F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.
ABSTRACT We assessed the activity of F15599, a selective and high efficacy 5-HT(1A) agonist that preferentially activates post- versus pre-synaptic receptors, in rat cognition/memory models. F15599 (0.16 mg/kg i.p.) partially alleviated detrimental effects of phencyclidine on working and reference memory deficit in a hole-board model. It also attenuated phencyclidine-induced deficit of cognitive flexibility in a reversal learning task, without effects of its own. F13714 (0.04 mg/kg) a chemical congener of F15599, and 8-OH-DPAT (0.01 or 0.16), were inactive against these phencyclidine-induced deficits, and/or even worsened basal performances. F15599 (0.04-2.5) was less disruptive than F13714 (0.005-0.16) or 8-OH-DPAT (0.01-0.63), on basal performance in models of attention (5-choice serial reaction time task) and working memory (delayed non-matching to position). Finally, unlike either comparator, F15599 reduced PPI with modest potency and only partially. To conclude, F15599, in models of memory/cognition, has a more favourable profile than F13714 and 8-OH-DPAT. This suggests that preferential activation of post-synaptic 5-HT(1A) receptors could prove useful in pathologies characterized by cognitive/memory deficiencies, such as schizophrenia and depression.
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ABSTRACT: GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an “off” or “on” conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand-specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as β-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Gα or Gβγ signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist “functional selectivity” (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications.Pharmacological reports: PR 12/2014; DOI:10.1016/j.pharep.2014.06.006 · 2.17 Impact Factor
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ABSTRACT: Disturbances in behavioural inhibition are key features in several neurological and psychiatric disorders, such as attention-deficit/hyperactivity disorder, Parkinson's disease and substance use disorders. Therefore, elucidating the neural correlates of inhibitory control processes is crucial for developing novel treatment strategies to ameliorate the symptomatology of these disorders and to improve the quality of life. The development of preclinical translational paradigms to study inhibitory control processes has greatly enhanced our neurobiological understanding of these cognitive processes. Over the last decades, emphasis has been mainly on monoamines including dopamine and serotonin and their contribution to behavioral inhibition. This short review will focus on the involvement of the serotonergic system, and in particular serotonin1A receptors, in inhibitory control processes.European Journal of Pharmacology 08/2014; DOI:10.1016/j.ejphar.2014.05.064 · 2.68 Impact Factor
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ABSTRACT: Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (complex treatment). Our aim was to determine the sex-specific effects of these interventions on several processes. Sensory gating to acoustic stimulation, pain sensitivity, motor behavior, spatial learning and memory deficits on the hole-board test were assessed in the 17(th) generation of selectively bred Wistar rats compared to their naive counterparts with or without complex treatment. We found differences between the sexes: selectively bred males with complex treatment showed the lowest pain sensitivity; however, the results of the prepulse inhibition test indicated that female rats showed enhanced impairment of sensory gating and increased acoustic startle reaction. The cognitive performance, working and reference memory ratios were significantly decreased by selective breeding and showed sex-specific alterations, with the smallest value in male rats of the new substrain. Based on these results, the animals of the new substrain could be classified into the high-risk for schizophreniform phenotype with the highest sensitivity of males with complex treatment. Decreased cognitive performance highlighted spatial learning deficits in the selectively bred and treated rats that escalate the validity of our new and complex rat model of schizophrenia. The results indicate the same sex selectivity as observed in humans, with increased incidence of risk ratios for men to develop schizophrenia relative to women. Copyright © 2015. Published by Elsevier B.V.Behavioural Brain Research 02/2015; 284. DOI:10.1016/j.bbr.2015.02.015 · 3.39 Impact Factor