Muscarinic antagonists are anxiogenic in rats tested in the black-white box

Central cholinergic (ACh) projections have been shown to modulate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and are integral to the expression of electrophysiological correlates of arousal, namely hippocampal theta rhythm. The degree to which these actions of ACh are behaviorally relevant has received comparatively less attention, and we sought to investigate if manipulations of ACh systems might also affect behaviors related to stress and arousal. We chose to examine indices of anxiety as revealed by changes in behavior elicited by the black-white box test, a relatively novel and recently validated model of rodent anxiety. Groups of rats were injected with either scopolamine hydrobromide (SCOP; 0, 0.05, and 0.10 mg/kg i.p.) or the peripherally acting scopolamine methyl bromide (methyl-SCOP; 0, 0.05, and 0.10 mg/kg i.p.) to compare and contrast the effects of central and peripheral ACh blockade on measures of anxiety. SCOP pretreatment significantly lowered latencies for rats to escape from the white to black compartment, while methyl-SCOP elevated latencies to reenter the white chamber from the black. Both drugs increased the amount of time rats spent in the black compartment and also suppressed exploration as revealed by decreased episodes of intercompartmental locomotion. Neither drug deleteriously affected locomotor activity, however; in fact, SCOP significantly increased locomotion in the white chamber. In the absence of motor disturbances to account for any group differences, we contend that both central and peripheral ACh blockade may affect measures of anxiety, perhaps by directly or indirectly affecting HPA activity. Central ACh systems may underlie sensory filtering whereby irrelevant stimuli are excluded from sensory processing. Antagonism of ACh transmission may render an animal incapable of correctly processing sensory information leading to hyperresponsiveness, which can manifest itself as enhanced anxiety and fear.