Impact of Psychoactive Drugs

Psychopharmacological research on attentional functions has intensified during recent years, fostered in part by an increasing understanding of the fundamental relevance of attentional capacities for learning and memory (Sarter and Lustig 2008), the identification of neuronal mechanisms and brain systems mediating attention (Raz and Buhle 2006), and the development and validation of tasks for the measurement of attentional processes and capacities in laboratory animals and humans. Psychopharmacological research in rodents has enormously progressed as a result of the introduction of translational tasks for the measurement of attentional capacities, particularly the ► five-choice serial reaction time task (Robbins 2002) and operant sustained and divided attention tasks (Arnold et al. 2003). Research in humans likewise has evolved, due in part to advances in cognitive theories of attention and the development of new test paradigms and their successful use in neuroimaging studies (Awh and Jonides 2001). The assessment of effects of psychoactive drugs on attentional performance-associated brain activity patterns ("phar-maco-fMRI'') represents a particularly informative new approach as effects on attention can be attributed to modulation of activity in the distributed neuronal circuits known to mediate attention. The literature on psychotro-pic drug effects on attention is extensive and diverse; below, selected major research themes on the psychophar-macology of attention are briefly discussed.

Do the ► amphetamines facilitate attention and benefit the attentional symptoms of ADHD? Amphetamine and related stimulants, including ► methylphenidate, produce a wide range of effects in laboratory animals, including effects on response output and response speed that are a function of baseline response rates and the type of response required. Furthermore, these drugs affect complex motivational processes, often in interaction with the requirements for responding, the testing environment, and the animals' motivational state. Attentional performance can be affected indirectly as a result of such effects on response output or motivational processes. However, the available evidence does not conclusively indicate that psychostimulants generally and selectively enhance atten-tional processes or capacities. Evidence from healthy humans likewise does not indicate robust support for psychostimulant-induced enhancement of attention (Koelega 1993).

Psychostimulant treatment benefits the behavior and academic performance of patients with ADHD. However, similar to effects of these drugs in laboratory animals, the behavioral and cognitive mechanisms underlying the beneficial treatment effects in ADHD patients have remained unsettled. Furthermore, psychostimulants may act primarily by attenuating the high levels of cognitive and behavioral impulsivity of ADHD patients. Studies show that the benefits of psychostimulants on overall behavior and academic performance, indicated typically by ratings from parents and teachers, in fact were not associated with normalization of cognitive deficits. Thus, collectively, psychostimulants produce a wide range of effects that may, depending on the testing conditions, produce limited beneficial effects on attentional performance. However, it seems less likely that these compounds specifically enhance the attentional capacity of healthy subjects and/or that they specifically attenuate the attentional impairments associated with ADHD.

Do wake-promoting drugs such as modafinil enhance attention? ► Modafinil is a well-tolerated and relatively safe drug, and has therefore become a widely and increasingly recreationally used treatment to combat sleepiness and the cognitive components of sleepiness, including attentional impairments (Minzenberg and Carter 2008). However, numerous studies also suggested that administration of modafinil enhances cognitive performance per se, independent of its main wake-promoting properties. Similar to the psychostimulants, modafinil appears to act via stimulation of dopaminergic neurotransmission, requiring functional ► dopamine D1 and D2 receptors to induce wakefulness. Likewise, modafinil was not found to produce selective effects on attention in animals that were not sleep-deprived. Furthermore, and also similar to the effects of psychostimulants, modafinil was demonstrated to enhance inhibitory response control in laboratory animals and to improve the symptoms of ADHD.

Modafinil was found to benefit the impaired attentional set-shifting capacities of schizophrenic patients, suggesting that this drug may have significant clinical usefulness as a co-treatment for this disorder. As the treatment of schizophrenic patients with amphetamine was also reported to benefit their cognitive abilities, it is intriguing to hypothesize that modafinil produces effects on attentional set-shifting by stimulating the down-regulated dopamine D1 receptors observed in the prefrontal cortex of these patients. Collectively, new wake-promoting compounds such as modafinil may produce relatively specific attentional enhancement in disorders associated with dopaminergic abnormalities in prefrontal regions.

Noradrenergic agents. Hypotheses concerning the contributions of forebrain noradrenergic afferents to the mediation of attention have originated from observations demonstrating increases in cortical "signal-to-noise" ratios following local administration of noradrenaline and the increased distractibility of animals with noradrenergic depletions. Neurophysiological recordings of the locus coeruleus, the main source of noradrenergic projections to the cortex, indicated multiple and complex contributions of phasic and tonic changes in noradrenergic activity to attention. However, the determination of specific attentional functions of the noradrenergic system in behavioral experiments, and their dissociation from more general effects on "arousal" or "alertness," continues to represent a challenging subject. These problems generalize to psychopharma-cological studies on the effects of noradrenergic compounds on attention. The studies have focused overwhelmingly on the effects of alpha-2 adrenergic receptor agonists (clo-nidine, guanfacine, dexmedetomidine) and, more recently, the noradrenaline-reuptake inhibitor ► atomoxetine.

