Konrad C. Retz

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.

Age-dependent enhancement of diazepam sensitivity is accelerated in New Zealand black mice

Separate age groups of C57BL/6 and autoimmune New Zealand Black (NZB) mice were compared for diazepam-induced ataxia and barbiturate-induced loss of righting reflex. Between 1 and 3 months of age, both strains showed a similar age-related decrease in ED50 for diazepam-induced ataxia. However, between 3 and 12 months the decrease in ED50 was markedly greater in NZB mice. In contrast, age-related increases in the durations of loss of righting reflex following hexobarbital or barbital were similar in both strains. The results suggest that NZB mice show relatively accelerated age-related increases in sensitivity to benzodiazepine, but not to barbiturates.

Differences in behavioral responses to oxotremorine and physostigmine in New Zealand black (NZB/B1NJ) and C57BL/6 mice

The NZB/BlNJ (NZB) mice are an autoimmune-prone strain, known to develop brain-reactive antibodies in serum at much earlier chronological ages than normal mice. Measurement of locomotor activity in 8-10 month old C57BL/6 (C57) mice following the administration of either oxotremorine or physostigmine, revealed a biphasic response consisting of inhibition at small doses, but increased motor activity at large doses. In contrast, age-matched NZB mice exhibited little inhibition at the smaller doses, but had much greater increases in activity after the larger doses. Similarly, when compared to C57 mice, NZB mice were less sensitive to oxotremorine-induced salivation, diarrhea and visible tremors. Moreover, oxotremorine-induced hypothermia occurred at smaller doses in C57 mice than in NZB mice and was of a greater magnitude. Thus, at an age when NZB mice possess high levels of brain-reactive antibodies, and exhibit impairment in tests of learning/memory, these mice also show diminished responses in several tests of cholinomimetic-induced behavior and physiological alterations.

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.

Cholinergic Neuropsychopharmacology and Neuropathology of Dementias

Currently it is estimated that more than five percent of the population above 65 years of age exhibit dementia and that the nursing home care for people so afflicted may exceed

Learning and memory deficits associated with autoimmunity: Significance in aging and Alzheimer's disease

6 billion per year (Katzman, 1976; Terry and Davies, 1980). Senile dementia has often been accepted as a normal feature of “growing old.” However, many people retain good cognitive ability well into the eigth or ninth decade in the absence of any other neurological symptoms. Presenile dementia typically appears in people in their fifth decade and consists of a progressive deterioration of cognitive functions, especially recent memory. This latter form of dementia, presenile dementia of the Alzheimer’s type (SDAT) produces a neuropathology that is similar to that of senile dementia including such features as: (a) neuritic plaques with an extracellular core of amyloid; (b) neurofibrillary tangles in the neuronal cell bodies; and (c) granulovacuolar degeneration especially in some hippocampal neurons (Constantinidis, 1978; Selkoe et al., 1982). Because some genetic studies have indicated that SDAT occurs as an autosomal dominant trait, it is possible that SDAT and senile dementia may share some common genetic basis (Folstein and Breitner, 1981; Heston et al., 1981).