Specific effects of idazoxan in a distraction task: Evidence that endogenous norepinephrine plays a role in selective attention in rats

Department of Psychology, Cornell University, Ithaca, New York 14853-6301, USA.
Behavioral Neuroscience (Impact Factor: 3.25). 11/1995; 109(5):903-11. DOI: 10.1037//0735-7044.109.5.903
Source: PubMed

ABSTRACT Rats were injected with the alpha 2-adrenergic antagonist idazoxan (IDZ) prior to testing on vigilance and distraction tasks. In the vigilance task, rats responded with nose pokes to brief visual cues presented at variable intervals following trial onset. The distraction task was similar except that irrelevant odor cues (distractors) were presented in the interval prior to light onset on some trials. IDZ injection had no effect on performance in the vigilance task. In the distraction task, however, the higher IDZ dose (1.0 mg/kg) modulated the propensity to make a premature response when the distractors were presented. Notably, the direction of the effect varied with the rats' baseline level of distractibility. This pattern of effects suggests that endogenous norepinephrine (NE) influences distractibility and/or selective attention.

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    • "Ablation of the ascending NE system increases distractibility (Carli et al., 1983) but agonists of the inhibitory alpha-2 autoreceptor, which decrease NE tone, suppress distractibility (Clark et al., 1989; Witte and Marrocco, 1997). Moreover, the effects of alpha-2 antagonists on distractibility are dependant on individual variation in baseline distractibility (Bunsey and Strupp, 1995). Additionally, it remains unclear whether variations in NE levels within the normal physiological range predict distractibility. "
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    ABSTRACT: Complex natural environments favor the dynamic alignment of neural processing between goal-relevant stimuli and conflicting but biologically salient stimuli like social competitors or predators. The biological mechanisms that regulate dynamic changes in vigilance have not been fully elucidated. Arousal systems that ready the body to respond adaptively to threat may contribute to dynamic regulation of vigilance. Under conditions of constant luminance, pupil diameter provides a peripheral index of arousal state. Although pupil size varies with the processing of goal-relevant stimuli, it remains unclear whether pupil size also predicts attention to biologically salient objects and events like social competitors, whose presence interferes with current goals. Here we show that pupil size in rhesus macaques both reflects the biological salience of task-irrelevant social distractors and predicts vigilance for these stimuli. We measured pupil size in monkeys performing a visual orienting task in which distractors-monkey faces and phase-scrambled versions of the same images-could appear in a congruent, incongruent, or neutral position relative to a rewarded target. Baseline pupil size under constant illumination predicted distractor interference, consistent with the hypothesis that pupil-linked arousal mechanisms regulate task engagement and distractibility. Notably, pupil size also predicted enhanced vigilance for social distractors, suggesting that pupil-linked arousal may adjust the balance of processing resources between goal-relevant and biologically important stimuli. The magnitude of pupil constriction in response to distractors closely tracked distractor interference, saccade planning and the social relevance of distractors, endorsing the idea that the pupillary light response is modulated by attention. These findings indicate that pupil size indexes dynamic changes in attention evoked by both the social environment and arousal.
    Frontiers in Neuroscience 05/2014; 8:100. DOI:10.3389/fnins.2014.00100 · 3.70 Impact Factor
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    • "In the present study, atipamezole administration enhanced cognitive function, specifically ED set-shifting, that had been compromised by CUS treatment. Blockade of α 2 -adrenergic autoreceptors enhances NE release in brain regions such as neocortex (Devauges and Sara, 1990; Garcia et al., 2004; Haapalinna et al., 1998), and improves performance in various learning and memory tests (Bunsey and Strupp, 1995; Devauges and Sara, 1990; Sara et al., 1994). Atipamezole has been shown to enhance acquisition in a linear-arm maze test, improve choice accuracy of poorly performing rats in a delayed three-choice test (Haapalinna et al., 1998), and facilitate passive avoidance retention in aged rats (Riekkinen et al., 1992). "
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    ABSTRACT: Chronic stress is a risk factor for many psychopathological conditions, including depression and anxiety disorders. Cognitive impairments associated with prefrontal cortical dysfunction are a major component of such illnesses. Using an attentional set-shifting test (AST), we have previously shown that elevating noradrenergic activity in rat medial prefrontal cortex (mPFC) can facilitate cognitive set-shifting, and that chronic unpredictable stress (CUS) caused set-shifting deficits. It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST. This deficit was abolished by acute systemic administration of the alpha(2)-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake blocker, desipramine, during the CUS treatment through behavioral testing. Again, CUS impaired cognitive set-shifting in vehicle-treated rats, and chronic desipramine treatment prevented such deficits. Acute blockade of post-synaptic alpha(1)-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating alpha(1)-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment of depression.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2010; 34(6):913-23. DOI:10.1016/j.pnpbp.2010.04.016 · 4.03 Impact Factor
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    • "learning, and memory (Aston-Jones et al., 1991; Bunzey and Strupp, 1995; Devauges and Sara, 1991; Lapiz and Morilak, 2006; Sara and Devauges,1989). In contrast, α 2 -AR agonists administration that reduces noradrenergic transmission has deleterious effects on attention (Smith and Nutt, 1996) and target detection (Coull et al., 2004). "
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    ABSTRACT: Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear. We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function. Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination. Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.
    Pharmacology Biochemistry and Behavior 10/2008; 90(3):372-81. DOI:10.1016/j.pbb.2008.03.011 · 2.82 Impact Factor
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