Central noradrenergic reactivity to stress in Maudsley rat strains.

Maudsley reactive (MR) and Maudsley nonreactive (MNRA) rats were submitted to a single session of acute 5-min immobilization stress and immediately sacrificed by decapitation. Subsequent neurochemical analysis revealed an elevation of 3,4-dihydroxyphenylacetic acid levels in the locus coeruleus and in the ventrolateral medulla, but not in the dorsomedial medulla, of rats of the two strains compared with nonstressed controls. This response was greater in the MR than in the MNRA group, suggesting a strain difference in the reactivity of the central noradrenergic cells to acute stress.

The Maudsley rat strains as a probe to investigate noradrenergic-cholinergic interaction in cognitive function.

Central noradrenergic function in relation to cognitive performance was studied in the Maudsley rat strains. Neurochemical studies revealed a higher response to acute stress in the locus coeruleus (LC) in the Maudsley reactives (MR) than in the Maudsley non-reactives (MNRA). Autoradiographic studies showed that MNRAs had greater 125I clonidine binding to alpha 2 receptors in LC, which was accompanied by a higher behavioral sensitivity to clonidine. MRs had a deficit in working memory, but were superior to MNRAs in two reference memory tasks. MRs displayed a stronger preference for novel objects, with no strain differences in general exploratory activity. The behavioral profile of the MRs is similar to rats treated with drugs which enhance noradrenergic function. Furthermore, MNRA rats had greater availability of muscarinic receptors, which correlated with behavioral performance in the spatial working memory task. The differences in noradrenergic and cholinergic systems and their relationship to the behavioral profile make the Maudsley strains a useful tool to probe the interaction between two neurotransmitter systems in cognitive function.

Maudsley rat strains, selected for differences in emotional responses, differ in behavioral response to clonidine and in [125I]clonidine binding in the locus coeruleus.

Maudsley rats, selectively inbred for emotionality for over sixty generations, differ in reactivity to stress, both at the peripheral level and within the central noradrenergic system. The present experiments examine to what extent these central differences might be due to differences in the inhibitory processes mediated by alpha 2 autoreceptors within the locus coeruleus. Maudsley reactive rats (MRs), the strain which showed a much higher central noradrenergic response to immobilisation stress, required higher doses of the alpha 2 receptor agonist, clonidine, to induce behavioral sedation than the Maudsley non-reactive rats (MNRA). Autoradiographic studies showed a significantly higher level of binding of 125iodeclonidine in the locus coeruleus of the MNRAs compared to the MRs, indicating that the former had more alpha 2 receptors and/or these receptors had a greater affinity for the agonist. Thus autoinhibitory processes within the locus coeruleus are different in the two strains, which could account for the differences in reactivity to stress seen in the biochemical and behavioral studies.

Limbic forebrain toxin trimethyltin reduces behavioral suppression by clonidine.

Trimethyltin (TMT) at moderate doses selectively damages hippocampus and related olfactory cortex and produces learning and memory impairments. TMT also increases forebrain beta-adrenergic ligand binding; this could be ancillary to reduced noradrenergic neurotransmission, which in turn could be involved in the cognitive deficit caused by TMT. If this hypothesis is correct, then the alpha 1-adrenergic agonist clonidine, which inhibits noradrenergic neurotransmission in normal subjects, should be less behaviourally effective after TMT poisoning. Thus, rats treated with water vehicle or TMT (6 mg/kg, PO) were given saline or clonidine IP (5, 10, or 20 micrograms/kg) 30 min before placement in a hole-board apparatus. Exploratory activity was reduced in controls by 10 or 20 micrograms/kg. Clonidine at 10 micrograms/kg was ineffective in rats given TMT. At 20 micrograms/kg, an apparent reduction in exploratory activity was not significant because variability of responding was higher after TMT treatment. The results suggest an impairment in noradrenergic neurotransmission following TMT poisoning.

Memory retrieval enhancement by locus coeruleus stimulation: evidence for mediation by beta-receptors.

Rats were trained in a complex food-motivated maze task, then implanted with indwelling stimulating electrodes in the noradrenergic nucleus locus coeruleus (LC). When tested 4 weeks later, they showed significant forgetting. Electrical stimulation of the LC alleviated forgetting in that stimulated rats made no more errors during the test than they did on the last learning trial. Systemic treatment with the beta noradrenergic antagonist propranolol blocked the effect of stimulation, suggesting that the memory facilitation is mediated through a beta-receptor.

Activation of the noradrenergic system facilitates an attentional shift in the rat.

The noradrenergic system was pharmacologically activated with the alpha 2 receptor antagonist, idazoxan (2 mg/kg i.p.), during the acquisition of a complex appetitive task requiring a shift in attention to stimulus dimension and in response strategy. Rats first learned a fixed path of 6 successive choices in a linear maze. The task was then changed to a visual discrimination task in which the spatial configuration of the correct path was indicated by visual cues and changed on each daily trial. During this part of the task, the rats were injected before each trial with idazoxan, a drug which increases the firing rate of neurons in the locus coeruleus and the release of noradrenaline in the cortex and hippocampus. Two control experiments showed that the drug treatment had no effect on the acquisition of either component of the task - the successive place learning or the visual discrimination. The drug was found to be effective only during the shift phase of the experiment, the idazoxan-treated rats taking fewer trials to reach criterion than the saline. A second experiment showed that idazoxan increased the amount of time spent investigating novel and unexpected objects in a familiar hole board. These results implicate the noradrenergic system in problem-solving which requires an attentional shift or a shift in responding from familiar to novel stimuli.

Idazoxan, an alpha-2 antagonist, facilitates memory retrieval in the rat.

The role of the noradrenergic system in cognitive function was studied by using the alpha-2 adrenoceptor antagonist idazoxan to increase noradrenergic activity. Rats were trained in a complex maze task for food reward. They were left undisturbed for a 4-week "forgetting" period and were treated with idazoxan, just before the retention test. The dose of idazoxan used had previously been shown to enhance firing of units of the locus coeruleus and to increase noradrenaline (NE) turnover in the forebrain. This pharmacological treatment effectively alleviated forgetting, while control rats showed significant decrement compared to their performance at the last training trial. A control experiment showed that the facilitative effect was not on learning or on ongoing performance of the task, since there was no effect on simple acquisition. The results are taken as support for the notion that NE plays a role in memory retrieval processes.

Priming stimulation of locus coeruleus facilitates memory retrieval in the rat.

Rats were trained to run a linear maze for food reinforcement. During the 5-week retention interval, they were implanted under electrophysiological control with fine stimulating electrodes aimed at the nucleus locus coeruleus (LC). When tested 5 weeks after training, control rats showed forgetting in that they made significantly more errors at the test trial than at the last training trial. Low-level stimulation of LC immediately before the test alleviated the forgetting in that this group made significantly fewer errors than the non-stimulated group on two successive days. The results are taken as behavioral evidence of a role for noradrenergic projections from LC in memory and attention.