novel benzodioxan derivative, via 5-HT1A- 47) Millan MJ, Rivet JM, Canton H, Le Marouille Girardon S, Gobert receptor agonist action in rats. Jpn. J. Pharmacol., 77, 211–217

A. Induction of hypothermia as a model of 5-hydroxytryptamine1A (1998). receptor-mediated activity in the rat: a pharmacological character- 65) Sakaue M, Ago Y, Murakami C, Sowa C, Sakamoto Y, Koyama ization of the actions of novel agonists and antagonists. J. Pharma- Y, Baba A, Matsuda T. Involvement of binding

col. Exp. Ther., 264, 1364–1376 (1993). sites in an antiaggressive effect by 5-HT1A receptor activation in 48) Hartley JE, Fletcher A. The effects of WAY-100135 and 8-hydroxy- isolated mice. Eur. J. Pharmacol., 432, 163–166 (2001). 2-(di-n-propylamino)tetralin on feeding in the rat. Eur. J. Pharma- 66) Matsuda T, Sakaue M, Ago Y, Sakamoto Y, Koyama Y, Baba A. col., 252, 329–332 (1994). Functional alteration of brain dopaminergic system in isolated ag- 49) Jhanwar-Uniyal M, Moorjani B, Kahn AH. Indications of pre- and gressive mice. Jpn. J. Neuropsychopharmacol., 21, 71–76 (2001).

post-synaptic 5-HT1A receptor interactions in feeding behavior and 67) Sakaue M, Ago Y, Sowa C, Sakamoto Y, Nishihara B, Koyama Y,

neuroendocrine regulation. Brain Res., 646, 247–257 (1994). Baba A, Matsuda T. Modulation of 5-HT2A receptors of aggressive 50) Uphouse L, Caldarola Pastuszka M. Female sexual behaviour fol- behavior in isolated mice. Jpn. J. Pharmacol., 89, 89–92 (2002).

lowing intracerebral infusion of 5-HT1A agonist, 8-OH-DPAT, into 68) Harasawa T, Ago Y, Itoh S, Baba A, Matsuda T. Role of serotonin the medal preoptic area. Brain Res., 601, 203–208 (1993). type 1A receptors in fluvoxamine-induced inhibition of marble- 51) Pomerantz SM, Hepner BC, Wertz JM. Serotonergic influences on burying behavior in mice. Behav. Pharmacol., 17, 637–640 (2006).

male sexual behavior of rhesus monkeys: effects of serotonin ago- 69) Traber J, Glaser T. 5-HT1A receptor-related . Trends nists. Psychopharmacology (Berl.), 111, 47–54 (1993). Pharmacol. Sci., 8, 432–437 (1987). 52) Uphouse L, Caldarola Pastuszka M, Montanez S. Intracerebral ac- 70) File SE, Gonzalez LE, Andrews N. Comparative study of pre- and

tions of the 5-HT1A agonists, 8-OH-DPAT and buspirone, and of postsynaptic 5-HT1A receptor modulation of anxiety in two etho-

the 5-HT1A /antagonist, NAN-190, on female sexual logical animal tests. J. Neurosci., 16, 4810–4815 (1996). behavior. Neuropharmacology, 31, 969–981 (1992). 71) Blier P, de Montigny C. Current advances and trends in the treat-

53) Colpaert FC. 5-HT1A receptor activation: new molecular and neu- ment of depression. Trends Pharmacol. Sci., 15, 220–226 (1994). roadaptive mechanisms of pain relief. Curr. Opin. Investig. Drugs, 72) Blier P, Bergeron R. Effectiveness of pindolol with selected anti- 7, 40–47 (2006). depressant drugs in the treatment of major depression. J. Clin. 54) Martel JC, Assié MB, Bardin L, Depoortère R, Cussac D, New- Psychopharmacol., 15, 217–222 (1995).

man-Tancredi A. 5-HT1A receptors are involved in the effects of 73) Artigas F, Romero L, de Montigny C, Blier P. Acceleration of on G-protein activation, neurotransmitter release and the effect of selected antidepressant drugs in major depression by

nociception. Br. J. Pharmacol., 158, 232–242 (2009). 5-HT1A antagonists. Trends Neurosci., 19, 378–383 (1996).

