Pro-cognitive Properties Research Articles

Cognitive Impairment in Schizophrenia: a Review of Developmental and Genetic Models, and Pro-cognitive Profile of the Optimised D3 > D2 Antagonist, S33138

In vivo animal models are indispensable both for clarifying the pathological bases of schizophrenia, and for evaluating the potential benefits and disadvantages of novel therapy. Procedures that model mnemonic impairment are of particular interest since currently-available drugs do little to improve cognitive symptoms: this is hardly surprising, in fact, since most of them potently antagonise histamine H1, muscarinic, and/or α1-adrenergic receptors. Further, their blockade of D2 receptors likewise compromises cognitive performance. By contrast, D3 receptor antagonism improves certain cognitive domains, suggesting that preferential antagonism of D3vs. D2 receptors may permit enhanced effectiveness against cognitive dysfunction. The novel agent, S33138, possesses such an “optimised” profile and shows a unique and broad-based pattern of pro-cognitive properties in rodents and primates, in the absence of extrapyramidal and metabolic side-effects. The present article surveys the preclinical pharmacology of S33138. It also reviews developmental and genetic risk factors for schizophrenia and their experimental modeling in rodents, with a particular emphasis on sensorimotor gating and cognitive deficits.

Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

BackgroundData indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.MethodsTASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.ResultsAt 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.ConclusionThese data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.

Brain histamine and schizophrenia: Potential therapeutic applications of H 3-receptor inverse agonists studied with BF2.649

BF2.649, a high affinity and selective non-imidazole histamine H 3-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C max or AUC values. At low oral doses (2.5–20 mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition. These observations suggest that H 3-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.

Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats

Although dopaminergic mechanisms are known to modulate cognitive function and cholinergic transmission, their pharmacological characterization remains incomplete. Herein, the role of D1 sites was evaluated employing neurochemical and behavioural approaches. By analogy to the acetylcholinesterase inhibitor, galantamine (0.0025-0.63 mg/kg s.c.), the selective and high efficacy D1 receptor agonist, SKF 82958, dose-dependently (0.0025-0.63), robustly and potently enhanced extracellular levels of acetylcholine (ACh) in the frontal cortex and hippocampus of freely moving rats. A further agonist, SKF 81297 (0.04-0.63), mimicked this action whereas the selective antagonist, SCH 23390 (0.00063-0.63), decreased levels of ACh. In the presence of SCH 23390 (0.08), the facilitatory influence of SKF 82958 (0.04) upon ACh levels was abolished. In a model of social memory (recognition of a juvenile by an adult rat), galantamine (0.04-0.63), SKF 82958 (0.01-0.16) and SKF 81297 (0.001-0.16) dose-dependently abrogated amnesic effects of the muscarinic receptor antagonist scopolamine (1.25). Further, under conditions of spontaneous loss of recognition, mimicking the effects of galantamine (0.04-2.5), SKF 82958 (0.01-0.16) and SKF 81297 (0.04-1.25) dose-dependently and specifically facilitated social recognition. Conversely, SCH 23390 (0.0025-0.04) exerted a modest negative influence upon social recognition and, in its presence, the pro-cognitive properties of SKF 82958 were blocked. In conclusion, D1 receptors exert a tonic, facilitatory influence upon cholinergic transmission and social recognition. Although the relationship between these actions awaits further clarification, these data underpin the relevance of D1 receptors to CNS disorders in which cholinergic transmission and social cognition are disrupted.

Tolerance to the procholinergic action of the D1 receptor full agonist dihydrexidine

It has been well established that dopamine D1 receptor agonists increase acetylcholine (ACh) release in the brain, an effect that has been suggested to contribute to their procognitive properties. We sought to examine whether the ACh-releasing action of the D1 receptor full agonist dihydrexidine HCl (DHX) is altered after repeated administration. DHX dose-dependently (3, 9, 18, and 36 mg/kg, i.p.) increased ACh efflux in the hippocampus of freely moving rats through D1 receptor stimulation, as the D1 receptor antagonist SCH 23390 (0.3 mg/kg, i.p.) abolished the effect of DHX (18 mg/kg, i.p.). Daily injections of DHX (18 mg/kg, i.p.) over 14 days did not significantly affect basal hippocampal ACh concentrations, but they significantly curtailed the stimulatory action of a challenge injection of DHX (18 mg/kg, i.p.) on ACh efflux. Tolerance to the procholinergic action of DHX develops with repeated administration.

P1-319 SRA-333: a novel 5-HT 1A receptor antagonist with procognitive properties in nonhuman primates

P1-319 SRA-333: a novel 5-HT 1A receptor antagonist with procognitive properties in nonhuman primates

The serotonin1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission and cognitive function in rodents: a combined neurochemical and behavioral analysis.

