Michael Grzelak

SCH 57790, a selective muscarinic M2 receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A2A receptors

Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A(1) or A(2A) receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A(2A) antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A(1) antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A(2A) agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3-10mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1-1mg/kg PO) and KW-6002 (1-3mg/kg PO), but not DPCPX (3-30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A(2A) receptor blockade, and selective A(2A) receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A(2A) agonists have potential as novel antipsychotics.