55) Asano S, Matsuda T, Yoshikawa T, Somboonthum P, Tasaki H, 74) Ago Y, Koyama Y, Baba A, Matsuda T. Regulation by 5-HT1A Abe M, Baba A. Interaction of orally administered 5-{3-[((2S)-1,4- receptors of the in vivo release of 5-HT and DA in mouse frontal benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole (MKC- cortex. Neuropharmacology, 45, 1050–1056 (2003).

242) with 5-HT1A receptors in rat brain. Jpn. J. Pharmacol., 74, 75) Brenes JC, Rodríguez O, Fornaguera J. Differential effect of 69–75 (1997). environment enrichment and social isolation on depressive-like

56) Hjorth S, Magnusson T. The 5-HT1A receptor agonist, 8-OH- behavior, spontaneous activity and serotonin and DPAT, preferentially activates cell body 5-HT autoreceptors in concentration in prefrontal cortex and ventral striatum. Pharma- rat brain in vivo. Naunyn Schmiedebergs Arch. Pharmacol., 338, col. Biochem. Behav., 89, 85–93 (2008). 463–471 (1988). 76) Hall FS, Wilkinson LS, Humby T, Inglis W, Kendall DA, Marsden

57) Sharp T, Bramwell SR, Grahame-Smith DG. 5-HT1 agonists re- CA, Robbins TW. Isolation rearing in rats: pre- and postsynaptic duce 5-hydroxytryptamine release in rat hippocampus in vivo as changes in striatal dopaminergic system. Pharmacol. Biochem. determined by brain microdialysis. Br. J. Pharmacol., 96, 283–290 Behav., 59, 859–872 (1998). (1989). 77) Jones GH, Hernandez TD, Kendall DA, Marsden CA, Robbins 58) Somboonthum P, Matsuda T, Asano S, Sakaue M, Baba A. TW. Dopaminergic and serotonergic function following isolation

MKC-242, a novel 5-HT1A receptor agonist, facilitates cortical rearing in rats. A study of behavioural responses and postmortem acetylcholine release by a mechanism different from that of 8-OH- and in vivo neurochemistry. Pharmacol. Biochem. Behav., 43, DPAT in awake rats. Neuropharmacology, 36, 1733–1739 (1997). 17–35 (1992). 59) Suzuki M, Matsuda T, Asano S, Somboonthum P, Takuma K, 78) Fulford AJ, Marsden CA. Effect of isolation-rearing on condi- Baba A. Increase of noradrenaline release in the hypothalamus of tioned dopamine release in vivo in the nucleus accumbens of the

freely moving rat by postsynaptic 5-hydroxytryptamine1A receptor rat. J. Neurochem., 70, 384–390 (1998). activation. Br. J. Pharmacol., 115, 703–711 (1995). 79) Ago Y, Sakaue M, Baba A, Matsuda T. Selective reduction by

60) Hajós-Korcsok E, McQuade R, Sharp T. Influence of 5-HT1A isolation rearing of 5-HT1A receptor-mediated dopamine release receptors on central noradrenergic activity: microdialysis studies in vivo in the frontal cortex of mice. J. Neurochem., 83, 353–359 using (±)-MDL 73005EF and its enantiomers. Neuropharmacol- (2002). ogy, 38, 299–306 (1999). 80) Friedman JI. Cholinergic targets for cognitive enhancement in 61) Sakaue M, Somboonthum P, Nishihara B, Koyama Y, Hashimoto schizophrenia: focus on cholinesterase inhibitors and muscarinic

H, Baba A, Matsuda T. Postsynaptic 5-hydroxytryptamine1A recep- agonists. Psychopharmacology (Berl.), 174, 45–53 (2004). tor activation increases in vivo dopamine release in rat prefrontal 81) Koda K, Ago Y, Kawasaki T, Hashimoto H, Baba A, Matsuda T. cortex. Br. J. Pharmacol., 129, 1028–1034 (2000). Galantamine and donepezil differently affect isolation rearing-in- 62) Sakaue M, Ago Y, Sowa C, Koyama Y, Baba A, Matsuda T. The duced deficits of prepulse inhibition in mice. Psychopharmacology

