title: CNS safety pharmacology: A focus on cognitive functions.
abstract: BACKGROUND
  The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint.
  
  
  METHODS
  The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule.
  
  
  RESULTS
  Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated.
  
  
  CONCLUSIONS
  Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under development.
authors.affiliation: Porsolt, Z.A. de Glatigné, Le Genest-Saint-Isle 53940, France.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Hernier
authors.affiliation: Porsolt, Z.A. de Glatigné, Le Genest-Saint-Isle 53940, France. Electronic address: cfroger@porsolt.com.
authors.forename: Christelle
authors.initials: C
authors.lastname: Froger-Colléaux
authors.affiliation: Porsolt, Z.A. de Glatigné, Le Genest-Saint-Isle 53940, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castagné
mesh_terms: D000818:Animals; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D003071:Cognition / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D023381:Endpoint Determination; D004924:Escape Reaction / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000523:psychology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects; D012055:Reinforcement Schedule; D012193:Reversal Learning / Q000187:drug effects; D012449:Safety
keywords: Behavioral methods; Cognition; Diazepam; Haloperidol; MK-801; Nicotine; Rodents; Safety pharmacology; Scopolamine