Clark T. Randt

Norepinephrine biosynthesis inhibition: effects on memory in mice.

Diethyldithiocarbamate, a dopamine beta hydroxylase inhibitor, decreases biosynthesis of norepinephrine in the brain. The effects of this inhibitor coincide with alterations in memory as demonstrated in single-trial passive avoidance in C57BL/6J mice.

Brain cyclic AMP and memory in mice

A phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (Rolipram, 10 mg/kg IP) administered immediately, but not 3 hr post-training, reversed an amnesia for an inhibitory avoidance response induced by the protein synthesis inhibitor anisomycin. Immediate post-training administration of Rolipram also enhanced retention for a weakly learned avoidance response. Unshocked animals did not show increased test latencies thus ruling out conditioned aversion as an explanation for the enhanced avoidance. Mice treated with Rolipram (10 mg/kg after training showed elevated cyclic AMP but not cyclic GMP in frontal cortex, thalamus, and hypothalamus. These results support the suggestion that cyclic AMP may play a role in memory processes.

Amnesic effects of cycloheximide on two strains of mice with different memory characteristics.

Abstract The amnesic effects of the protein synthesis inhibitor cycloheximide were studied in two strains of mice ( C57BL 6J ; DBA 2J ) which have opposite temporal gradients of retention for single trial passive avoidance learning. Mice were given a single trial in a passive avoidance apparatus 30 min after a saline or a cycloheximide injection and tested for retention at seven intervals from 1 min to 72 hr following. Saline-injected C57BL 6J mice showed poor initial retention followed by progressive improvement which was sustained for 72 hr. In contrast, saline-injected DBA 2J mice showed good retention shortly after training followed by absence of retention 6 hr after training. A 3-mg dose of cycloheximide produced significant amnesia in both strains but the memory impairment was greater in the C57BL 6J strain when tested at 5 min. Increased early amnesia occurred when DBA 2J mice were given 5 mg of cycloheximide even though this dose did not significantly increase degree of protein synthesis inhibition. These results indicate that cyclohexamide can disrupt short-term as well as long-term memory and, in addition, raise the question whether the amnesic effect is due exclusively to inhibition of protein synthesis.

Localization of action of two amnesia producing drugs in freely moving mice.

Abstract Two drugs previously shown to produce amnesia in mice, cycloheximide, a protein synthesis inhibitor, and diethyldithiocarbamate (DDC), a dopamine beta hydroxylase inhibitor, altered the electrical activity recorded from the midbrain reticular formation and parietal cortex of freely moving awake mice. Under similar circumstances, the averaged visual evoked responses were consistently altered only from the dorsal hippocampus. It is suggested that both of these drugs have similar actions and that their primary effect is on the midbrain reticular formation and the cerebral cortex.

Amino acid transport inhibition: Brain and behavioral correlates

In vivo inhibition of uptake 14C-L-valine by brain following subcutaneous administration of either of two gamma-glutamyl cycle enzyme inhibitors, 2-imidazolidone-4-carboxylic acid (ICA), or, L-methionine-S-sulfoximine (MSO) is documented in C57BL/6J mice. Dose related decrease in exploratory activity, impairment of memory for foot shock, and reduced operant responding for food reinforcement parallels the time course for interference with uptake of a large neutral amino acid by these two compounds previously shown to inhibit different enzymes in the gamma-glutamyl cycle subserving active amino acid transport.

Motivation for electrical stimulation of the brain and for natural reinforcement in mice

Abstract Strength of motivation for electrical self-stimulation of the brain (ESB) and for a conventional reinforcer (water) was compared in C57BL 6 mice with electrodes in the lateral hypothalamus (LHA) and in the septum. Latency to begin lever pressing was longer and rate slower in septally implanted mice than in mice with LHA electrodes. None of the mice required priming to initiate lever pressing. Extinction tests immediately and 60 min following continuous reinforcement showed that mice with LHA electrodes made fewer responses 60 min later than immediately after continuous reinforcement, while mice with septal electrodes made more responses during extinction after a delay of 60 min than immediately following continuous reinforcement. Resistance to extinction following water reinforcement was similar to that of subjects receiving ESB to the septum. Mice with LHA electrodes worked for ESB and for water reinforcement on schedules up to FR 32. Mice with septal implants worked up to FR 32 for a water reward but would not go beyond FR 8 for ESB. With a progressive ratio reinforcement schedule, the mice with LHA electrodes would make up to 76 presses to obtain a single ESB reinforcement and their performance on this schedule was comparable to that of a food rewarded mouse. These results indicate that in mice motivational similarity of ESB and conventional rewards dependes both on site of stimulation in the brain and the behavioral indices of motivation employed.

Pre-natal amino acid transport inhibition: Long term influences on behavior and protein metabolism

DBA/2J mice were exposed in utero, between days 15-18 of gestation, to either of two enzyme inhibitors, previously shown to decrease blood-brain, large-neutral amino acid transport in adults: L-methionine-RS-sulfoximine and 2-imidazolidone-4-carboxylic acid. The young mice demonstrated persistently altered motor behavior relative to saline controls when 40-42 days old and evidence of differences in the entry and incorporation of 14C-valine in brain at up to 80 days of age. The findings suggest that interference with blood-brain amino acid transport in utero has long term consequences. This may be related to some human conditions such as maternal phenylketonuria.

Retention of visual discrimination learning reinforced by brain stimulation in mice

Abstract Visual discrimination learning of stripes vs black were compared in two groups of C57Bl/6J mice, one group (n = 11) bar-pressed for 10 electrical self-stimulations of the brain (ESB) and the other (n = 10) earned a 20 mg pellet of food reward in a T maze. The ESB animals had a stereotaxically placed electrode in the medial forebrain bundle lateral hypothalamic area and the food reward mice had been reduced to 80% body weight. Comparison of ESB to food reinforcement showed fewer trials to criterion in the ESB group for acquisition, reacquisition after one day and retention after 7 days. The results demonstrate sufficiency of ESB to support a pattern of learning and excellent retention in mice.