5-HT1A receptor agonist MKC-242 increases the exploratory activ- (Berl.), 196, 293–301 (2008). ity of mice in the elevated plus-maze. Eur. J. Pharmacol., 458, 82) Yano K, Koda K, Ago Y, Kobayashi H, Kawasaki T, Takuma K, 141–144 (2003). Matsuda T. Galantamine improves -induced deficits 1880 Vol. 36, No. 12

in prepulse inhibition via muscarinic ACh receptors in mice. Br. J. mine signaling in the mesolimbic pathway during social defeat in Pharmacol., 156, 173–180 (2009). rats. Neuroscience, 161, 3–12 (2009). 83) Ago Y, Koda K, Ota Y, Kita Y, Fukada A, Takuma K, Matsuda 101) Ago Y, Araki R, Tanaka T, Sasaga A, Nishiyama S, Takuma K, T. Donepezil, but not galantamine, blocks muscarinic receptor- Matsuda T. Role of social encounter-induced activation of prefron- mediated in vitro and in vivo responses. Synapse, 65, 1373–1377 tal serotonergic systems in the abnormal behaviors of isolation- (2011). reared mice. Neuropsychopharmacology, 38, 1535–1547 (2013). 84) Koda K, Ago Y, Yano K, Nishimura M, Kobayashi H, Fukada 102) Ago Y, Araki R, Yano K, Kawasaki T, Chaki S, Nakazato A, Onoe A, Takuma K, Matsuda T. Involvement of decreased muscarinic H, Hashimoto H, Baba A, Takuma K, Matsuda T. The selective receptor function in prepulse inhibition deficits in mice reared in metabotropic glutamate 2/3 receptor agonist MGS0028 reverses social isolation. Br. J. Pharmacol., 162, 763–772 (2011). isolation rearing-induced abnormal behaviors in mice. J. Pharma- 85) Kita Y, Ago Y, Takano E, Fukada A, Takuma K, Matsuda T. col. Sci., 118, 295–298 (2012).

Galantamine increases hippocampal insulin-like growth factor 2 103) Berrocoso E, Mico JA. Role of serotonin 5-HT1A receptors in the expression via α7 nicotinic acetylcholine receptors in mice. Psy- antidepressant-like effect and the antinociceptive effect of venla- chopharmacology (Berl.), 225, 543–551 (2013). faxine in mice. Int. J. Neuropsychopharmacol., 12, 61–71 (2009).

86) Kawasaki T, Ago Y, Yano K, Araki R, Washida Y, Onoe H, Chaki 104) Berrocoso E, De Benito MD, Mico JA. Role of serotonin 5-HT1A S, Nakazato A, Hashimoto H, Baba A, Takuma K, Matsuda T. In- and receptors in the antiallodynic effect of tramadol in the creased binding of cortical and hippocampal group II metabotropic chronic constriction injury model of neuropathic pain in rats. Psy- glutamate receptors in isolation-reared mice. Neuropharmacology, chopharmacology (Berl.), 193, 97–105 (2007). 60, 397–404 (2011). 105) Colpaert FC, Tarayre JP, Koek W, Pauwels PJ, Bardin L, Xu XJ, 87) Hashimoto T, Nishino N, Nakai H, Tanaka C. Increase in sero- Wiesenfeld-Hallin Z, Cosi C, Carilla-Durand E, Assié MB, Vacher

tonin 5-HT1A receptors in prefrontal and temporal cortices of B. Large-amplitude 5-HT1A receptor activation: a new mechanism brains from patients with chronic schizophrenia. Life Sci., 48, of profound, central analgesia. Neuropharmacology, 43, 945–958 355–363 (1991). (2002).

