Tatsuki Yoshino

Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine.

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. The present study was undertaken to demonstrate that nervous systems other than the 5-HT system also participate in the pathophysiology of 5-HT syndrome. Concentrations of 5-HT, dopamine (DA) and glutamate in the hypothalamus were measured in two different 5-HT syndrome animal models using a microdialysis technique. The first model was induced by tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor (3.5 mg/kg) and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (10 mg/kg). The second model was induced by clorgyline, an MAO-A inhibitor (1.2 mg/kg) and 5-hydroxy-L-tryptophan, a precursor of 5-HT (5-HTP) (80 mg/kg). In the first model, the levels of 5-HT and DA increased by 40-fold and 44-fold, respectively, compared with the preadministration levels. In the second model, the concentrations of 5-HT increased by up to 140-fold, whereas DA levels increased by only 10-fold, of the preadministration levels. Although the level of glutamate in the second model barely changed, a delayed increase in the glutamate level was observed in the first model. These findings suggest that not only hyperactivity of the 5-HT system, but also hyperactivity of the DA system, are present in 5-HT syndrome, and that the glutamatergic system is influenced in some 5-HT syndrome cases in which the DA concentration markedly increases.

Tandospirone potentiates the fluoxetine-induced increases in extracellular dopamine via 5-HT1A receptors in the rat medial frontal cortex

Recent clinical studies suggest that 5-HT(1A) receptor agonists, including buspirone, may have an antidepressant effect and potentiate the efficacy of selective serotonin reuptake inhibitors (SSRI) in major depressive disorders. In the present study, we investigated the effect of tandospirone, a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release and potentiation of fluoxetine-induced dopamine outflow in the medial frontal cortex using microdialysis in freely moving rats. Intraperitoneal injection of tandospirone (5 mg/kg) increased dopamine release to about 190% of basal levels. Pretreatment with the selective 5-HT(1A) receptor antagonist, WAY 100635 (1mg/kg), blocked the effect of tandospirone. Local application of WAY 100635 (10 microM) via microdialysis probe antagonized the increase in dopamine release in the medial frontal cortex induced by systemic injection of tandospirone. Fluoxetine (10 mg/kg) also increased dopamine release in the medial frontal cortex, to 200% of basal levels, and the simultaneous administration of tandospirone and fluoxetine increased the release to 380%. These results indicate that tandospirone potentiates the fluoxetine-induced increase in dopamine release via 5-HT(1A) receptors in the rat medial frontal cortex, and suggest that tandospirone may have therapeutic potential for the treatment of depression.

Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.

Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT1A receptor agonism as well as 5-HT2A and D2 receptor antagonism. We investigated the effect of perospirone in combination with fluoxetine on dopamine release in the rat medial prefrontal cortex using microdialysis. Perospirone and fluoxetine increased dopamine release to 270 and 210% of the baseline value, respectively. A combination of perospirone and fluoxetine markedly increased dopamine release to 800% of the baseline value. Pretreatment with a selective 5-HT1A receptor antagonist, WAY 100635, suppressed the increase in dopamine levels induced by the administration of perospirone and fluoxetine to 330% of the baseline value. These findings suggest that perospirone potentiates fluoxetine-induced dopamine increases in part via the action of the 5-HT1A receptor and may augment the effect of fluoxetine in treatment-resistant depression.

Susceptibility to subsequent episodes of spontaneous recurrence of methamphetamine psychosis

We examine susceptibility to subsequent spontaneous recurrences of methamphetamine psychosis (i.e. flashbacks) in 11 flashbackers with a single episode and in nine flashbackers with subsequent episodes. All had undergone frightening stressful experiences during previous MAP use. Mild psychosocial stressors then triggered flashbacks. During flashbacks, the nine flashbackers with subsequent episodes had more markedly increased norepinephrine levels, with slightly increased 3-methoxytyramine levels. The duration of imprisonment in this subgroup approached significantly long levels than in the 11 flashbackers with a single episode. Robust noradrenergic hyperactivity with slightly increased dopamine release may therefore predict subsequent flashbacks. Longer exposure to distressing situations may also contribute to robust noradrenergic hyperactivity.

Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. Hyperthermia is the most serious symptom of this syndrome. Hyperthermia in 5-HT syndrome is reportedly the result of activation of 5-HT(2A) receptors. Mirtazapine is a novel antidepressant and a potent 5-HT(2) receptor antagonistic. Although mirtazapine has been reported to cause 5-HT syndrome, the pharmacological profile of mirtazapine suggests that it improves hyperthermia in 5-HT syndrome. In the present study, we evaluated whether mirtazapine attenuates hyperthermia in a rat model of 5-HT syndrome. This model was induced by administration of tranylcypromine, a nonselective monoamine oxidase inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor. Upon injection of these two drugs, the rectal temperature of the rats increased to over 40 degrees C. Pre- and post-administration of mirtazapine abolishes hyperthermia in this model of 5-HT syndrome. Post-administration of ritanserin, a 5-HT(2A) receptor antagonist, completely inhibited hyperthermia and pre-administration of WAY100635, a 5-HT(1A) receptor antagonist, significantly attenuated the ability of mirtazapine to abolish hyperthermia. The results of the present study suggest that mirtazapine inhibits hyperthermia in an animal model of 5-HT syndrome by blocking the activation of 5-HT(2A) receptors, and that it partly inhibits hyperthermia by activating the 5-HT(1A) receptors. The present study indicates that mirtazapine is unlikely to cause 5-HT syndrome and may be a useful drug for treating this condition.