The evidence concerning the attentional effects of alpha-2 agonists in animals and humans is conflicting and remains inconclusive. In animals and humans, beneficial as well as detrimental effects on attention following the treatment of clonidine and guanfacine were reported. The presence and direction of the attentional effects of these drugs appear to depend on specific task parameters, testing conditions, and the subjects' level of "alertness" at baseline. The interpretation of these conflicting findings is further complicated by results indicating that alpha-2 antagonists such as idaxozan and atipamezole likewise enhance aspects of attentional performance in healthy volunteers and patients. A definition of the experimental conditions that foster the demonstration of beneficial versus detrimental attentional effects of alpha-2 agonists is clearly needed. Treatment with drugs such as guanfacine may benefit the attentional impairments of particular disorders, based perhaps on an "optimization" of noradrenergic neurotransmission (Arnsten et al. 2007).

This latter statement may also hold true for the atten-tional effects of the noradrenaline uptake inhibitor ato-moxetine. Beneficial attentional effects of this drug were demonstrated in animals with reduced levels of noradren-ergic neurotransmission, but not consistently in intact animals. While recent clinical studies suggested efficacy in patients with ADHD, the precise cognitive mechanisms that are enhanced by atomoxetine is not known. Extensive psy-chopharmacological research, involving controlled studies and the test of hypotheses predicting specific attentional mechanisms that are modulated by noradrenergic drugs, are required in order to render conclusions about the general pro-attentional efficacy of noradrenergic drugs.

Attentional enhancement by agonists at ► nicotinic ace-tylcholine receptors (nAChRs). The cortical cholinergic input system represents a key branch of the forebrain circuits that mediate attentional functions and capacities (Sarter et al. 2005). Recent evidence indicated that pre-frontal cholinergic activity mediates a switch from intrinsic or associational processing to the processing of external stimuli, and thereby the detection and selection of stimuli in attention-demanding situations. Neuroimaging studies suggested that administration of nicotine enhances the processing of attentional information by attenuating the activity of the brain during resting periods.

Therefore, it would be expected that drugs that block or stimulate the fast and reversible component of post-synap-tic cholinergic neurotransmission, the nAChR, robustly impair or benefit, respectively, attentional performance. While robust impairments in attentional performance following nAChR blockade with ► mecamylamine can be readily shown in humans and animals, the demonstration of nicotine-evoked attentional enhancement in healthy (nonsmoking) humans and drug-naive animals has been less straightforward. Several experiments in humans and animals clarified that in interaction with increased demands on attentional performance, including the demands for top-down processing (e.g., by requiring performance during the presence of distractors), ► nicotine reliably enhances attentional performance. Collectively, these findings indicate the importance of integrating variations of the demands on attention as a secondary independent variable into experiments testing the effects of nicotine on attentional performance (Hahn et al. 2003).

Compared to the effects of nicotine, drugs that act at subtypes of the nAChR, particularly at alpha4/

beta2*nAChRs, were found to produce more robust effects on attentional capacities in humans and animal experiments. Ligands that selectively stimulate alpha4/beta2*-nAChRs and have been under investigation for treating cognitive disorders include ABT-089, ABT-418, isproni-cline, and SIB1765F. Furthermore, promising effects of such drugs in tests of their therapeutic efficacy in patients with ADHD, schizophrenia, and dementia were reported. The attentional benefits of compounds acting at other nAChR subtypes, such as alpha7 nAChRs, remain less clear, largely because little evidence on the effects of these drugs has accumulated.

The neuropsychopharmacological reasons why agonists at alpha4/beta2*nAChRs may exhibit greater atten-tional enhancement than nonspecific agonists such as nicotine are largely unknown. However, evidence from experiments determining the effects of nAChR agonists on the transient increases in prefrontal cholinergic activity that mediate the detection of cues begins to form the basis for hypotheses. This evidence indicated that selective agonists at alpha4/beta2*nAChRs augment these transient increased without altering the "shape" (rise and clearance rates) of these transients. In contrast, nicotine, via stimulation of additional receptors and mechanisms, not only is less potent in augmenting the amplitude of these transients but drastically prolongs the duration of cholinergic activity. It is intriguing to speculate that such "blunting" of a critical neuronal signal interferes with, or at least limits, the enhancement of the detection process that is key to improving attentional performance.

Collectively, drugs that directly stimulate subtypes of nAChRs or modulate the stimulation of these subtypes by acetylcholine appear to produce specific and efficacious effects on attentional functions and thus are promising candidates for clinical use. Moreover, the accumulating evidence on the attentional effects of these drugs informs theories concerning the general neurobiological mediation of attention.

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