Feb 13, 2007 - pfiesteria piscicida exposure in rats: attention and visual function vs. Behavioral plasticity. Neurotoxicology and. Teratology 23, 609â616.
International Journal of Neuropsychopharmacology (2008), 11, 63–70. Copyright f 2007 CINP doi:10.1017/S1461145706007528
Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats
ARTICLE
CINP
Amir H. Rezvani, Ehsan Kholdebarin, Elizabeth Dawson and Edward D. Levin Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
Abstract Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p Light >VI 2–4 s Signal trial Blank lever
Hit
Food
Miss
Time out
False alarm
Time out
Levers extended Signal lever No signal Blank trial Blank lever
Correct rejection
Food
Time
Figure 1. Signal detection task sequence of trials. This task comprised two types of trials, signal and blank, which differed only in that a light signal was presented in each signal trial and omitted in blank trials. In each trial, the rat pressed either of two retractable levers to report that a light signal had or had not occurred in that trial. Four possible outcomes can result in each trial : hit, miss, false alarm and correct rejection. Hits and correct rejections were followed by delivery of food ; misses and false alarms by a 2 s ‘time out’ period without delivery of food. VI stands for variable intervals for pre- and post-signal during the signal trial.
Each signal trial included a pre-signal interval, the signal (cue light), and a post-signal interval. The presignal intervals were selected randomly from 12 different values ranging from 0.3 to 24.4 s. Following the signal, a post-signal interval of 2, 3 or 4 s (selected randomly) occurred. These temporal parameters yielded a trial presentation rate of five trials/min. Blank trials were presented identically to the signal trials but without a signal light. The training sessions were initiated a few days after rats arrived in the laboratory. First, rats were handled for 5–10 min for 3–4 d to become accustomed to human handling. Then they were trained to perform the visual signal detection task (Bushnell, 1998 ; Bushnell et al., 1997 ; Rezvani et al., 2005, 2006 ; Rezvani and Levin, 2003a,b). Training started with simple tasks of eating pellets from the food cup, pressing a designated lever under an illuminated signal light to receive a pellet, and pressing another designated lever without a signal light to receive a pellet. As the training progressed and their levels of performance reached around 70 %, the signal light was gradually moved up. Eventually, the signal light was located above the food cup at the centrer of the front panel, 28 cm above the floor of the chamber. It should be noted that regardless of the location of the signal light it was always associated with a designated lever (right lever for half of the chambers and left lever for other half). It took around 3 months to train the rats for this task.
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A trial began with both levers retracted from the chamber. Then at the end of the post-signal interval both levers were inserted into the chamber simultaneously. At this point, the rats had the option to press or not to press either lever. The levers were both retracted when one was pressed or if 5 s elapsed without a response. If the rat failed to press a lever, a response failure was recorded and the trial was not repeated. Every correct response (i.e. a press on the signal lever in a signal trial or a press on the blank lever in a blank trial) was immediately followed by the illumination of the food cup and delivery of one 20-mg food pellet. After each incorrect response (i.e. a press on the signal lever in a blank trial or a press on the blank lever in a signal trial), or response failure, the rat received a 2 s period of total darkness (time out) (Figure 1). For half the rats, the left lever was defined as the signal lever and the right lever as the blank lever ; the opposite assignment was made for the remaining rats (Rezvani et al., 2002 ; Rezvani and Levin, 2003a,b). Behavioural measures and statistical analysis of data Percent hit and percent correct rejection were taken as dependent variables in each experiment. The analysis of percent hit also included light stimulus intensity as a within-subject factor. The test session was divided into three blocks of 80 trials and measures of response accuracy were analysed across blocks as a repeated measure. The threshold for significance for tests of the hypotheses of drug-induced changes in performance was set at p