88) Sumiyoshi T, Stockmeier CA, Overholser JC, Dilley GE, Meltzer 106) Colpaert FC. 5-HT1A receptor activation: new molecular and neu-

HY. Serotonin1A receptors are increased in postmortem prefrontal roadaptive mechanisms of pain relief. Curr. Opin. Investig. Drugs, cortex in schizophrenia. Brain Res., 708, 209–214 (1996). 7, 40–47 (2006). 89) Wȩdzony K, Maćkowiak M, Fijal K, Golembiowska K. 107) Coudereau JP, Monier C, Bourre JM, Frances H. Effect of isola-

enhances the dopamine outflow via 5-HT1A receptors in the rat tion on pain threshold and on different effects of morphine. Prog. prefrontal cortex. Eur. J. Pharmacol., 305, 73–78 (1996). Neuropsychopharmacol. Biol. Psychiatry, 21, 997–1018 (1997). 90) Mason SL, Reynolds GP. has sub-micromolar affinity 108) Horiguchi N, Ago Y, Asada K, Kita Y, Hiramatsu N, Takuma K,

for 5-HT1A receptors in human brain tissue. Eur. J. Pharmacol., Matsuda T. Involvement of spinal 5-HT1A receptors in isolation 221, 397–398 (1992). rearing-induced hypoalgesia in mice. Psychopharmacology (Berl.), 91) Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard 227, 251–261 (2013). M, Verriele L, Audinot V, Millan MJ. Agonist and antagonist ac- 109) Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in 35 tions of antipsychotic agents at 5-HT1A receptors: a [ S]GTPγS rodents: recent developments and future needs. Trends Pharmacol. binding study. Eur. J. Pharmacol., 355, 245–256 (1998). Sci., 23, 238–245 (2002). 92) Sato M, Ago Y, Koda K, Nakamura S, Kawasaki T, Baba A, Mat- 110) Ago Y, Arikawa S, Yata M, Yano K, Abe M, Takuma K, Mat-

suda T. Role of postsynaptic serotonin1A receptors in risperidone- suda T. Antidepressant-like effects of the glucocorticoid receptor induced increase in acetylcholine release in rat prefrontal cortex. antagonist RU-43044 are associated with changes in prefrontal Eur. J. Pharmacol., 559, 155–160 (2007). dopamine in mouse models of depression. Neuropharmacology,

93) Sakaue M, Ago Y, Baba A, Matsuda T. The 5-HT1A receptor 55, 1355–1363 (2008). agonist MKC-242 reverses isolation rearing-induced deficit of pre- 111) Gregus A, Wintink AJ, Davis AC, Kalynchuk LE. Effect of re- pulse inhibition in mice. Psychopharmacology (Berl.), 170, 73–79 peated corticosterone injections and restraint stress on anxiety (2003). and depression-like behavior in male rats. Behav. Brain Res., 156, 94) Olivier B, Mos J, van del Heyden J, Hartog J. Serotonergic modu- 105–114 (2005). lation of social interactions in isolated male mice. Psychopharma- 112) Johnson SA, Fournier NM, Kalynchuk LE. Effect of different cology (Berl.), 97, 154–156 (1989). doses of corticosterone on depression-like behavior and HPA axis 95) White SM, Kucharik RF, Moyer JA. Effects of serotonergic agents responses to a novel stressor. Behav. Brain Res., 168, 280–288 on isolation-induced aggression. Pharmacol. Biochem. Behav., 39, (2006). 729–736 (1991). 113) Kalynchuk LE, Gregus A, Boudreau D, Perrot-Sinal TS. Corti- 96) Sánchez C, Arnt J, Hyttel J, Moltzen EK. The role of serotonergic costerone increases depression-like behavior, with some effects on mechanisms in inhibition of isolation-induced aggression in male predator odor-induced defensive behavior, in male and female rats. mice. Psychopharmacology (Berl.), 110, 53–59 (1993). Behav. Neurosci., 118, 1365–1377 (2004). 97) De Boer SF, Lesourd M, Mocaer E, Koolhaas JM. Selective an- 114) Zhao Y, Ma R, Shen J, Su H, Xing D, Du L. A mouse model of tiaggressive effects of in resident-intruder test are depression induced by repeated corticosterone injections. Eur. J.

