The identities of the alpha1-adrenoceptor subtypes present in various tissues of the pig were studied using [3H]prazosin radioligand binding. The subtypes were characterized by performing competition experiments for various subtype selective drugs. In the cerebral cortex, spleen and heart, both alpha1A- and alpha1B-adrenoceptors were detected. In the liver was found only the alpha1A-subtype, while in the aorta was found only the alpha1B-subtype. An alpha1-adrenoceptor subtype was present in the adrenal gland with a high affinity for prazosin, the pKd value being 9.6, but with relatively low affinities for other alpha1-adrenoceptor binding drugs. The adrenal gland alpha1-adrenoceptor did not seem to represent the classical alpha1D-subtype, since drugs selective for the alpha1D-subtype in other species, including BMY7378 and SKF104856, showed low affinities for the pig adrenal gland alpha1-adrenoceptor.

01 Apr 1996·PsychopharmacologyQ3 · MEDICINE

α2-Adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat

Q3 · MEDICINE

Article

Author: Winslow, James T. ; Camacho, Fernando ; Smith, Craig P. ; Vargas, Hugo M.

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.

01 Nov 1993·Neurobiology of AgingQ2 · MEDICINE

Postsynaptic alpha-2 receptor stimulation improves memory in aged monkeys: Indirect effects of yohimbine versus direct effects of clonidine

Q2 · MEDICINE

Article

Author: A.F.T. Arnsten ; J.X. Cai

Very low doses (0.00001 mg/kg) of the alpha-2 adrenergic antagonist, yohimbine, improved working memory performance in a subset of aged monkeys. Improvement appeared to result from increased norepinephrine (NE) release onto postsynaptic alpha-2 adrenoceptors, as the response was blocked by the "postsynaptic" alpha-2 antagonist, SKF104078. Cognitive-enhancing effects of low dose yohimbine treatment may depend on aged animals retaining an intact, endogenous NE system. In contrast to yohimbine, the alpha-2 agonist, clonidine, has improved working memory in all aged animals examined. In the present study, clonidine's beneficial effects were also blocked by the postsynaptic antagonists SKF104078 and SKF104856, suggesting that clonidine acts by directly stimulating postsynaptic alpha-2 adrenoceptors. Beneficial doses of clonidine (0.01 mg/kg) and yohimbine (0.00001 mg/kg) were combined to see if they would produce additive effects on memory enhancement. This strategy was successful in young monkeys with intact NE systems but was not effective in the aged monkeys. These findings demonstrate that drugs that indirectly stimulate postsynaptic alpha-2 receptors by increasing NE release are not as reliable in aged monkeys as directly acting agonists that can replace NE at postsynaptic alpha-2 receptors.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Diseases	Discovery	-	Smithkline Beecham Plc	-
Hypertension	Discovery	-	Smithkline Beecham Plc	-

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