Premium
Discriminative stimulus effects of novel carbonic anhydrase activator BD117
Author(s) -
Spoon Taylor Alexis,
Sanku Rajesh Kishore Kumar,
Draghici Bogdan,
Ilies Marc A,
Walker Ellen
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.662.8
Subject(s) - carbonic anhydrase , acetazolamide , chemistry , stimulus control , bicarbonate , carbonic anhydrase ii , carbonic anhydrase inhibitor , pharmacology , activator (genetics) , biochemistry , neuroscience , enzyme , psychology , medicine , receptor , organic chemistry , nicotine
Carbonic anhydrase is a zinc enzyme that catalyzes the reversible hydration of carbon dioxide to bicarbonate and protons and is involved in brain homeostasis and regular cerebral function. Previous research from our laboratory has suggested that activation of carbonic anhydrase may protect against scopolamine, ketamine, and acetazolamide induced recognition memory deficits. However, the underlying pharmacology of carbonic anhydrase activation is unknown and what neurotransmitter systems are modified by a general activation of brain carbonic anhydrase isozymes. The purpose of the current project was to train our lead, novel carbonic anhydrase activator BD117 as a discriminative stimulus. Our in vitro and ex vivo studies indicate BD117 is brain penetrant and will activate key carbonic anhydrase isozymes in the brain such as hCA‐IV, hCA‐VA, and hCA‐IX. We hypothesize that BD117 can serve as a discriminative stimulus and other carbonic anhydrase activators with a similar profile will substitute for BD117. In addition, we predict the discriminative stimulus effects of BD117 will be antagonized by carbonic anhydrase inhibitor acetazolamide. Initial experiments examined doses of BD117 on response rates in Swiss‐Webster, male mice (n=11). We found doses above 3 mg/kg reduced responding for food reinforcement. Therefore, a lower dose of 0.3 mg/kg BD117 and saline were initially chosen as the discriminative stimuli for food‐reinforced responding using a two‐choice operant training procedure. After 20 training sessions, no evidence of discriminative control was obtained and no evidence of rate‐decreasing effects was observed. Therefore, the training dose was increased to 1.0 mg/kg BD117. After meeting testing criterion, six consecutive days of correct nose‐poke appropriate responding, mice were tested with additional doses of BD117. BD117 produced dose‐dependent substitution without decreasing response rates at the doses tested. In summary, BD117 was established as a discriminative stimulus. To the best of our knowledge, this is the first example of a central nervous system enzyme activator trained as a discriminative stimulus. These results and additional future studies will further our understanding of the role carbonic anhydrase in functional processes in the brain.