Prenatal protein malnutrition enhances stimulus control by CDP, but not a CDP/THIP combination in rats

In the present study, the effects of prenatal protein malnutrition on stimulus control exerted by the benzodiazepine (BZ), chlordiazepoxide (CDP) and the GABA-A receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) were characterized. The adult, male offspring of female Sprague-Dawley rats fed either low (6% casein) or adequate (25% casein) protein diets 5 weeks prior to mating and throughout pregnancy served as subjects. Subjects were first trained to discriminate CDP (8.0 mg/kg ip) from saline using drug discrimination procedures. Once a criterion level of performance was achieved, generalization tests were performed to lower doses of CDP (4.0, 2.0, 1.0, 0.5 and 0.25 mg/kg) and then to several doses of THIP (10.0, 7.5, 5.6 and 3.2 mg/kg). Lastly, the ability of a single dose of THIP (3.0 mg/kg) to enhance discriminative control by several low doses of CDP (4.0, 2.0, 1.0 and 0.5 mg/kg) was assessed. Although both diet groups acquired the original CDP/saline discrimination at the same rate, malnourished rats exhibited significantly more generalization to low doses of CDP than their well-nourished counterparts. Neither diet group exhibited significant generalization to THIP nor a difference in THIP's ability to enhance the CDP cue. These results suggest that a subject's sensitivity to the stimulus properties of drugs can be selectively modified by prenatal malnutrition.