Clonidine disrupts aged‐monkey delayed response performance

Abstract

Davis, R E . , M.J. Callahan, and D.A. Downs: Clonidine disrupts aged-monkey delayed response performance. Drug Dev. Res. 12:279-286, 1988. Clonidine (0.03-0.06 mglkg), in a dose-and delay-dependent manner impaired the ability of aged rhesus monkeys to perform a microcomputer-controlled delayed response test similar to that used previously by Bartus et al. (J. Gerontol. 33:858-871, 1978). These doses of clonidine produced overt sedation, increased response latencies and decreased the percentage of correct responses. Continued disruption of delayed response performance was seen during 11 days of repeated daily clonidine (0.04 mg/kg) administration. Performance immediately returned to preexisting baseline levels on the day following cessation of this repeated drug regimen. In addition, repeated clonidine administration did not alter responsivity to acutely administered clonidine, suggesting that tolerance did not develop rapidly to the disruptive effects of this agent. These data indicate that clonidine impairs delayed response performance in aged rhesus monkeys under these testing conditions.

Specific decrease of high-affinity agonist states of alpha2-adrenoceptors in the aging mouse brain

“…The same seems to account for the alphaz-adrenoceptors labeled in mouse brain membranes by the specific binding of 3H-UK-14,304, since in accordance with these studies pretreatment of mouse brain membranes with the stable GTP analogue Gpp(NH)p nearly abolished the specific binding of this ligand without having any effect on specific 3H-yohimbine binding (data not shown). Since the high-affinity component coupled to the regulatory protein is usually considered as that part of alphazadrenoceptors which can be activated by agonist (Schloss et al, 1987;Neubig et al, 1988) our findings about a specific loss of high-affinity agonist sites in the course of normal aging could further explain the age-related dysfunctions of central noradrenergic neurotransmission (Arnsten and Goldman-Rakic, 1987;Davis et al, 1988). The loss of about one third of the high-affinity agonist component of the alpha2-adrenoceptor is considerably more pronounced than age-related decrease of brain norepinephrine concentrations or of cell counts in the locus coeruleus (Carlsson, 1987) and seems to be an excellent candidate to explain the beneficial effect of treatment with agonists like clonidine on cognitive performance in aged but not young animals GoldmanRakic, 1985, 1987;Joly and Sanger, 1988).…”

“…A variety of data indicate that pharmacological manipulations leading to increased noradrenergic activity in the CNS improve cognitive performance in animals and man and the reverse is the case for manipulations decreasing central noradrenergic activity (Zornetzer, 1985;Arnsten and Goldman-Rakic, 1987;Davis et al, 1988). Since noradrenergic neurotransmission is impaired in the course of normal aging in animals and man and is further substantially reduced in dementia of the Alzheimer's type (SDAT) with a pronounced loss of catecholaminergic cells of the locus coeruleus, it has been suggested that deficits of central noradrenergic neurotransmissoin might contribute to the impairment of cognitive functions in age-associated memory impairment (AAMI) and SDAT (Bondareff et al, 1982;Carlsson, 1987).…”

“…While clonidine usually impairs mental performance when given to young animals or young man, recent data suggest that clonidine can improve cognitive functions in aged rodents as well as aged monkeys Goldman-Rakic, 1985, 1987;Joly and Sanger, 1988). However, negative findings have also been reported (Bartus and Dean, 1988;Davis et al, 1988). The biochemical basis of the specific responsiveness of aged animals to clonidine is not known, especially since the loss of noradrenergic cells in the course of normal aging is rather small (Carlsson, 1987).…”

Psychopharmacological Strategies in the Search for Cognition Enhancers

“…This result, it was suggested, may be relevant to the report that c10nidine can improve the memory disorder of patients sufTering from Korsakoff's disease (McEntee and Mair, 1980). However, two other research groups, using an automated version of a more com-pIex delayed-response task, were unable to find a similar efTect (Bartus and Dean, 1988;Davis et al, 1988). Fig.…”