Selective impairment of paired associate learning after administration of a centrally-acting adrenergic agonist (clonidine)

Abstract

Eight normal volunteers had IV infusions of 200 micrograms clonidine (a centrally-acting adrenergic agonist which reduces noradrenaline release), and saline in a "double-blind" cross-over design. Clonidine reduced subjective estimates of arousal but did not affect performance on the Digit Symbol Substitution Test. Clonidine impaired paired-associate learning, but it did not affect performance on a number of measures of short and long term memory. The findings suggest either 1) that there is a specific (adrenergic) mechanism involved in the acquisition of novel associations, but not in other types of learning, or 2) that paired associate learning is more vulnerable than other learning tasks to disruption of adrenergic transmission.

Effects of Acute and Subchronic Administration of Dexefaroxan, an α2-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

“…A rationale for using these pharmacological probes to induce cognitive deficits in animals is provided by the amnesic properties that these classes of agents exert in humans. For example: 1) the ␣ 2 -adrenoceptor agonist clonidine disrupts memory performance in healthy volunteers (Frith et al, 1985) and in patients with AD (Riekkinen et al, 1999); 2) consistent with the cholinergic hypothesis of learning and memory, centrally active muscarinic cholinergic receptor antagonists such as scopolamine have amnesic properties in rodents, subhuman primates, and in humans (Chopin and Briley, 1992;Bartus, 2000). Similarities in the memory impairments between Alzheimer patients and scopolamine-treated animals have been reported, and it has been proposed that scopolamine could serve as a useful pharmacological tool to produce a partial model of the disorder (Bartus, 2000); 3) the deficit induced by diazepam is consistent with the anterograde amnesia induced by benzodiazepines in animals and nonanxious volunteer subjects (Curran, 1991).…”

Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

“…The nonlinear dose-response curve of clonidine to modulate PAL performance may be explained by assuming that the drug acted on both pre-and postsynaptic alpha2-adrenoceptors. It is generally assumed that the 0.5 g/kg dose acts presynaptically in humans to reduce LC noradrenergic activity (Frith et al 1985;Coull et al 1995b). This is less clear for the higher doses (2 and 5 g/kg), which probably have additional postsynaptic actions, especially the highest 5 g/kg dose (Coull et al 1995b).…”

“…Coull et al (1995a) reported some improvement in paired associates learning of nonverbal material in healthy volunteers by clonidine 2.5 g/kg intravenously, but there are also studies conducted with healthy volunteers reporting no effect (Coull et al 1997) or an impairment (Frith et al 1985) in paired associates learning after clonidine. The difference in the effect of similar clonidine administration on nonverbal paired associates learning in the two studies of Coull et al (1995aCoull et al ( , 1997 may result from the variation in the experimental design.…”

“…Indeed, in only the second study (Coull et al 1997), the subjects were scanned with a positron emission tomography, and the battery of cognitive tests measured were also different in these two studies. Frith et al (1985) reported that a fixed 200-g dose of clonidine injected intravenously impaired paired associates learning of difficult, but not easy, word pairs in healthy volunteers. Therefore, it is possible that the effect of clonidine may be doubly dissociable depending upon the type of information processed (i.e., nonverbal vs. verbal).…”

Treatment with the Noradrenergic Alpha-2 Agonist Clonidine, But Not Diazepam, Improves Spatial Working Memory in Normal Young Rhesus Monkeys

“…In human volunteers, clonidine has been found to both increase or decrease task performance, depending on the task and the dose used. Most typically, low doses of clonidine, in the range of 0.001-0.003 mg/kg have been found to impair human subjects on tasks involving sustained attention (Clark et al 1989;Coull et al 1995b) and paired associate learning (Frith et al 1985). Imaging studies have found these impairments to be accompanied by decreases in rCBF in the thalamus, mostly during low-arousal states (Coull et al 1997).…”