Galen R. Wenger

Symposium overview: the use of delayed matching-to-sample procedures in studies of short-term memory in animals and humans.

Behavioral paradigms applicable for use in both human and nonhuman subjects for investigating aspects of working/short-term memory are presented with a view towards exploring their strengths, weaknesses, and utility in a variety of experimental situations. Such procedures can be useful in teasing out specific aspects of mnemonic processes including discrimination, encoding, and retention. Delayed matching-to-position, delayed matching-to-sample (DMTS), and titrating matching-to-sample procedures are highlighted. Additionally, the application of DMTS tasks in preclinical and clinical settings is presented: drug effects on memory processes can be explored preclinically in animal models; normative data have been developed in human populations where they have been used in adults to explore the relationships between mnemonic processes and specific clinical entities such as Parkinsonism, senile dementia of the Alzheimers type, schizophrenia, and depression. Studies in children indicate that encoding and retention processes improve rapidly in the early years, plateauing prior to puberty. Noninvasive imaging techniques such as positron emission tomography (PET) indicate that activity in specific brain areas is associated with DMTS task performance and may serve to confirm roles for such structures in mnemonic processes.

Cumulative dose-response curves in behavioral pharmacology☆☆☆

Cumulative dose-response curves have been widely used in many areas of pharmacology. To date, the applicability of cumulative dose-response curves has not been assessed in behavioral pharmacology. To determine the feasibility of this procedure, mice were trained to respond under a multiple time-out 5 min, fixed-ratio 30 (mult TO 5, FR 30) schedule of reinforcement. The FR 30 component consisted of 15 presentations of an FR 30 schedule of reinforcement. At the start of each TO 5 component, an intraperitoneal (IP) injection was given, and the effect on the response rate during the following 15 presentations of the FR 30 schedule was assessed. d-Amphetamine (0.3--30 mu moles/kg), pentobarbital (3-300 mu moles/kg), morphine (1-100 mu moles/kg), ketamine (3-300 mu moles/kg), and phencyclidine (1-100 mu moles/kg) all produced dose-related decreases in FR responding. In each case the lowest dose tested was without effect, and the highest dose tested essentially eliminated responding. As a control, the normal 4th dose in the ascending series of each drug was given preceded by 3 saline injections. Whether this dose of each drug was preceded by 3 separate saline injections or by 3 lower ascending doses of the same drug, the observed effect was identical. Five consecutive saline injections during the experimental session were without effect. The application of this procedure should greatly decrease the time required to examine the behavioral effects of a wide range of doses.

Neuropathology of trimethyltin intoxication: I. Light microscopy study

Abstract BALB c mice with average body weight of 25 g were injected intraperitoneally with trimethyltin chloride (TMT) at a dosage of 3.0 mg TMT/kg body wt. Control animals were injected with saline solution. Mice were found to be extremely sensitive to TMT toxicity. Within 24 hr postinjection, the TMT-treated animals displayed severe tremor, hyperexcitability, and aggression. All animals were sacrificed at 48 hr postinjection by intracardial perfusion with glutaraldehyde. Neuronal degradation could be observed in the neocortex, hippocampus, pyriform cortex, amygdaloid nucleus, and brain stem. In the hippocampus, severe neuronal necrosis was found among the granule cells of the fascia dentata with relatively sparing of the pyramidal cells of the Ammons horn. Degeneration of some large brain stem neurons was also a prominent finding, particularly those neurons in the mesencephalic trigeminal nuclei. Chromatolytic and hyalinization of these nerve cells occurred with eventual disintegration and vacuolation of the neurons. Electron microscopic findings will be presented in future papers of the series.

