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

Department of Psychology, Cornell University, Ithaca, New York 14853-6301, USA.
Behavioral Neuroscience (Impact Factor: 2.73). 11/1995; 109(5):903-11. DOI: 10.1037//0735-7044.109.5.903
Source: PubMed


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(8):100. DOI:10.3389/fnins.2014.00100 · 3.66 Impact Factor
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    • "Specific effects of idazoxan in a distraction task have been previously shown in adult offspring, following maternal IV cocaine, without similarly affecting vigilance implicating endogenous norepinephrine influences on distractibility and/or selective attention (Bayer et al., 2002). The pattern of results and the specificity of the IDZ dose effect rules out non-specific alterations in performance (Bunsey and Strupp, 1995). Given that the noradrenergic system appears to be involved in the focusing of attention, possibly by attenuating distraction caused by irrelevant stimuli (Coull, 1994; Aston-Jones and Cohen, 2005), these data suggest alterations in the ascending noradrenergic system provide the basis for this “distracting” effect. "
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    ABSTRACT: One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants' startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long-Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8-20 (1×/day-GD8-14, 2×/day-GD15-20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18-20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90-100), a linear dose-response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α(2)-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.
    Frontiers in Psychiatry 06/2011; 2:38. DOI:10.3389/fpsyt.2011.00038
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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 · 3.69 Impact Factor
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