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Antipsychotics & 5-HT1A

Key message: compounds with a suitable “balance” of combined D2/D3 antagonism and 5-HT1A agonism may display superior antipsychotic profiles. 

  • The atypical antipsychotic, clozapine, like some antipsychotics (ziprasidone, quetiapine) but not others (risperidone, haloperidol, olanzapine…) exhibits 5-HT1A receptor agonist properties.
  • Drugs that possess D2/D3 antagonism and 5-HT1A agonism, such as aripiprazole (Abilify®) and F15063 (pre-clinical, discontinued), are able to oppose PCP-induced social interaction and cognitive deficits.
  • Compounds that combine 5-HT1A agonism with D2/D3 antagonism show antipsychotic-like activity in rodents but do not elicit catalepsy.
  • Antipsychotics possessing 5-HT1A agonism, such as aripiprazole and ziprasidone, but not haloperidol, protect against excitotoxic lesions in mice.
  • Aripiprazole, and other compounds combining D2/D3 antagonism and 5-HT1A agonism, exhibit favorable profiles in transational models in dog and non-human primate.


Title Filter 

# Article Title
1 Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT1A receptor activation. (REVIEW)
2 Antipsychotic Agents: Biased Agonism at Serotonin 5-HT1A Receptors (POSTER).
3 Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. (REVIEW)
4 The importance of 5-HT1A receptor agonism in antipsychotic drug action: Rationale and perspectives. (REVIEW)
5 Neuropharmacological profile of bifeprunox: merits and limitations in comparison with other third-generation antipsychotics. (REVIEW)
6 Pharmacology of “atypicality” of antipsychotic drugs: status and perspectives. (REVIEW) PDF
7 Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia.
8 Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain. PDF
9 Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties.
10 F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile. PDF
11 F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia. PDF
12 F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms. PDF
13 F15063, a potential antipsychotic with dopamine D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (IV) duration of brain D2-like receptor occupancy and antipsychotic-like activity versus plasma concentration in mice.
14 F15063, a potential antipsychotic with dopamine D2/D3 receptor antagonist, 5-HT1A receptor agonist and dopamine D4 receptor partial agonist properties: influence on neuronal firing and neurotransmitter release.
15 F15063, a potential antipsychotic with dopamine D2/D3 receptor antagonist and 5-HT1A receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum.
16 The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063.
17 Effects of novel antipsychotics with mixed D2 antagonist/5-HT1A agonist properties on PCP-induced social interaction deficits in the rat.
18 Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade. PDF
19 Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats.
20 Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation.
21 Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release.
22 Clozapine is a partial agonist at cloned, human serotonin 5-HT1A receptors.
23 Efficacy of antipsychotic agents at human 5-HT1A receptors determined by [3H]WAY100,635 binding affinity ratios: relationship to efficacy for G-protein activation.
24 Apomorphine-induced emesis in dogs: differential sensitivity to established and novel dopamine D2/5-HT1A antipsychotic compounds.
25 Differences among conventional, atypical and novel putative D2/5-HT1A antipsychotics on catalepsy-associated behaviour in cynomolgus monkeys.
26 Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.
27 Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase.
28 Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.
29 Comparison of hippocampal G protein activation by 5-HT1A receptor agonists and the atypical antipsychotics clozapine and S16924.
30 Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin 5-HT1A receptors.
31 Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.
32 Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice.
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