Neuropharmacologic Studies on the Brain Serotonin_1A Receptor Using the Selective Agonist Osemozotan

Abstract

Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuropsychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodulatory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT 1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT 1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT 1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT 1A 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-HT 1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced abnormal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encounter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan attenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT 1A receptor and other receptors. This review summarizes the neuropharmacology of the 5-HT 1A receptor, focusing on our studies using osemozotan, and suggests that the 5-HT 1A receptor may be a target molecule for the treatment of psychiatric disorders, pain, and drug dependence.

The Potential Role of Serotonin1A Receptors in Post-weaning Social Isolation–Induced Abnormal Behaviors in Rodents

“…Isolation rearing-induced aggression has been proposed to be useful as an animal model for assessing benzodiazepine and non-benzodiazepine anxiolytic activities. We have found that the selective 5-HT 1A receptor agonist osemozotan (previously called as MKC-242) (3,15) as well as the g-aminobutyric acid A (GABA A )-receptor agonist diazepam reduced isolation-induced aggressive behavior (16,17). The antiaggressive effect of osemozotan was observed at low doses, suggesting the involvement of presynaptic 5-HT 1A receptor activation (6).…”

“…The serotonin (5-HT) 1A receptor, a metabotropic G protein-coupled receptor linked to the G i/o signaling pathway, plays a crucial role in the brain development (1) and has been implicated in the etiology and treatment of schizophrenia, depression, anxiety, and pain (2,3). Positron emission tomography studies also show the altered 5-HT 1A receptor binding in patients with major depression and panic disorder (4,5).…”

“…Rearing of rodents in social isolation from early in life causes abnormal behaviors in adulthood, such as hyperactivity, aggression, depression-and anxiety-like behaviors, deficits of prepulse inhibition, cognitive (3,7,8). These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders such as schizophrenia.…”

Effects of Activation and Blockade of Serotonin 5-HT1A Receptors on the Immune Response in Rats Selected for Different Levels of Aggressiveness

“…The immunoinhibitory 5-HTergic system is closely linked to other neurotransmitter systems including the dopamine (DA) ergic system [43] [46], which has been found to exert the stimulating influence on immunity [12] [30] [44] [47]- [49]. Moreover, a number of studies indicate that activation of presynaptic 5-HT 1A receptors having the effect of inhibitory regulation on the release of 5-HT, may stimulate the release of DA in several corticolimbic areas [4] [46].…”

“…Moreover, a number of studies indicate that activation of presynaptic 5-HT 1A receptors having the effect of inhibitory regulation on the release of 5-HT, may stimulate the release of DA in several corticolimbic areas [4] [46]. These brain structures are also considered to play a role in immunostimulation [12] [30] [47]- [49].…”