Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT1A receptors in ventral prefrontal cortex in schizophrenia

Simpson, M.D.C.; Lubman, Dan I.; Slater, P.; Deakin, Bill

doi:10.1016/0006-3223(95)00026-7

Cited by 111 publications

(70 citation statements)

References 38 publications

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“…In the light of the proposed deficiency in dopaminergic neurotransmission in this brain area in schizophrenic patients, this 5-HT 1A receptor-mediated augmentation of cortical DA tone should help in alleviating negative and cognitive deficits of schizophrenia. In addition, 5-HT 1A receptor expression is increased in the dorsolateral prefrontal, temporal, and orbital frontal cortices of autopsied brains from chronic schizophrenics (Hashimoto et al, 1991;Simpson et al, 1996;Burnet et al, 1997). Further, PET studies have revealed an increase in cortical 5-HT 1A receptor binding in schizophrenia (Kasper et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Auclair

Kleven

Besnard

et al. 2006

Neuropsychopharmacol

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The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D 2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D 2 antagonist property, various levels of 5-HT 1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D 2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT 1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT 1A agonist, did not. New generation antipsychotics with marked 5-HT 1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT 1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT 1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D 2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT 1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D 2 and 5-HT 1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

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Section: Introductionmentioning

confidence: 98%

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Auclair

Kleven

Besnard

et al. 2006

Neuropsychopharmacol

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“…Among them, 5-HT 1A receptors are highly enriched in prefrontal cortex (Kia et al, 1996a;Feng et al, 2001). Increased prefrontal 5-HT 1A receptor density has been found in schizophrenia patients (Simpson et al, 1996;Sumiyoshi et al, 1996). Mice lacking 5-HT 1A receptors show elevated anxiety (Heisler et al, 1998;Ramboz et al, 1998), and this defect can be rescued by expression of 5-HT 1A receptors in the forebrain (Gross et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Yuen¹

2005

Journal of Neuroscience

207

197

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The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT 1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT 1A receptors. This effect of 5-HT 1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signalregulated kinase) abolished the 5-HT 1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT 1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT 1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesinbased dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT 1A -NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.

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“…The present study focused on the interaction of estrogen with central serotonin-1A (5-HT 1A ) receptor function. Evidence for the importance of 5-HT 1A receptors in schizophrenia includes post-mortem research (Burnet et al, 1997;Simpson et al, 1996) and some atypical antipsychotics having high affinity for 5-HT 1A receptors (Bantick et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

Gogos

Nathan

Guille

et al. 2005

Neuropsychopharmacol

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The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT 1A ) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT 1A receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

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Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT1A receptors in ventral prefrontal cortex in schizophrenia

Cited by 111 publications

References 38 publications

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

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