5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex

Rollema, Hans; Lu, Yasong; Schmidt, Anne W.; Sprouse, Jeffrey; Zorn, Stevin H.

doi:10.1016/s0006-3223(00)00850-7

Cited by 184 publications

(121 citation statements)

References 33 publications

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“…Thus, SSR181507 enhanced basal DA efflux in the nucleus accumbens and medial prefrontal cortex, but not in the striatum. A similar regional selectivity was previously found for the atypical antipsychotics ziprasidone, clozapine, olanzapine, and risperidone, while haloperidol increased DA efflux more markedly in the striatum than in the nucleus accumbens, and was inactive in the prefrontal cortex (Kuroki et al, 1999;Rollema et al, 2000). The limbic selectivity of SSR181507 is likely related to 5-HT 1A receptor activation, as its cortical response is antagonized (results not shown) by a 5-HT 1A antagonist (SL88.0338-08).…”

Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Prosupporting

confidence: 79%

“…The limbic selectivity of SSR181507 is likely related to 5-HT 1A receptor activation, as its cortical response is antagonized (results not shown) by a 5-HT 1A antagonist (SL88.0338-08). Moreover 5-HT 1A agonists are known to increase cortical DA efflux without affecting striatal DA efflux (Arborelius et al, 1993;Rollema et al, 2000). Ichikawa et al (2001) recently hypothesized that simultaneous blockade of 5-HT 2A and DA D 2 receptors causes an increase in cortical DA efflux by facilitating 5-HT 1A agonist activity by endogenous 5-HT.…”

Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Promentioning

confidence: 99%

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SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Claustre

Peretti

Brun

et al. 2003

Neuropsychopharmacol

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monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT 1A receptors (K I ¼ 0.8, 0.2, and 0.2 nM for human D 2 , D 3 , and 5-HT 1A , respectively). In vivo, SSR181507 inhibited [ 3 H]raclopride binding to D 2 receptors in the rat (ID 50 ¼ 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D 2 antagonist and 5-HT 1A agonist properties in the same concentration range in vitro (IC 50 ¼ 5.3 nM and EC 50 ¼ 2.3 nM, respectively, in the GTPgS model) and in the same dose range in vivo (ED 50 ¼ 1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D 2 receptor antagonism and 5-HT 1A agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.

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Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Prosupporting

confidence: 79%

Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Promentioning

confidence: 99%

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Claustre

Peretti

Brun

et al. 2003

Neuropsychopharmacol

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“…In addition, the 3 mg/kg dose of ziprasidone was selected in the present study, because doses in this range are usually used in other biochemical and pharmacological animal studies (see e.g. Rollema et al 2000). Thus, it is estimated that the doses of the antipsychotic compounds tested result in a greater than 50% occupancy of D 2, 5-HT 2 , or both receptors in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, it has been well established that 5-HT 1A receptor agonistic action results in a significant increase in ACh outflow in the brain (Izumi et al 1994;Wilkinson et al 1994). This receptor activity might be of importance for the neurobiological effects of, primarily, clozapine and ziprasidone (Rollema et al 1997(Rollema et al , 2000. Similarly, it is unequivocally recognized that ␣ 2 adrenoceptor antagonists increase ACh efflux in the brain (Tellez et al 1997;, and that ␣ 2 adrenoceptor antagonism may underlie some of the central actions of clozapine, risperidone, and to a lesser extent of olanzapine (Hertel et al 1999a,b).…”

Section: Discussionmentioning

confidence: 99%

Effects of Typical and Atypical Antipsychotics and Receptor Selective Compounds on Acetylcholine Efflux in the Hippocampus of the Rat

Shirazi-Southall

2002

Neuropsychopharmacology

191

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Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as (MDL 100,907), the 5-HT 2C (SB 242,084), the 5-HT 6 KEY WORDS : Antipsychotic; Schizophrenia; Olanzapine; Clozapine; Microdialysis; Acetylcholine Impairments in cognitive processes, such as deficits in executive function, verbal memory and attention, are prevalent in most patients with schizophrenia (Breier 1999). Some atypical antipsychotic drugs appear to improve not only the positive symptoms, but also the negative symptoms and the cognitive deficits when compared with classical neuroleptics (Kinon and Lieberman 1996;Meltzer and McGurk 1999;Remington and Kapur 2000). For example, some atypical antipsychotic drugs have been shown to improve attention, motor and executive function in schizophrenic patients (Meltzer and McGurk 1999 NO . 5 cal and clinical studies have indicated that atypical antipsychotics, such as clozapine, olanzapine and risperidone, potently inhibit serotonin 5-HT 2 receptor function and affect a variety of other receptors in the brain (Meltzer et al. 1989;Leysen et al. 1992;Bymaster et al. 1996). In particular, clozapine and olanzapine show a complex pharmacological profile, being described as "multi-acting-receptor-targeted antipsychotic agents" (MARTAs) .Acetylcholine has been shown to be an important neurotransmitter in motor function, attention and various aspects of cognition. Cholinergic synapses are prevalent in many areas of the brain, including the striatum, the prefrontal cortex and the hippocampus. Neuronal processes within the hippocampus, in particular, mediate declarative memory, and participate in cognitive mapping in both experimental animals and humans (Eichenbaum et al. 1999). It appears likely therefore that a dysfunction in cholinergic neurotransmission within the hippocampus may be responsible for the cognitive impairments often encountered in schizophrenia. In turn, the beneficial effects of some atypical antipsychotic drugs in the treatment of cognitive deficits in schizophrenia may be related to their selective action on cholinergic function in the hippocampus, as a consequence of their multireceptor pharmacological profile.Earlier in vivo microdialysis experiments have revealed a selective action of clozapine on ACh outflow in limbocortical, dopaminergic regions of the brain, such as the prefrontal cortex, as compared with classical neuroleptics (Parada et al. 1997;Moore et al. 1999). In general, antipsychotic drugs appear to either increase or have no effect on ACh efflux within the striatum, a dopaminergic region of the brain related to...

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“…It has moderate affinity for the a 1 and H 1 receptors. In rats, ziprasidone inhibits DRN firing (Sprouse et al, 1999) and increases prefrontal cortical dopamine release (Rollema et al, 2000). The former effect is prevented and the latter roughly halved by the 5-HT 1A antagonist WAY-100635.…”

Section: Introductionmentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex

Cited by 184 publications

References 33 publications

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Effects of Typical and Atypical Antipsychotics and Receptor Selective Compounds on Acetylcholine Efflux in the Hippocampus of the Rat

Occupancy of Agonist Drugs at the 5-HT1A Receptor

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