Effect of risperidone on acute methamphetamine-induced hyperthermia in rats

The abuse of methamphetamine (METH) is popular in many parts of the world. The number of fatal cases related to METH-induced hyperthermia is increasing, but no definitive therapy has yet been found. In the present study, we investigated the ability of risperidone to attenuate acute METH-induced hyperthermia and the mechanism of its action. When administered before and after a single high METH dose (10 mg/kg), risperidone significantly suppressed acute METH-induced hyperthermia in a dose-dependent manner. The same effect was produced by dopamine-1 (DA(1)) and serotonin-2A (5-HT(2A)) receptor blockers, but not by D₂, 5-HT(1A), 5-HT(2B/2C), or 5-HT(2C) receptor blockers, demonstrating that risperidone suppressed METH-induced hyperthermia by blocking the D(1) and 5-HT(2A) receptors. A microdialysis study showed that when METH (10 mg/kg) was subcutaneously injected into rats, the levels of DA, 5-HT, glutamate, and the nitric oxide (NO) metabolites NOx (NO₂⁻+ NO₃⁻) in the anterior hypothalamus increased. Risperidone pretreatment significantly attenuated increases in the levels of DA, 5-HT, glutamate, and NOx. The present study indicates that risperidone may be an effective drug for treating METH-induced hyperthermia in humans and that METH influences the DA and 5-HT neuron systems as well as other neuron systems, including the glutamate and NO systems.

Risperidone attenuates the increase of extracellular nitric oxide and glutamate levels in serotonin syndrome animal models.

Serotonin (5-hydroxytryptamine; 5-HT) syndrome is a potentially life-threatening neurotoxic condition provoked by pharmacologically induced excess serotonergic activity. Several studies report that nitric oxide (NO) and glutamate play a role in psychostimulant-induced hyperthermia related to neurotoxicity. In the present study, the involvement of NO and glutamate, as well as the effect of risperidone, a potent 5-HT(2A) and D(2) (and a less potent D(1)) receptor antagonist, were investigated in animal models of 5-HT syndrome. Two 5-HT syndrome animal models were utilized. The first model was induced by administration of tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor, and fluoxetine, a selective 5-HT reuptake inhibitor. The second model was induced by the administration of clorgyline, an MAO-A inhibitor, and 5-hydroxy-l-tryptophan, a precursor of 5-HT. Changes in the level of NO metabolites and glutamate in the anterior hypothalamus were measured using microdialysis. In both models, NO metabolite levels significantly increased, and this increase was significantly attenuated by risperidone pretreatment. Extracellular levels of glutamate were increased only in the tranylcypromine and fluoxetine model, and this increase was significantly attenuated by risperidone pretreatment. These results indicate that NO and glutamate may be involved in the development of 5-HT syndrome and that risperidone may be effective against neurotransmitter abnormalities in 5-HT syndrome.

Complex visual disturbances during maprotiline treatment.

KLINEFELTER SYNDROME (KS) is the commonest sex chromosome disorder and 47,XXY is the commonest karyotype. Hypoactive sexual desire due to hypogonadism is frequent in KS patients. We report a KS patient who, despite hypogonadism, had hyperactive sexual desire which markedly interfered with social and academic functioning. The sexually adverse effect of sertraline was successfully recruited in his management. The patient gave the authors written informed consent to publish this letter. M., a 22-year-old man, reported poor academic performance. He had earlier been diagnosed with 47,XXY KS. His phenotype was classical: he was tall, with narrow shoulders, broad hips, gynecomastia, and micro-orchidism. Enquiry elicited progressively increasing sexual desire from puberty, manifesting as sexual fantasizing and watching pornography for several hours a day, masturbating 1–5 times a day, and visiting prostitutes 3–4 times a week. He enjoyed these sexual activities, did not consider them abnormal and could not abstain for even a day; although he admitted that they were excessive. The phenomena were not resisted, and did not meet criteria for obsessive–compulsive symptomatology. The time-consuming sexual behaviors interfered with his studies, and he was expelled from his university. He had heterosexual orientation. There was no history of childhood sexual abuse or environmental triggers for the sexual preoccupations. There was no anxiety or mood disturbance, neither depression nor hypomania–mania. There was no history of substance use, including tobacco and alcohol. His IQ was 114. His language and social development were adequate. In non-academic matters, he was independent and self-reliant. Two years earlier, he had been evaluated in Canada for his gynecomastia and micro-orchidism, then diagnosed as having KS and had been advised intramuscular testosterone (200 mg every 2 weeks) to prevent hormonal complications of hypogonadism. Treatment partially reduced gynecomastia but had no other benefit. He fulfilled Kafka criteria for hypersexual disorder. With his consent, he was started on sertraline (100 mg/day) as decreased libido is a known adverse effect of serotonin reuptake inhibitors (SRI); testosterone was continued because, despite testosterone replacement, the peak and trough testosterone levels were low normal (300 and 200 ng/dL, respectively). Four weeks later, he reported decreased sexual desire, fantasies, masturbation, and use of pornography; and his concentration on studies had improved. Sertraline was uptitrated to 150 mg/day and, 6 months later, he reported substantial reduction in sexual preoccupation, and improved academic grades. KS is unusual here because, despite hypogonadism requiring testosterone replacement, our patient had puberty-onset hyperactive sexual desire causing clinical impairment. We cannot say with confirmation that KS is responsible for hypersexuality in this case, but we could not find other possible causes in the form of obsessive–compulsive disorder, addiction, autism or mood disorder, and the condition started well before testosterone replacement. We recruited a known SRI adverse effect (decreased sexual drive) to reduce sexual preoccupations and behaviors and thereby improve his ability to focus on studies, an issue for which he had sought clinical assistance. Sertraline, at 150 mg/day, was effective and well accepted.