mediated via 5-hydroxytryptamine1A receptors: a comparative Pharmacol., 581, 113–120 (2008). pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ip- 115) Belanoff JK, Flores BH, Kalezhan M, Sund B, Schatzberg AF. sapirone, buspirone, , and WAY-100635. J. Pharmacol. Rapid reversal of psychotic depression using mifepristone. J. Clin. Exp. Ther., 288, 1125–1133 (1999). Psychopharmacol., 21, 516–521 (2001). 98) Mendoza DL, Bravo HA, Swanson HH. Antiaggressive and anx- 116) DeBattista C, Belanoff J, Glass S, Khan A, Horne RL, Blasey C, iolytic effects of in mice, and their attenuation by WAY Carpenter LL, Alva G. Mifepristone versus placebo in the treat- 100635. Pharmacol. Biochem. Behav., 62, 499–509 (1999). ment of psychosis in patients with psychotic major depression. 99) van Erp AM, Miczek KA. Aggressive behavior, increased accum- Biol. Psychiatry, 60, 1343–1349 (2006). bal dopamine, and decreased cortical serotonin in rats. J. Neuro- 117) Flores BH, Kenna H, Keller J, Solvason HB, Schatzberg AF. Clini- sci., 20, 9320–9325 (2000). cal and biological effects of mifepristone treatment for psychotic 100) Anstrom KK, Miczek KA, Budygin EA. Increased phasic dopa- depression. Neuropsychopharmacology, 31, 628–636 (2006). December 2013 1881

118) Butts KA, Phillips AG. Glucocorticoid receptors in the prefrontal Nakazato A, Onoe H, Hashimoto H, Baba A, Takuma K, Matsuda cortex regulated dopamine efflux to stress via descending gluta- T. Activation of metabotropic glutamate 2/3 receptors attenuates mataergic feedback to the ventral tegmental area. Int. J. Neuropsy- methamphetamine-induced hyperlocomotion and increase in chopharmacol., 16, 1799–1807 (2013). prefrontal serotonergic neurotransmission. Psychopharmacology 119) Czyrak A, Maćkowiak M, Chocyk A, Fijał K, Gądek-Michalska A, (Berl.), 217, 443–452 (2011). Wędzony K. 8-OHDPAT-induced disruption of prepulse inhibition 136) Ago Y, Hiramatsu N, Ishihama T, Hazama K, Hayata-Takano in rats is attenuated by prolonged corticosterone treatment. Neuro- A, Shibasaki Y, Shintani N, Hashimoto H, Kawasaki T, Onoe psychopharmacology, 28, 1300–1310 (2003). H, Chaki S, Nakazato A, Baba A, Takuma K, Matsuda T. The 120) Saphier D, Farrar GE, Welch JE. Differential inhibition of stress- selective metabotropic glutamate 2/3 receptor agonist MGS0028

induced adrenocortical responses by 5-HT1A agonists and by reverses psychomotor abnormalities and recognition memory

5-HT2 and 5-HT3 antagonists. Psychoneuroendocrinology, 20, deficits in mice lacking the pituitary adenylate cyclase-activating 239–257 (1995). polypeptide. Behav. Pharmacol., 24, 74–77 (2013). 121) Ago Y, Yano K, Araki R, Hiramatsu N, Kita Y, Kawasaki T, Onoe 137) Ago Y, Nakamura S, Baba A, Matsuda T. Sulpiride in combination H, Chaki S, Nakazato A, Hashimoto H, Baba A, Takuma K, Mat- with fluvoxamine increases in vivo dopamine release selectively suda T. Metabotropic glutamate 2/3 receptor antagonists improve in rat prefrontal cortex. Neuropsychopharmacology, 30, 43–51 behavioral and prefrontal dopaminergic alterations in the chronic (2005). corticosterone-induced depression model in mice. Neuropharma- 138) Ago Y, Harasawa T, Itoh S, Nakamura S, Baba A, Matsuda T. cology, 65, 29–38 (2013). Antidepressant-like effect of coadministration of sulpiride and 122) Ago Y, Arikawa S, Yata M, Yano K, Abe M, Takuma K, Matsuda fluvoxamine in mice. Eur. J. Pharmacol., 520, 86–90 (2005). T. Role of prefrontal dopaminergic neurotransmission in glucocor- 139) Ago Y, Sato M, Nakamura S, Baba A, Matsuda T. Lack of en- ticoid receptor-mediated modulation of methamphetamine-induced hanced effect of antipsychotics combined with fluvoxamine on hyperactivity. Synapse, 63, 7–14 (2009). acetylcholine release in rat prefrontal cortex. J. Pharmacol. Sci., 123) Pierce RC, Kalivas PW. A circuitry model of the expression of 102, 419–422 (2006). behavioral sensitization to amphetamine-like psychostimulants. 140) Egashira N, Harada S, Okuno R, Matsushita M, Nishimura R, Brain Res. Brain Res. Rev., 25, 192–216 (1997). Mishima K, Iwasaki K, Orito K, Fujiwara M. Involvement of the

