Response to the letter to the editors: The latent inhibition model of schizophrenic attention disorder and of antipsychotic drug action: comment on Dunn, Atwater and Kilts (Psychopharmacology, 1993, 112:315–323)

Abstract

The contributions of Weiner and Feldon are seminal to the literature on latent inhibition (LI). We recognized the priority of their work, theoretical and experimental, in our introduction. Our introduction is a very succint effort to provide a rationale for the use of LI as an animal behavioral model of antipsychotic drug action to a reader new to the paradigm. It is not an inclusive review of the literature. The prominent position of the work of Weiner and Feldon on LI and its use in understanding drug effects on attention, particularly as they relate to schizophrenia, is such that we did not feel the issue of precedence needed to be addressed in any greater detail. Our paper derives from the work of Christison et al. (1988), which was ongoing at the time of Weiner and Feldon's 1987 publication on haloperidol enhancement of LI. It was presented in part in 1989 as noted in the paper. Though it follows Weiner and Feldon's 1987 and 1991 publications, it is not accurate to suggest that it is derived from those works. I applaud Dr. Weiner and Dr. Feldon's finding that LI is enhanced by clozapine in their paradigm. This important finding strengthens the use of LI in antipsychotic drug discovery. I look forward to reading more about their ability to tap into the atypical profile of clozapine. I disagree with their comments about the lack of enhancement we reported after acute haloperidol treatment. I stand by our argument that this finding was an artifact resulting from the effort to balance vehicle treatment effects between animals treated for varying lengths of time. Inspection of our Fig. 2 supports this view. We stressed in the paper that these findings should be interpreted as an increase in LI effect with prolonged treatment rather than a lack of acute effect. We have data showing enhancement of LI by acute haloperidol treatment at a dose of 0.3 mg/kg using the same procedure described in our paper. Results were: haloperidot 0 PE 0.021 SE=0.002 n=10 haloperidol 20 PE 0.318 SE=0.020 n=l 1 vehicle 0 PE 0.122 SE=0.020 n=10 vehicle 20 PE 0. t90 SE=0.024 n=10 LI was enhanced (t=2.265, P0.025). We did not include this data as we felt the other data set (with six daily vehicle injections followed by an acute haloperidol injection) was logically more appropriate for comparison to the other treatment groups. Also, we have data showing a clear disruption of LI following acute administration of amphetamine (0.75 mg/kg free base, IR 15 rain before pre-exposure) again using the same paradigm. Results were: amphetamine 0 PE amphetamine 20 PE vehicle 0 PE vehicle 20 PE 0.008 SE=0.001 n=7 0.164 SE=0.028 n=7 0.060 SE=0.021 n=6 0.298 SE=0.016 n=7 LI was disrupted (t=2.112, P0.025). We performed these studies as pilot work to assure ourselves that our paradigm maintained aspects of face and construct validity demonstrated for other LI procedures reported in the literature. In general we have found that 7-day drug administration improves the stability and reduces variance in measurements of drug effects by allowing some tolerance to develop to sedation and motor effects of the drugs, and better acclimation to handling associated with training, testing and drug injection. I do not believe the observed differences between our paradigm and Weiner and Feldon's are a result of one session versus two sessions for pre-exposure and conditioning. LI paradigms are exquisitely sensitive to procedural parameters. Such differences as tone versus light, number and length of the CS, CS and US intensities, different parameters for defining suppression ratios, drug timing and delivery, and age and strain of the rats used can alter the experimental outcomes. Not all of these parameters are fully explored in the literature on LI, though many are reviewed by Lubow (1989). I would agree in general with Weiner and Feldon's final comment, but would broaden it to say that all of the parameters of an LI procedure should be taken into consideration when evaluating the effect of drug administration on LI.