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1.
Br J Pharmacol ; 154(5): 1104-15, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18454168

ABSTRACT

BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.


Subject(s)
Hippocampus/drug effects , Muscarinic Agonists/pharmacology , Piperidines/pharmacology , Quinolones/pharmacology , Receptors, Muscarinic/drug effects , Action Potentials , Animals , CHO Cells , Calcium Signaling/drug effects , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Hippocampus/metabolism , Humans , Injections, Intraperitoneal , Injections, Subcutaneous , Inositol Phosphates/metabolism , Muscarinic Agonists/administration & dosage , Muscarinic Agonists/pharmacokinetics , Patch-Clamp Techniques , Permeability , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M1 , Receptors, Muscarinic/genetics , Receptors, Muscarinic/metabolism , Recombinant Proteins/agonists , Time Factors , Transfection
2.
Br J Pharmacol ; 130(7): 1713-9, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10928979

ABSTRACT

We report here the use of rat high-light social interaction to model the temporal anxiolytic/antidepressant effects of SSRIs seen in the clinic. Compared to vehicle controls, 21, but not 14, days of paroxetine treatment (3 mg kg(-1), p.o., daily) produced a marked increase in rat social interaction (Vehicle=71.3+/-7.3 s; Paroxetine=116.7+/-14.7 s; P<0.01) with no concurrent effect on locomotor activity, consistent with anxiolysis. To assess whether concurrent 5-HT(1A) receptor blockade reduces the time to onset of anxiolysis seen with paroxetine alone (21 days), rats were implanted with osmotic minipumps to continuously infuse the 5-HT(1A) receptor antagonist WAY100635 (1 mg kg(-1) day(-1), s.c., 7 days) alone or in combination with paroxetine (3 mg kg(-1), p.o., daily, 7 days), prior to anxiety testing. Paroxetine (Veh/Par=61.9+/-7.9 s) or WAY100635 (WAY/Veh=71.6+/-4.7 s) alone, had no effect on social interaction time compared to vehicle treated controls (Veh/Veh=76.4+/-4.9 s), whilst coadministration of WAY100635 with paroxetine, produced a marked elevation in social interaction (WAY/Par=149.3+/-16.8 s; P<0.01) relative to all other groups with no concurrent change in locomotor activity. In contrast, acute administration of WAY100635 (0.03 mg kg(-1), s.c.) with paroxetine (3 mg kg(-1), p.o.) did not alter any behavioural measure, suggesting that the anxiolysis induced by the combination after 7 days is attributable to a CNS adaptive response. This data demonstrates that coadministration of a 5-HT(1A) receptor antagonist with paroxetine markedly reduces the latency to anxiolysis, in the rat. This study supports the use of the rat social interaction test to further delineate adaptive changes in the CNS responsible for the anxiolytic/antidepressant action of SSRIs seen in humans.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety/prevention & control , Paroxetine/therapeutic use , Piperazines/therapeutic use , Pyridines/therapeutic use , Receptors, Serotonin/metabolism , Serotonin Antagonists/therapeutic use , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Anti-Anxiety Agents/administration & dosage , Anxiety/chemically induced , Disease Models, Animal , Drug Interactions , Hyperkinesis/chemically induced , Hyperkinesis/prevention & control , Interpersonal Relations , Male , Paroxetine/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/drug effects , Receptors, Serotonin, 5-HT1
3.
Obstet Gynecol ; 90(3): 381-6, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9277648

ABSTRACT

OBJECTIVE: To compare the sleep patterns, mood states, and cognitive functioning of primiparous mothers during the first 3 weeks postpartum with those of a control group of nonpostpartum women and to assess the relationships among these variables. METHODS: For the first 3 weeks postpartum, 30 primiparous women and 28 nonpostpartum mothers completed daily assessments of mood and recorded multiple aspects of sleep including time of retiring, occurrence and duration of sleep interruption, time of awakening, and morning alertness. Objective measures of memory, attention/concentration, and psychomotor performance were obtained on three occasions. RESULTS: Postpartum women reported more evening awakenings, more time awake after retiring, and more naps than controls, but overall sleep time was similar. New mothers experienced a higher level of dysphoric mood during the first week than nonpostpartum controls; however, controlling for the effect for "time awake" at night eliminated the significant effect for dysphoric mood. Few differences were observed on the multiple assessments of cognitive function; however, performances of new mothers on memory and psychomotor tasks were likely to be influenced by sleep loss. CONCLUSION: Women must make important adjustments in their sleep patterns during the postpartum period. In the study group, these adjustments were largely successful, particularly after the first week postpartum, in avoiding the negative consequences of sleep disturbances such as dysphoric mood and impaired cognitive function. Nevertheless, the significant associations between sleep indices and mood and objective measures of cognitive function point to the importance of encouraging appropriate amounts of sleep for recently delivered women.


Subject(s)
Affect/physiology , Cognition/physiology , Postpartum Period/physiology , Postpartum Period/psychology , Sleep/physiology , Adult , Female , Humans , Prospective Studies
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