Enhancement of attentional performance by selective stimulation of alpha4beta2(*) nAChRs: underlying cholinergic mechanisms

Abstract

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2(*) nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.

Figure 1

Baseline SAT performance and effects of S 38232 and nicotine on SAT performance: (a) depicts baseline hit rate as a function of signal duration and (b) shows the correct rejection rate of the three blocks of trials. Baseline performance did not differ between groups that were treated with nicotine or S 38232, respectively. Administration of the highest dose of nicotine decreased the number of hits to longest signals (c). All doses of nicotine decreased the correct rejection rate in block 1 (e). Administration of S 38232 did not affect hits (d). A small decrease in the relative number of correct rejections in block 2 was caused by the highest dose (f). The main effects of signal duration are indicated in (c) and (d). (For this and subsequent figures: ^*p<0.05, ^**p<0.01; ^***p<0.001; based on multiple comparisons conducted on the basis of significant results of ANOVA; see Results.).

Figure 2

Characterization of the effects of distractor presentation on performance: (a) depicts the relative number of hits for all three signal durations and across the three blocks of trials. Note that the hit rate to longest, but not to shortest, signals recovered partly during the post-distractor block of trials. In contrast, correct rejections recovered completely (b). (c) Administration of S 38232 significantly benefited the hit rate during the post-distractor block of trials. As shown in (d), the administration of nicotine did not affect dSAT performance. In contrast, co-administration of nicotine and MLA enhanced the hit rate in all three blocks of trials (e). Although (d) suggests that the beneficial effects of this co-treatment were most pronounced during the post-distractor block of trials, ANOVA indicated that the effects of treatment and block did not interact significantly. ^*p<0.05; ^**p<0.01; ^***p<0.001.

Figure 3

Transient increases in prefrontal acetylcholine release evoked by S 38232 and nicotine (the data on nicotine are used for comparison and were adopted from Parikh et al, 2008). (a, b) provide examples of individual traces evoked by S 38232 (a) and nicotine (b; arrows indicates the time of drug administration). These traces exemplify the strikingly ‘sharper' transients evoked by the α4β2^* nAChR agonist when compared with the slower decay rate of nicotine-evoked cholinergic transients. The slower decay of nicotine-evoked transients indicates ongoing and only slowly decreasing acetylcholine release; (b) also illustrates the ‘sharpening' of nicotine-evoked cholinergic transients by blocking the α7 nAChR with MLA. (c) The time required for transients to reach peak amplitude (‘rise time') increased dose dependently for nicotine, but not for S 38232; indeed, the rise time for transients evoked by 2000 pmol of S 38232 did not differ from rise times of transients evoked by 200 or 40 pmol. Furthermore, by the second highest dose of drug (200 pmol), nicotine-evoked transients required significantly more time to reach peak amplitude when compared with α4β2^* nAChR agonist-evoked transients. The two individual data points shown in (c) indicate that blocking the α7 nAChR, by co-administration of MLA, shortened the rise time of nicotine-evoked cholinergic transients. (d) S 38232 was more potent, but not more efficacious, with respect to the peak amplitudes of cholinergic transients. The two lower doses of S 38232 evoked significantly larger amplitudes than similar doses of nicotine. The two individual data points in (d) indicate that blocking the α7 nAChR did not robustly reduce the amplitudes of nicotine-evoked transients. As described in Results, blocking α4β2^* nAChR almost completely attenuated the amplitudes that were evoked by S 38232 (2 nmol). (e) Transients evoked by nicotine were relatively slow to return to baseline, requiring 70 s after the highest dose to decrease to 50% of peak current (t₅₀). In contrast, t₅₀ values of transients evoked by S 38232 were largely flat across doses and remained under 10 s.Co-administration of MLA accelerated the decay rate of nicotine-evoked cholinergic signals, reducing t₅₀ values close to those for transients evoked by the selective α4β2^* nAChR agonist (see individual data points). Taken together, the results shown in (c–e) indicate that S 38232 evokes ‘sharper' cholinergic transients than nicotine.