These studies examined the influence of the selective 5-hydroxytryptamine (serotonin) (5-HT)(1A) receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] upon cholinergic transmission and cognitive function in rodents. In the absence of acetylcholinesterase inhibitors, S15535 dose-dependently (0.04-5.0 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex and dorsal hippocampus of freely moving rats. In the cortex, the selective 5-HT(1A) receptor antagonist WAY100,635 [(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide) fumarate] dose-dependently (0.0025-0.63) blocked this action of S15535. By contrast, in dorsal hippocampus, WAY100,635 mimicked the induction of acetylcholine release by S15535. In a social recognition paradigm, S15535 dose-dependently (0.16-10.0) improved retention, an action blocked by WAY100,635 (0.16), which was ineffective alone. Furthermore, S15535 dose-dependently (0.04-2.5) and WAY100,635 reversibly abolished amnesic properties of the muscarinic antagonist scopolamine (0.63) in this procedure. Cognitive deficits provoked by scopolamine in autoshaping and Morris water-maze procedures were likewise blocked by S15535 at doses of 0.63 to 10.0 and 0.16 to 2.5, respectively. In a two-platform spatial discrimination task, in which S15535 similarly abrogates cognitive deficits elicited by scopolamine, injection of S15535 (1.0 and 10.0 microg) into dorsal hippocampus blocked amnesic effects of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin (0.5 microg). Finally, S15535 (0.16-0.63) improved performance in a spatial, delayed nonmatching to sample model in mice, and in an operant delayed nonmatching to sample model in old rats, S15535 (1.25-5.0 mg/kg p.o.) increased response accuracy and reduced latency to respond. In conclusion, S15535 reinforces frontocortical and hippocampal release of acetylcholine and displays a broad-based pattern of procognitive properties. Its actions involve both blockade of postsynaptic 5-HT(1A) receptors and engagement of 5-HT(1A) autoreceptors.

Improvement in the selectivity and metabolic stability of the serotonin 5-HT(1A) ligand, S 15535: a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols.

S 15535 (1) displays a distinctive profile of agonist and antagonist (weak partial agonist) activity at pre- and postsynaptic 5-HT(1A) receptors, respectively. It has proven to be active in several models predictive of anxiolytic, antidepressant, and procognitive properties. In an attempt to increase its selectivity and metabolic stability, and guided by the results of human metabolic studies, we prepared a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols. Irrespective of the nature of the arylcycloalkylamine moiety or the presence of substituents on the indanol ring, trans isomers invariably showed the highest affinity for human, recombinant h5-HT(1A) receptors. Among them, compounds 39, 42, 45, 49, 52, 53, 54, 57, 61, 64, 67, and 70 displayed similar or higher affinity than the parent compound 1 (pK(i) > or = 9.1). Lack of selectivity toward alpha1-adrenoceptors has been frequently encountered with 5-HT(1A) ligands. While S 15535 itself presents reasonable selectivity (158-fold) in this respect, trans piperazine derivatives 4-trans,35, 39, 41, 47, 64, 68, 69, 70, 71 displayed even more pronounced selectivity vs alpha1-adrenoceptors, with the nitro derivative 70 being highly selective (1259-fold). However, among the set of trans piperidines prepared, only 64, which also bears a nitro on the indanol ring, displayed selectivity greater than the parent compound 1. All trans derivatives behaved as partial agonists at h5-HT(1A) receptors, as determined by their submaximal stimulation of [35S]GTPgammaS binding to a level comparable to that observed with S 15535. In metabolic stability studies in vitro using human microsomes and hepatocytes, only trans piperazines and, in particular, 35, 39, 41, 68, 69, and 70, showed an improvement relative to 1, whereas trans piperidines did not. Compounds 35, 39, 41, and 70, which combined both improved selectivity and metabolic stability, and which retained the distinctive pharmacological characteristics of S 15535, were evaluated in animal models of anxiety. Of these, 35, which showed the highest oral bioavailability in vivo in rats, was resolved into its two isomers 36 and 37. The eutomer 37 displayed 47% oral bioavailability in the rat and was potently active (0.1-0.5 mg/kg, s.c.) in the rat ultrasonic vocalization and social interaction models, predictive of anxiolytic activity. In conclusion, 2-(arylcycloalkylamine) 1-indanols represent a novel class of potent 5-HT(1A) ligands in which the presence of the hydroxyl group in the benzylic position enhances selectivity, while substituents on the phenyl ring of the indanol moiety improve both selectivity and metabolic stability.

5-HT4 receptors: gene, transduction and effects on olfactory memory.

In this paper we discuss 1) the primary structures, pharmacology, and brain distribution of cloned 5-HT4 receptors; 2) the chromosomal localization of the h5-HT4 receptor; 3) whether benzamides are full or partial agonists because of a species or a coupling difference; 4) the intrinsic activity of 5-HT4 receptors and inverse agonism of GR125487 in COS-7 cells but not in colliculi neurons; 5) the modulation of 5-HT4 receptor binding and activity; and 6) the long-term blockade of K+ channels by 5-HT4 agonists and its effect on olfactory memory. We conclude that 1) the cloning of 5-HT4 receptors in different species using RT-PCR from different tissues reveals the presence of several splice variants for 5-HT4 receptors differing in the C-terminal part, downstream from the amino acid L358; 2) the pharmacological properties of 5-HT4 receptors are dependent on the cellular context in which they are expressed; and 3) 5-HT4 agonists can be added to the list of compounds having pro-cognitive properties.