Faculty Bibliography

Neuromodulatory properties of noradrenaline (NA) suggest that the coreruleo-cortical NA projection should play an important role in attention and memory processes. Our research is aimed at providing some behavioral evidence. Single units of the locus coeruleus (LC) are recorded during controlled behavioral situations, in order to relate LC activation to specific behavioral contexts. LC cells respond in burst to imposed novel sensory stimuli or to novel objects encountered during free exploration. When there is no predictive value of the stimulus or no behavioral response required, there is rapid habituation of the LC response. When a stimulus is then associated with reinforcement, there is a renewed response, which is transient. During extinction, LC neuronal responses reappear. Thus, LC cells respond to novelty or change in incoming information, but do not have a sustained response to stimuli, even when they have a high level of biological significance. The gating and tuning action of NA released in target sensory systems would promote selective attention to relevant stimuli at the critical moment of change. The adaptive behavioral outcome would result from the integration of retrieved memory with the sensory information selected from the environment

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 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

Effects of chronic nicotine treatment on spatial memory were studied in rats. After 3 weeks of administration of 2.5mg/kg/day in drinking water, the rats were submitted to a spatial learning task in an eight-arm radial maze, during which time the treatment was maintained. Chronic nicotine treatment improved daily spatial memory performance after the animals reached an asymptotic level. Nicotine-treated animals showed significantly better performance than control animals regarding the first error and the total correct path choices

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

Rats with unilateral or bilateral partial section of the fornix were impaired on an eight arm radial maze task. Neurochemical analysis of hippocampal tissue four weeks after the lesions revealed a 50% reduction of choline acetyltransferase (ChAT) activity. The cholinergic marker was correlated negatively with the number of errors in the maze; the lower the ChAT activity, the higher the error score. The fornix lesion also induced a 50% reduction in norepinephrine (NE), but no change in the noradrenergic metabolite methylhydroxyphenylglycol (MHPG), suggesting a net increase in turnover of NE in these animals. Additional lesion of the noradrenergic system with the neurotoxin DSP4 reduced both MHPG and NE levels by more than 90%, compared to nonlesioned controls, and reversed the behavioral deficit. This treatment had no further effect on cholinergic markers. There was a significant negative correlation between ChAT activity and the index of NE turnover, suggesting that hyperactivity in the noradrenergic system after fornix section inhibits the spared cholinergic function and thus exacerbates the cognitive deficit. The pattern of neurochemical results bear a striking resemblance to those seen in some Alzheimer's patients and suggest that an equilibrium among neurotransmitters is important to cognitive function

Glutamate pressure ejections in the vicinity of locus coeruleus (LC) neurons have been shown to produce both short and long-lasting potentiation of perforant path (PP) evoked population spike amplitude in the dentate gyrus (DG). These effects of LC-glutamate activation resemble those produced by direct application of NE in vitro or in vivo. The present study monitored the cellular response of LC neurons to local glutamate ejections concomitant with stimulation of the PP evoked potential. Double barrel micropipettes or 33 ga cannula-electrode assemblies permitted LC unit recording and glutamate ejection at or near the same site in urethane anesthetized rats. Glutamate ejections produced a burst of LC activity lasting 250-400 ms and followed by a depression of unit activity lasting 4.6 min. The maximal spike potentiation produced by LC activation was 158%. The first spike to exceed the control range occurred 34 s after the LC burst. Comparable silent intervals in LC unit activity induced by systemic clonidine were not accompanied by population spike amplitude potentiation. The mean duration of potentiation was 4.4 min except in four cases where responses remained potentiated for the duration of the experiment. The duration of potentiation was not correlated with the termination of LC depression. LC units recovered to baseline rates following glutamate induced depression of activity. The occurrence of potentiation appeared to require that glutamate activation reach a critical number of LC neurons since small glutamate ejections could produce a local burst without eliciting potentiation. Long-lasting changes were also related to larger glutamate volumes (100 nl).(ABSTRACT TRUNCATED AT 250 WORDS)

Rats received knife-cuts to the dorsal fornix or sham-operations. Half of the animals from each group were injected with clonidine (0.01 mg/kg) and the others with saline before each daily trail of a 10-trial radial 8-arm maze task. The number of choices before the first repetition and the run time were used as performance indices. Lesioned rats were significantly impaired in the acquisition of this task. Clonidine-treated rats, lesioned or not, had an acquisition profile indistinguishable from that of sham-operated saline-injected rats, in spite of their increased run time. When tested one week after the last learning trial in a no-drug condition, lesioned rats treated with clonidine throughout learning maintained a high level of performance during the 5-day retraining phase. A parallel analysis of theta rhythms recorded in an independent group of rats placed in equivalent treatment and/or lesion conditions was then performed. Preoperatively, clonidine injections decreased theta frequency during both alert immobility and movement. Partial fornix lesions produced an increase in theta frequency. Finally, clonidine in fornix-damaged rats decreased theta frequency, thus reinstating the postoperative values at a level statistically no different from that recorded preoperatively. The role of clonidine in restoring the function of the septo-hippocampal input in partially fornix-damaged rats through a noradrenergic modulation of hippocampal acetylcholine release is discussed

Idazoxan (IDA), an alpha 2 receptor antagonist which increases firing rate of noradrenergic neurons in the locus coeruleus (LC) and release of noradrenaline (NA) in target structures, was used to study the neuromodulatory effects of NA in the hippocampus in awake rats. After IDA the population spike in the dentate gyrus (DG), evoked by a single pulse to the perforant path, was greatly enhanced with no effect of the drug on excitatory postsynaptic potentials (EPSPs). Paired pulses with short interpulse intervals (25-30 ms) produced inhibition of the response to the second pulse which was increased by IDA. This drug effect was independent of its effect on the amplitude of the first spike, since the increase in inhibition was seen at stimulation intensities which did not increase the response amplitude to the initial pulse. Thus both excitability and inhibitory processes can be enhanced in the same population of neurons by an alpha 2 adrenoceptor antagonist

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