Attention-modulating effects of cognitive enhancers

Abstract

Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

Figure 1

Diagram of operant signal detection attention task. This task comprised two types of trials, signal and blank, which differed only in that a signal was presented in each signal trial and omitted in blank trials. In each trial, the rat pressed either of two retractable levers to report that a signal had or had not occurred in that trial. Four possible outcomes result: hit, miss, false alarm and correct rejection. Hits and correct rejections were followed by delivery of food; misses and false alarms by a 2 sec “time out” period without food. An increase in hit and or correct rejection indicates improvement in sustained attention and a decrease in these parameters indicates impairment in attentional performance. VI stands for variable intervals for pre- and post-signal during the signal trial (Bushnell, 1998; Bushnell et al., 2003; Bushnell et al., 1997b; Rezvani et al., 2002; Rezvani et al., 2011; Rezvani et al., 2009a; Rezvani et al., 2009b; Rezvani et al., 2008).

Figure 2

Attentional performance of rats and humans on signal detection Tasks (SDTs) on proportions of hits relative to the total signal trial responses [P(hit]) and false alarms relative to the total blank trial responses [P(fa)] as a function of the signal intensity (Bushnell et al., 2003). The effect of the rate of trial presentation (trials per minute or TPM) was assessed. Both rats and humans showed a specific TPM for optimal attentional accuracy.

Figure 3

Effects of cholinergic and alpha2-adrenergic drugs on proportions of hits relative to the total signal trial responses P(hit) and false alarms relative to the total blank trial responses [P(fa)] as a function of the signal intensity. In each panel, the upper curves show values of P(hit) and lower curves P(fa). The values on the abscissa indicate the intensities of the 300-msec signals as increments in intensity above a background illumination of 1.20 lux. In the key, Saline refers to vehicle; Low, Medium and High refer to the three doses of each drug administered. Doses were as follows: Pilocarpine: 1.0, 1.8, and 3.0 mg/kg; Scopolamine: 0.030, 0.056, 0.10 mg/kg; Nicotine: 0.083, 0.25, and 0.75 mg/kg; Mecamylamine: 1.8, 3.0, and 5.6 mg/kg; Clonidine: 0.003, 0.010, 0.030 mg/kg; and Idazoxan: 1.0, 3.0, and 10.0 mg/kg. Values are means; the error bars indicate SEM above and below the means.

Figure 4

Methylphenidate attenuated the percent correct rejection impairment (Rezvani et al., 2009b; Rezvani et al., 2008) on the operant signal detection attention task in rats caused by:

1. The muscarinic cholinergic antagonist scopolamine;

2. The nicotinic antagonist mecamylamine; and

3. The NMDA glutamate antagonist dizocilpine: percent correct rejection (mean±sem)