Winslow JT

References (3)

Title : Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease - Smith_1997_J.Pharmacol.Exp.Ther_280_710
Author(s) : Smith CP , Bores GM , Petko W , Li M , Selk DE , Rush DK , Camacho F , Winslow JT , Fishkin R , Cunningham DM , Brooks KM , Roehr J , Hartman HB , Davis L , Vargas HM
Ref : Journal of Pharmacology & Experimental Therapeutics , 280 :710 , 1997
Abstract : 1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.
ESTHER : Smith_1997_J.Pharmacol.Exp.Ther_280_710
PubMedSearch : Smith_1997_J.Pharmacol.Exp.Ther_280_710
PubMedID: 9023283

Title : Alpha 2-adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat - Camacho_1996_Psychopharmacology_124_347
Author(s) : Camacho F , Smith CP , Vargas HM , Winslow JT
Ref : Psychopharmacology , 124 :347 , 1996
Abstract : The cholinergic hypothesis of Alzheimer's disease (AD) has strongly influenced research on learning and memory over the last decade. However, there has been limited success treating AD dementia with cholinomimetics. Furthermore, there are indications that other neurotransmitter systems affected by this disease may be involved in cognitive processes. Animal studies have suggested that norepinephrine and acetylcholine may interact in learning and memory. The current experiments investigate this interaction in a step-down passive avoidance paradigm after coadministration of acetylcholinesterase inhibitors and alpha 2-adrenoceptor antagonists. Administration of acetylcholinesterase inhibitors heptylphysostigmine (0.625-5.0 mg/kg, IP), tacrine (2.5-10.0 mg/kg, PO), velnacrine (0.312-2.5 mg/kg, SC), and galanthamine (0.312-2.5 mg/kg IP) each enhanced retention of a passive avoidance response at selected moderate doses administered 30-60 min prior to training. The alpha 2-adrenoceptor antagonists idazoxan (0.312-2.5 mg/kg, IP), yohimbine (0.078-0.312 mg/kg, IP) and P86 7480 (0.156-0.625 mg/kg, IP) alone failed to enhance learning in this paradigm. Coadministration of a subthreshold dose of heptylphysostigmine (0.625 mg/kg, IP) with doses of idazoxan, yohimbine or P86 7480 enhanced passive avoidance learning. This synergistic interaction may represent effects of antagonism of presynaptic alpha 2-adrenoceptor since coadministration of heptylphysostigmine and the selective postsynaptic alpha 2-adrenoceptor antagonist SKF 104856 did not result in enhanced learning. Taken together these data suggest noradrenergic activation through pre-synaptic alpha 2-adrenoceptor blockade may potentiate cholinergic activity in the formation of a long-term memory trace. These observations may have implications for the treatment of AD with cholinergic and adrenergic agents.
ESTHER : Camacho_1996_Psychopharmacology_124_347
PubMedSearch : Camacho_1996_Psychopharmacology_124_347
PubMedID: 8739550

Title : Cholinergic modulation of a decrement in social investigation following repeated contacts between mice - Winslow_1995_Psychopharmacology.(Berl)_121_164
Author(s) : Winslow JT , Camacho F
Ref : Psychopharmacology (Berl) , 121 :164 , 1995
Abstract : Social recognition has been inferred from a decline in olfactory investigation of conspecific intruders during repeated or protracted confrontation with a resident rat. A stimulus-response relationship defined by lack of response remains somewhat ambiguous. Since it is likely that behavior continues to be emitted by the resident animal, how behavior reorganizes as the resident becomes familiar with an intruder represents an important issue in the characterization of recognition. We examined the decline in olfactory investigation of ovariectomized females by adult male mice. The duration and frequency of olfactory investigation was measured during four 1 minute confrontations with 10-min intertrial intervals (Training trials). If the same female was presented in each trial, investigation declined to less than 50% of initial levels. Aggressive behavior gradually increased with repeated trials. No decline in investigation or increased aggression was measured when females were changed in each trial. Administration of doses of scopolamine (0.16-1.0 mg/kg, IP) blocked decrements in olfactory investigation in repeated confrontations and significantly reduced aggression. Co-administration of heptylphysostigmine (0.32-5.0 mg/kg, IP) reversed scopolamine's effects on olfactory investigation but not aggression. Acetylcholinesterase inhibitors heptylphysostigmine, galanthamine (0.63-2.5 mg/kg, IP) and tacrine (0.63-10.0 mg/kg, IP) all enhanced the rate of decrement of olfactory investigation when administered alone, but had differential effects on aggression. The decline in investigation corresponds to criteria for habituation. Increased responsivity expressed as aggression indicates recognition may also be characterized as a change in behavioral strategy dependent on the sexual and social status of the stimulus animal. Pharmacological data support a role for acetylcholine release in the development of social recognition as an olfactory memory, or through modulation of olfactory perception.
ESTHER : Winslow_1995_Psychopharmacology.(Berl)_121_164
PubMedSearch : Winslow_1995_Psychopharmacology.(Berl)_121_164
PubMedID: 8545521