Arthur Cherkin

Autoradiographic distribution of L-proline in chicks after intracerebral injection ☆ ☆☆

Abstract Intracerebral injection of C14-labeled L-proline resulted in its distribution in periventricular tissue (including septum, hippocampus, and hypothalamus) in neonatal chicks decapitated 1 min after injection. Delay of decapitation for 3, 9 or 45 min resulted only in an increased spread of label into the fourth ventricle. A simple, effective chick head-holder is also described.

Memory enhancement: Supra-additive effect of subcutaneous cholinergic drug combinations in mice

The amnesias characteristic of Alzheimers disease and other age-related dementias are refractory to conventional pharmacotherapy. a recent treatment strategy is to combine present drugs to improve their memory enhancing effect. We used mice weakly trained on active avoidance in a T-maze to compare the effect of cholinergic drugs, given alone and in two-drug combinations, on retention test performance. All drugs were injected SC immediately after training. Memory retention was tested 1 week later. A dose-response curve was determined for each of four drugs (arecoline, edrophonium, oxotremorine, tacrine) and for each of the six possible two-drug combinations. Each drug and each combination improved retention test performance up to an optimal dose; the improvement decreased with further increases in dose. A striking reduction (66.2%–95.7%) in the optimal dose for enhanced retention was observed with these two-drug combinations.

Fluoxetine enhances memory processing in mice

Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory processing (“consolidation”) and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 μg per mouse). FLU enhanced retention when administered prior to training (1–5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance over the dose range 0.5–35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min, as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU (15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this task as well as in the active avoidance task.

Effect of acute arecoline, tacrine and arecoline + tacrine post-training administration on retention in old mice

The amnesias characteristic of Alzheimers disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine drugs to improve their memory enhancing effect. We previously reported that in young weakly trained mice, the combination of arecoline and tacrine was more effective on a mg/kg basis than either drug administered alone. This was true whether the route of administration was intracerebroventricular, subcutaneous or oral. We now report that 24 month old mice trained to avoid footshock in a T-maze show poor retention when tested one week later. Subcutaneous administration of arecoline, tacrine (also referred to as tetrahydroaminoacridine, THA) and arecoline plus tacrine administered immediately after T-maze footshock avoidance training enhanced retention of 24 month old mice compared to the saline-injected control. Since the combination was as effective as the single drug treatments even though 96% less arecoline and 99.7% less tacrine was administered, the combination showed marked potentiation of drug action of memory processing.

Amnestic effect of L-proline does not depend upon inhibition of brain protein synthesis

GRECC and Psychobiology Research Laboratory, Veterans Admhdstration Medical Center, Sepulveda, CA 91343 and Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, CA 90024, (E.L.B.) Division of Chemical Biodynamics, Lawrence Berkeley Laboratorv, University of California, Berkeley, CA 94720 and ( J.L.D.) Aging and Behavioral Biology Research Laboratory, Veterans Administration Medical Center, Sepulveda, CA 91343 and Department of Psychiatry and Biobehavioral Sciences School of Medicine, University of California, Los Angeles, CA 90024 ( U.S.A.}

The effects of adrenergic, opioid and pancreatic polypeptidergic compounds on feeding and other behaviors in neonatal leghorn chicks.

The present study examined the effects of intracerebral (IC) administration of pancreatic polypeptide (PP), neuropeptide Y (NPY), norepinephrine (NE), dynorphin and naloxone on food intake in 2-day-old Leghorn chicks. Of the compounds studied, only PP (20 micrograms) and naloxone (10 and 20 micrograms) elevated food intake significantly as compared to saline injections. NPY, a potent orexigenic agent in mammals, did not elevate consumption significantly in a dose-related fashion. This latter finding was attributed to the occurrence of tonic-clonic convulsions following NPY administration. However, for those chicks which did not exhibit behavioral convulsions, food intake appeared to be elevated by 1, 5 and 10 micrograms of NPY. Similarly, NE did not elevate food intake but instead induced sedation and narcolepsy, a behavioral response which could be distinguished from the convulsions observed after NPY. In a separate group of chicks, the effect of NPY on cortical activity was examined. Bipolar electrodes were used to record EEG activity before and after IC injections of saline, NPY or NE. The behavioral convulsions induced by NPY corresponded with an increase in high amplitude sharp-wave activity, which persisted for up to 30 min post-injection. Collectively, these results suggest that the neurochemical substrates for feeding in 2-day-old Leghorn chicks are distinct from those underlying food intake in adult mammals.

Retrograde amnesia in neonatal chicks: induction by L-proline is not accompanied by occult seizures.

Abstract Chronically-implanted neonatal chicks (N = 25) were intracerebrally injected with L-proline (N = 15), L-isoleucine (N = 5) or saline (N = 5) after a 15 min baseline recording of electrophysiological activities. Electrographic seizure spiking or an EEG isoelectricity were not observed as a consequence of the amino acid or saline injections. A slight but brief depression of electrophysiological activities, followed by a transient rebound hyperexcitability, were observed specifically after the L-proline treatment.

One-Trial Learning and Biphasic Time Course of Performance in the Goldfish

Goldfish (N = 408) spontaneously swam against flowing water into a calm-water well. After a single trial punished by brief electric shock, the fish avoided the well, as indexed by increased latencies of reentry. Avoidance declined during the first minute after shock, then rose to a peak 1 hour later. The biphasic time course is compatible with the two-store theory of memory formation.

Memory retention test performance in mice: Improvement by chronic oral cholinergic drug treatment

Mice consumed solutions containing 0, 0.025, 0.050 or 0.075 mg/ml of arecoline hydrobromide (ARE) one week prior to training (T-maze, footshock, active avoidance) and a total of two weeks prior to testing memory retention. The mean daily doses of ARE were estimated to be 0, 157, 302, or 500 micrograms per mouse, respectively. An inverted-U dose-response curve was obtained; the best retention test performance was by the group receiving 0.050 mg/ml of ARE. Measures of activity and weight taken over the experiment indicated no significant differences between ARE groups and the control group; thus no apparent toxicity. Separate groups of mice consumed 0 or 0.050 mg/ml of ARE for one week, then were trained to a criterion of 5 avoidances in 6 training trials. There were no significant differences in trials to first avoidance response or to criterion. Thus the enhanced retention test performance of the 0.050 mg/ml ARE group reflected improved memory processing rather than better learning.

Memory enhancement in mice: role of drug dose and training-testing interval

Pharmacologic probes are useful for studying memory mechanisms. For eight drug treatments affecting a variety of transmitter systems [arecoline, piribedil, clonidine, fluoxetine, naloxone, ACTH (4-10)], we determined how long memory retention would remain improved with a dose sufficient to improve 3-hour retention. While all 6 treatments enhanced 3-hour retention test performance at p less than 0.05, only 5 treatments significantly enhanced retention 24 hour after training and none of the treatments significantly affected retention at 168 hours. A detailed analysis of the dose and retention interval interaction for arecoline indicated that at low doses retention decreased as the retention interval increased while higher doses improved retention up to 3 hours and only the highest dose tested enhanced retention at 3 and 24 hours. Drug doses that enhance short-term retention (3 hours) were not adequate to enhance long term retention (168 hours). The 6 drug treatments had no significant or systematic effect on activity or on acquisition. We conclude that short-term retention performance was better because of enhanced memory processing or recall and not because of performance effects per se.