124) Robinson TE, Becker JB. Enduring changes in brain and behavior sigma1 receptor in inhibiting activity of fluvoxamine on marble- produced by chronic amphetamine administration: a review and burying behavior: comparison with . Eur. J. Pharmacol., evaluation of animal models of amphetamine psychosis. Brain Res. 563, 149–154 (2007). Rev., 11, 157–198 (1986). 141) Hashimoto K, Fujita Y, Iyo M. Phencyclidine-induced cognitive 125) Kalivas PW, Stewart J. Dopamine transmission in the initiation deficits in mice are improved by subsequent subchronic adminis- and expression of drug- and stress-induced sensitization of motor tration of fluvoxamine: role of sigma-1 receptors. Neuropsycho- activity. Brain Res. Brain Res. Rev., 16, 223–244 (1991). pharmacology, 32, 514–521 (2007). 126) Przegaliński E, Siwanowicz J, Baran L, Filip M. Activation of 142) Hindmarch I, Hashimoto K. Cognition and depression: the effects

serotonin (5-HT)1A receptors inhibits amphetamine sensitization in of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Hum. mice. Life Sci., 66, 1011–1019 (2000). Psychopharmacol., 25, 193–200 (2010). 127) Przegalinski E, Siwanowicz J, Nowak E, Papla I, Filip M. Role of 143) Nishimura T, Ishima T, Iyo M, Hashimoto K. Potentiation of nerve

5-HT1B receptors in the sensitization to amphetamine in mice. Eur. growth factor-induced neurite outgrowth by fluvoxamine: role of

J. Pharmacol., 422, 91–99 (2001). sigma-1 receptors, IP3 receptors and cellular signaling pathways. 128) Ago Y, Nakamura S, Uda M, Kajii Y, Abe M, Baba A, Matsuda T. PLoS ONE, 3, e2558 (2008).

Attenuation by the 5-HT1A receptor agonist osemozotan of the be- 144) Ishikawa M, Ishiwata K, Ishii K, Kimura Y, Sakata M, Naganawa havioral effects of single and repeated methamphetamine in mice. M, Oda K, Miyatake R, Fujisaki M, Shimizu E, Shirayama Y, Neuropharmacology, 51, 914–922 (2006). Iyo M, Hashimoto K. High occupancy of sigma-1 receptors in 129) Ago Y, Nakamura S, Kajita N, Uda M, Hashimoto H, Baba A, the human brain after single oral administration of fluvoxamine: Matsuda T. Ritanserin reverses repeated methamphetamine- a positron emission tomography study using [11C]SA4503. Biol. induced behavioral and neurochemical sensitization in mice. Syn- Psychiatry, 62, 878–883 (2007). apse, 61, 757–763 (2007). 145) Bermack JE, Debonnel G. The role of sigma receptors in depres- 130) Seiden LS, Sabol KE, Ricaurte GA. Amphetamine: effects on cat- sion. J. Pharmacol. Sci., 97, 317–336 (2005). echolamine systems and behavior. Annu. Rev. Pharmacol. Toxicol., 146) Cobos EJ, Entrena JM, Nieto FR, Cendán CM, Del Pozo E. Phar-