Neuropathology of trimethyltin intoxication: III. Changes in the brain stem neurons

Young adult BALB/c mice were administered trimethyltin chloride (TMT) at a dosage of 3.0 mg TMT/kg body wt. Animals displayed severe toxic signs (tremor and aggression) within 24 hr and were sacrificed at 48 and 72 hr postinjection. The brain stems of these animals were examined with light and electron microscopy. Degenerative and vacuolar changes were observed in many large brain stem neurons, especially those in the mesencephalic trigeminal nuclei. These neurons acquired a chromatolytic character with eccentric nuclei, loss of Nissl substance, and hyalinoid cytoplasm. Extensive vacuolation was also found in these nerve cells. Electron microscopy examination revealed progressive loss of the Nissl substance (rough endoplasmic reticulum) and distention of the cytoplasmic membranes (endoplasmic reticulum and Golgi complex). Severe distention of these membranes resulted in large membrane-limited vacuoles within these nerve cells. This intraneuronal vacuolation reflects an intracellular edema condition of these nerve cells and is potentially reversible. Mitochondrial damage in these neurons was only moderate. Further investigation is needed to elucidate the full toxic impact and pathogenetic mechanisms of TMT in the nervous system.

Neuropathology of trimethyltin intoxication: II. Electron microscopic study on the hippocampus

Abstract When mice ( BALB c ) were given a single injection of trimethyltin chloride (TMT) at a dosage of 3.0 mg TMT/kg body wt, extensive lesions were observed in the hippocampus at 48 hr after TMT administration. Electron microscopy revealed extensive neuronal necrosis among the granule cells and many of these necrotic neurons also displayed the phenomenon of karyorrhexis (fragmentation of the pyknotic nuclei). Although few necrotic cells were found among the pyramidal neurons, extensive accumulation of lysosomes was found within the neuronal bodies and processes of these nerve cells. Intracellular edema was a prominent finding in both cell types of the hippocampus. Such phenomenon was represented by severe distention of the cytoplasmic membrane systems (endoplasmic reticulum and Golgi complex) within the pyramidal cells and extensive swelling of the cytoplasm and neuronal processes of the granule neurons. Vacuolation of both cell types occurred as a result of these edematous conditions. It is postulated that TMT induced a severe disruption of oxidative phosphorylation and ATP production in these neurons leading to rapid cell death and/or cellular edema of these nerve cells.

Effects of drugs of abuse and scopolamine on memory in rats : delayed spatial alternation and matching to position

Abstract Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and 30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat.

The role of control activity levels in the reported strain differences to the behavioral effects of drugs in mice

The effect of d-amphetamine (3-100 mumoles/kg), scopolamine (0.3-100 mumoles/kg) and morphine (3-1000 mumoles/kg) were studied on the spontaneous motor activity (SMA) of four strains of mice: CF-1, DBA/2, C57BL/6 and CD-1. All three drugs increased the SMA of the CF-1, C57BL/6, and CD-1 strains at low to moderate doses and decreased SMA at higher doses. In the DBA/2 strain, d-amphetamine and scopolamine increased SMA at low doses and decreased SMA at high doses; only decreases in SMA were observed with morphine. When the drug effect was expressed relative to control levels of SMA, large apparent strain differences were shown to exist for all three drugs. In general, these strain differences were shown to exist for all three drugs. However, the majority of these strain differences could be attributed to the large differences which existed in the control level of SMA among the four strains. One important exception to this statement was shown to exist. The DBA strain responded differently (only decreases in SMA were observed) to morphine than did the other three strains. This decrease was not related to the control SMA level and could not be antagonized by naloxone (3 mumoles/kg, IP).

Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys

The acute effects of various drugs of abuse on the acquisition of chains of behavior were assessed in squirrel monkeys trained to respond on three keys for food. Each new session the monkeys acquired a different four-response chain by responding sequentially on three keys in the presence of four different stimuli. Incorrect responses inactivated the keys and darkened the chamber for 10 s (time-out). Dose-effect curves were obtained by administering the drugs intramuscularly before the session and recording their effects on the rate and accuracy of responding. Cocaine,d-amphetamine, and Δ9-tetrahydrocannabinol all decreased the accuracy and rate of responding within the dose range of 0.56–3 mg/kg. The highest dose of morphine tested (3 mg/kg) produced parallel decreases in the accuracy and rate of responding in some monkeys but had no effect at lower doses. These drugs decreased within-session accuracy though clearly acquisition did occur, but high doses of caffeine (30 and 56 mg/kg) prevented acquisition and recovery of performance and, furthermore, at 30 mg/kg these effects were observed in the absence of decreases in the rate of responding. The drugs of abuse tested all produced dose-related decreases in both the accuracy and rate of responding, and the decreases in accuracy were primarily observed only at doses that also decreased response rates. Therefore, based on these results from nonhuman primates each of these drugs has the potential to alter learning particularly when doses that disrupt other behaviors are administered.

Behavioral effects of trimethyltin in two strains of mice. I. Spontaneous motor activity.

Adult male mice (C57BL/6N and BALB/c) were administered single doses of trimethyltin X Cl (TMT) by the ip route. The effects of TMT administration were determined on lethality (3-6 mg/kg), spontaneous motor activity (SMA), and the physical appearance of the mice (0.3-3 mg/kg). The effects of TMT on lethality were strain dependent in that a single dose of 3 mg/kg, ip, produced approximately 35% lethality in the C57BL/6N strain during the first 72 hr following administration. Less than 15% lethality was observed at this dose in the BALB/c strain. In both strains, 3.5 mg/kg, ip, produced more than 70% lethality during the first 144 hr after administration. Higher doses produced proportionally greater lethality. The SMA of both strains was not affected significantly at doses below 1 mg/kg, ip. At 1 mg/kg a small decrease in activity was observed during the first 24 hr. At 3 mg/kg, SMA was initially decreased in both strains. However, the decrease was of smaller magnitude in the C57BL strain and was followed by a large increase in SMA which did not return to control levels for approximately 1 week. An increase in SMA was observed in the BALB/c strain on the fifth day following TMT but returned to control values by Day 6. At 3 mg/kg, ip, the C57BL mice were observed to have severe whole body tremors and were hypersensitive to external stimuli. The whole body tremor was not as marked in the BALB/c strain. Neuropathological studies on the treated mice indicated that the behavioral studies paralleled the pathology produced by TMT. These data confirm the initial observation of greater sensitivity of the mouse to toxic effects of TMT compared to the rat.

Behavioral effects of cocaine and its interaction with d-amphetamine and morphine in rats.

Drugs of abuse are commonly co-abused, and frequently these combinations produce effects which cannot be predicted by studying the effects of the individual drugs. To investigate the behavioral interactions which occur following combinations of cocaine plus amphetamine or cocaine plus morphine, rats were trained to respond under a differential reinforcement of low rates (DRL) schedule (10-14 sec). Cocaine (0.1-10 mg/kg) and d-amphetamine (0.1-3 mg/kg) decreased the percentage of reinforced responses (efficiency) at doses which had no effect on overall rate of responding. Following moderate doses of either drug, the interresponse time (IRT) distribution showed an increase in the percentage of shorter (less than 10 sec) IRTs. Morphine (0.1-10 mg/kg) also decreased efficiency, but the decrease which occurred was only observed at doses which also decreased overall response rates. As might be expected, the IRT distribution for morphine showed a dose-related increase in the percentage of long IRTs (greater than 14 sec). When doses of morphine which had no significant effect when administered alone (1 or 3 mg/kg) were combined with cocaine, the cocaine dose-response curve for efficiency was shifted down and to the left and response rates were increased. Analysis of the IRT distribution showed that the combination of an ineffective dose of cocaine, 1 mg/kg, plus 3 mg/kg morphine produced a shift in the IRT distribution to the left (an increase in the percentage of short IRTs). When cocaine was combined with 0.3 mg/kg d-amphetamine, a dose which had no effect when given alone, no significant interactions were observed on efficiency or overall rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)