Age differences in acquisition and retention of one-way avoidance learning in C57BL/6NNia and autoimmune mice.

Acquisition and 48-h retention of a step-up active avoidance response were studied in separate age groups of C57BL/6NNia mice (aged 1.5, 3.5, 6, 12, or 26 months) and five strains of genetically autoimmune mice differing in life span. The C57BL/6NNia mice showed no change in ability to acquire the avoidance response between 1.5 and 3.5 months, but showed a steady decline in that ability thereafter. Mouse strains with early-onset autoimmune disorder (NZB/B1NJ, MRL/MpJ-lpr, and BXSB/MpJ) showed declines in acquisition capability between 1.5 and 3.5 months of age, whereas mouse strains with mild, late-onset autoimmune disorder (MRL/MpJ- + and NZBWF1/J) showed stable or improved acquisition during that period. Both the C57BL/6NNia and NZB/B1NJ mice showed age-dependent declines in 48-h retention performance by 12 months of age. These findings suggested that while 48-h retention performance deficits were most related to chronological age, avoidance acquisition deficits were related to development of autoimmunity.

Evidence of a central mechanism mediating tolerance to the discriminative stimulus properties of cocaine.

Rats were trained to detect intraperitoneal (IP) administration of cocaine, 10.0 mg/kg, using a two-lever choice discrimination procedure. Following training, cocaine was generalized to the cocaine training stimulus in a dose-dependent manner. Subsequently, bilateral cannulae were implanted in the lateral ventricles in ten animals, and intracerebroventricular (ICV) administration of cocaine was also generalized to the IP training dose in a dose-dependent manner with maximum generalization occurring with 80 micrograms cocaine. After baseline testing, training was halted and cocaine, 20 mg/kg/8-hr, was injected chronically in all rats for 6 days, and then the dose-effect curve for generalization of cocaine was redetermined. Chronic administration of cocaine significantly shifted the dose-effect curve three-fold to the right for both IP and ICV routes of administration. These data suggest that the stimulus properties of cocaine administered centrally are generalized in rats trained by peripheral administration and supports the hypothesis of central mediation of the cocaine stimulus. Also, the comparable shift of the cocaine dose-effect curve following chronic cocaine administration suggests that a central pharmacodynamic mechanism mediates tolerance to the discriminative stimulus properties of cocaine.

Motor responses of autoimmune NZB/B1NJ and C57BL/6Nnia mice to arecoline and nicotine.

In 11-13 month C57BL/6Nnia mice, arecoline produced a dose-dependent decrease in motor activity at doses of 0.64-2.5 mg/kg, whereas at doses of 5.0-20.0 mg/kg arecoline produced a dose-dependent increase in motor activity. In marked contrast, age-matched NZB/B1NJ (New Zealand Black) mice failed to exhibit the first phase of the response, but showed a greater dose-dependent increase in motor activity following the doses of 10 and 20 mg/kg. Nicotine, 0.64-2.5 mg/kg, produced a dose-dependent decrease in motor activity in both strains. The effects of arecoline and nicotine were antagonized by scopolamine (2.5 mg/kg) and mecamylamine (1.0 mg/kg), respectively. These findings suggest that muscarinic neurotransmission may be altered in NZB/B1NJ mice, which produce brain-reactive autoantibodies, exhibit learning/memory dysfunctions, and also exhibit a loss of neurons staining positive for choline acetyltransferase.