A behavioural operant discrimination model for assessment and pharmacological manipulation of visual function in rats.
A large number of commercially available drugs are known to cause visual side effects in humans. Therefore, it would be advantageous to screen for alterations in visual function at a pre-clinical stage. Available methods, however, lack control for motivational and motoric side effects. The aim of the present study was therefore to develop a behavioural test to detect and quantify drug-induced visual side effects while simultaneously controlling for other side effects. We here present a novel model based on operant conditioning methodology with a food rewarded two-choice design to assess visual acuity and contrast sensitivity in rats. Rats were trained to discriminate between computer-generated sine-wave gratings and homogenous grey stimuli of equal luminance. They were subsequently tested with novel stimuli differing to training stimuli according to either spatial frequency or contrast. Finally, we tested how visual acuity was affected by oral administration of quinine HCl, a compound known to affect visual function in man. The rats learned to discriminate visual stimuli within 4-5weeks of twice daily training. A training procedure with moving stimuli achieved faster learning than with static stimuli. The visual detection threshold for discrimination of grating patterns decreased as a function of the contrast level, ranging from a spatial frequency of 0.8cycles/degree (c/d) at 100% contrast to 0.2c/d at 12.5%. Administration of quinine HCl was shown to affect the visual acuity threshold in a dose- and time dependent manner. In addition, response rate was affected by quinine administration but temporally isolated from the attenuation of visual acuity demonstrating that this model can separate the visual effects from motoric and motivational side effects.
Carlsson
Mikael A
MA
Department of Safety Pharmacology, AstraZeneca R&D, SE-15185 Södertälje, Sweden. mikael.carlsson@zoologi.su.se
Swedberg
Michael D B
MD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D015350:Contrast Sensitivity / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D009125:Muscle Relaxants, Central / Q000633:toxicity; D011803:Quinine / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D014792:Visual Acuity / Q000187:drug effects*
D009125:Muscle Relaxants, Central; D011803:Quinine