Anticholinergic activity in the nervous system: Consequences for visuomotor function.

Acetylcholine is present in the peripheral and central nervous system, where it is involved in a number of fundamental physiological and biochemical processes. In particular, interaction with muscarinic receptors can cause adverse effects such as dry mouth, drowsiness, mydriasis and cognitive dysfunction. Despite the knowledge that exists regarding these common side-effects, little is known about how anticholinergic medications influence central motor processes and fine motor control in healthy individuals. This paper reviews critical visuomotor processes that operate in healthy individuals, and how controlling these motor processes are influenced by medications that interfere with central cholinergic neurotransmission. An overview of receptor function and neurotransmitter interaction following the ingestion or administration of anticholinergics is provided, before exploring how visuomotor performance is affected by anticholinergic medications. In particular, this review will focus on the effects that anticholinergic medications have on fixation stability, saccadic eye movements, smooth pursuit eye movements, and general pupil dynamics.

Medications influencing central cholinergic pathways affect fixation stability, saccadic response time and associated eye movement dynamics during a temporally-cued visual reaction time task.

RATIONALE: Anticholinergic medications largely exert their effects due to actions on the muscarinic receptor, which mediates the functions of acetylcholine in the peripheral and central nervous systems. In the central nervous system, acetylcholine plays an important role in the modulation of movement. OBJECTIVE: This study investigated the effects of over-the-counter medications with varying degrees of central anticholinergic properties on fixation stability, saccadic response time and the dynamics associated with this eye movement during a temporally-cued visual reaction time task, in order to establish the significance of central cholinergic pathways in influencing eye movements during reaction time tasks. METHODS: Twenty-two participants were recruited into the placebo-controlled, human double-blind, four-way crossover investigation. Eye tracking technology recorded eye movements while participants reacted to visual stimuli following temporally informative and uninformative cues. The task was performed pre-ingestion as well as 0.5 and 2 h post-ingestion of promethazine hydrochloride (strong centrally acting anticholinergic), hyoscine hydrobromide (moderate centrally acting anticholinergic), hyoscine butylbromide (anticholinergic devoid of central properties) and a placebo. RESULTS: Promethazine decreased fixation stability during the reaction time task. In addition, promethazine was the only drug to increase saccadic response time during temporally informative and uninformative cued trials, whereby effects on response time were more pronounced following temporally informative cues. Promethazine also decreased saccadic amplitude and increased saccadic duration during the temporally-cued reaction time task. CONCLUSION: Collectively, the results of the study highlight the significant role that central cholinergic pathways play in the control of eye movements during tasks that involve stimulus identification and motor responses following temporal cues.

Medications influencing central cholinergic neurotransmission affect saccadic and smooth pursuit eye movements in healthy young adults.

RATIONALE: Acetylcholine is an important neuromodulator in the central nervous system, where it plays a significant role in central functions such as the regulation of movement. OBJECTIVE: This study investigated the pharmacological effects of over-the-counter anticholinergic medications on saccadic and smooth pursuit eye movements, in order to establish the significance of central cholinergic pathways in the control of these centrally regulated oculomotor processes. METHODS: Sixteen subjects (mean age 23 ± 3 years, 9 females) performed pro-saccadic, anti-saccadic and smooth pursuit eye movement tests, while an eye tracker collected eye movement data. Oculomotor assessments were performed pre-ingestion, 0.5 and 2 h post-ingestion of drugs with varying degrees of central anticholinergic properties. The drugs tested were promethazine, hyoscine hydrobromide, hyoscine butylbromide and placebo. RESULTS: The drug intervention with stronger central anticholinergic properties, promethazine, decreased amplitude and increased velocity in the pro-saccadic task and increased duration in the anti-saccadic task. Promethazine, once again, was the only drug to decrease eye velocity in the smooth pursuit test. CONCLUSION: The prominent effects of the stronger central anticholinergic promethazine, on saccadic and smooth pursuit eye movements, potentially conveys the significance of central cholinergic pathways in the control of these centrally regulated oculomotor processes.

Central cholinergic pathway involvement in the regulation of pupil diameter, blink rate and cognitive function.

Anticholinergic medications can exert their effects by acting on muscarinic receptors, which mediates the function of acetylcholine in the central nervous system. Acetylcholine plays a number of roles, particularly in regard to the control of muscle activity and normal cognitive functioning. Eighteen subjects were recruited into the human, double-blind, placebo-controlled, four-way crossover study. Pupil diameter and blink rate were assessed at rest while eye tracking technology recorded eye characteristics. Thereafter a cognitive task was performed, where pupil size and blink rate were once again measured. Assessments were performed pre-ingestion, 0.5h and 2h following the ingestion of a strong centrally acting anticholinergic (promethazine hydrochloride), a moderate centrally acting anticholinergic (hyoscine hydrobromide), an anticholinergic devoid of central effects (hyoscine butylbromide) and placebo. At rest, hyoscine hydrobromide was the only medication to increase pupil diameter and no drug intervention influenced blink rate. During performance of the cognitive task, hyoscine hydrobromide increased pupil diameter and promethazine increased blink rate. Promethazine was the only medication to influence the modified attention network test (ANT) by increasing the conflict effect and grand mean reaction time (RT). Pupil diameter and blink rate were both influenced by the central anticholinergics during performance of the cognitive test, thus highlighting the importance of central cholinergic pathways in the control of pupil diameter and blink rate. The collective effects of central anticholinergics on the modified ANT and on pupil diameter and blink rate during its performance, conveys the importance of central cholinergic pathways in cognitive function.

The effects of antihistamines with varying anticholinergic properties on voluntary and involuntary movement.

OBJECTIVE: Recent evidence indicates that antihistamines can affect movement, which is most likely due to altered neurotransmission in cholinergic and histaminergic pathways. The purpose of this study was to determine if antihistamines with varying anticholinergic properties differentially affect voluntary and involuntary movement control. METHODS: Eleven healthy subjects were enlisted into a human double blind, placebo-controlled, five-way crossover study. Drowsiness, reaction time, and physiological tremor were examined 1-, 2-, and 3-hr post-ingestion of antihistamines with known anticholinergic profiles. These were the first-generation promethazine, and second-generation loratadine, desloratadine, and fexofenadine. Hyoscine butylbromide was used in an additional experiment to determine how a peripheral antimuscarinic drug influenced neuromotor function. RESULTS: Promethazine, desloratadine and fexofenadine increased drowsiness. Promethazine increased simple and choice reaction time and reduced tremor. Desloratadine increased choice reaction time and tremor, while loratadine slowed simple and choice reaction time. CONCLUSION: Central anticholinergic and antihistaminergic properties of antihistamines potentially contribute to movement dysfunction. SIGNIFICANCE: Second-generation antihistamines have provided the consumer with a safer alternative to the first-generation sedating antihistamine. However, the results of this study suggest that loratadine and desloratadine have the potential to affect movement control, and further research is warranted to understand the clinical relevance of these findings.