Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests.
BACKGROUND
Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF(1) receptor antagonists are being developed as potential novel anxiolytics, but while CRF(1) receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF(1) receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF(1) receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.


OBJECTIVE
The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF(1) receptor antagonists in these tests.


RESULTS
The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF(1) receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects.


CONCLUSIONS
The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF(1) receptor antagonists seem to have a wider therapeutic index than benzodiazepines.
Hogan
John B
JB
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT, 06492, USA.
Hodges
Donald B
DB
Lelas
Snjezana
S
Gilligan
Paul J
PJ
McElroy
John F
JF
Lindner
Mark D
MD
D000054:Acceleration; D000284:Administration, Oral; D000525:Alprazolam / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001288:Attention / Q000187:drug effects; D002707:Chlordiazepoxide / Q000008:administration & dosage / Q000009:adverse effects*; D003071:Cognition / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D013550:Swimming; D013997:Time Factors; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000099052:CRF Receptor, Type 1
C417190:4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)pyrimidine; C404928:DMP 696; D011720:Pyrazoles; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; D002707:Chlordiazepoxide; D000525:Alprazolam