33, 639–677 (1993). macology and therapeutic potential of sigma1 receptor ligands. 131) Ago Y, Nakamura S, Baba A, Matsuda T. Neuropsychotoxicity of Curr. Neuropharmacol., 6, 344–366 (2008). abused drugs: Effects of serotonin receptor ligands on metham- 147) Delgado PL. Depression: the case for a monoamine deficiency. J. phetamine- and cocaine-induced behavioral sensitization in mice. Clin. Psychiatry, 61 (Suppl. 6), 7–11 (2000). J. Pharmacol. Sci., 106, 15–21 (2008). 148) Delgado PL, Moreno FA. Role of norepinephrine in depression. J. 132) Ago Y, Tanaka T, Kita Y, Tokumoto H, Takuma K, Matsuda T. Clin. Psychiatry, 61 (Suppl. 1), 5–12 (2000).

Lithium attenuates methamphetamine-induced hyperlocomotion 149) Kobayashi T, Matsuno K, Murai M, Mita S. σ1 receptor subtype is and behavioral sensitization via modulation of prefrontal mono- involved in the facilitation of cortical dopaminergic transmission amine release. Neuropharmacology, 62, 1634–1639 (2012). in the rat brain. Neurochem. Res., 22, 1105–1109 (1997). 133) Ago Y, Nakamura S, Hayashi A, Itoh S, Baba A, Matsuda T. 150) Rhodes ME, Li PK, Flood JF, Johnson DA. Enhancement of hip- Effects of osemozotan, ritanserin and on cocaine- pocampal acetylcholine release by the neurosteroid dehydroepian- induced behavioral sensitization in mice. Pharmacol. Biochem. drosterone sulfate: an in vivo microdialysis study. Brain Res., 733, Behav., 85, 198–205 (2006). 284–286 (1996). 134) Nakamura S, Ago Y, Hayashi A, Itoh S, Kakuda M, Hashimoto H, 151) Zheng P. Neuroactive steroid regulation of neurotransmitter release Baba A, Matsuda T. Modification of cocaine-induced behavioral in the CNS: Action, mechanism and possible significance. Prog. and neurochemical effects by serotonin1A receptor agonist/antago- Neurobiol., 89, 134–152 (2009). nist in mice. Synapse, 60, 479–484 (2006). 152) Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, 135) Ago Y, Araki R, Yano K, Hiramatsu N, Kawasaki T, Chaki S, Wong DT, Perry KW. , but not other selective serotonin 1882 Vol. 36, No. 12

uptake inhibitors, increases norepinephrine and dopamine extra- sant-like effect induced by σ1-receptor agonists and neuroactive cellular levels in prefrontal cortex. Psychopharmacology (Berl.), steroids in mice submitted to the forced swimming test. J. Phar- 160, 353–361 (2002). macol. Exp. Ther., 298, 1269–1279 (2001). 153) Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, 156) Ago Y, Yano K, Hiramatsu N, Takuma K, Matsuda T. Fluvox- Koyama T. increases extracellular levels not only of amine enhances prefrontal dopaminergic neurotransmission in serotonin, but also of dopamine in the nucleus accumbens and adrenalectomized/castrated mice via both 5-HT reuptake inhibi-

striatum of rats. Eur. J. Pharmacol., 647, 90–96 (2010). tion and σ1 receptor activation. Psychopharmacology (Berl.), 217, 154) Phan VL, Su TP, Privat A, Maurice T. Modulation of steroidal 377–386 (2011). levels by adrenalectomy/castration and inhibition of neurosteroid 157) Hiramatsu N, Ago Y, Hasebe S, Nishimura A, Mori K, Takuma K,

synthesis enzymes affect σ1 receptor-mediated behaviour in mice. Matsuda T. Synergistic effect of 5-HT1A and σ1 receptor activation Eur. J. Neurosci., 11, 2385–2396 (1999). on prefrontal dopaminergic transmission under circulating steroid 155) Urani A, Roman FJ, Phan VL, Su TP, Maurice T. The antidepres- deficiency. Neuropharmacology, 75, 53–61 (2013).