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This study investigated the effects of fetal rat umbilical cord compression on anatomical, biochemical, and behavioral parameters of development. Further, the study examined the ability of the calcium channel antagonist nimodipine to afford protection from this insult. Near the day of birth (E21), the umbilical cord of individual fetuses was not clamped or clamped for 2, 6, or 12 min. Before clamping, mothers were given 70 μg/kg (i.p.) nimodipine in a polyethylene glycol (PEG) vehicle or the vehicle alone. Selected animals were sacrificed for cytochrome oxidase histochemistry. The remainder of the pups were given to foster mothers and allowed to develop through adulthood. At the end of testing all animals were sacrificed and the brains weighed and measured. Histochemical analysis revealed that clamping resulted in a decrease in cytochrome oxidase reaction product in the hippocampus. The reduction in this marker of oxidative metabolism was not as pronounced in animals from drug-treated mothers. Alterations in behavior produced by clamping were detectable as early as the third day after birth (P3). At this age, pups subjected to cord clamping exhibited impaired righting and diminished avoidance of a 'cliff' on which they had been placed. On P67-P75, clamped animals exhibited hyperactivity in an open field, low rates of spontaneous alternation in a T-maze, and impaired learning and memory in a Pavlovian conditioned aversion-to-brightness test. The calcium channel blocker afforded protection from the effects of cord clamping, since the nimodipine-treated animals were less impaired in these behavioral tests. Animals that had been subjected to cord clamping showed reduced brain volumes and dimensions on P80. Nimodipine treatment normalized these parameters of brain development relative to non-clamped controls. Taken together, these results indicate that brief periods of umbilical cord occlusion near the time of birth can have both immediate and long-term effects on different parameters of development. In addition, the calcium channel blocker nimodipine affords partial protection from damage induced by compression of the fetal umbilical cord.

This study was undertaken to evaluate the effects of pretreatment with calcium channel antagonists (nimodipine or verapamil) on the formation of methemoglobin produced by sodium nitrite. Unexpectedly, the pretreatment of animals with control injections of physiological saline 2 hours before the nitrite administration reduced the amount of methemoglobin found in the blood 25 minutes later. When either of the calcium channel antagonists was given 2 hours before the administration of sodium nitrite, the saline effect was eliminated. When the injections of physiological saline or either of the calcium channel blockers were divided 24 hours before the nitrite administration, all reduced the amount of methemoglobin formed relative to rats that received no pretreatment. A tentative hypothesis is that the reduction of the nitrite-induced methemoglobin can be induced by the stress of handling and intraperitoneal injection and that this stress effect can last at least 24 hours. It is likely that whatever stress-related mechanism is involved in reducing methemoglobin levels, this effect can be reduced by the presence of "L channel" voltage-sensitive calcium antagonists or their active metabolites.

The effects of ethanol and dihydropyridines on atrial membrane potentials (MP) were studied. Rat atrial strips superfused with Tyrode's solution (36 degrees C) were driven at 5 Hz while recording MP with intracellular microelectrodes. Bay K 8644 7 X 10(-7) M (BAYK) increased the amplitude of the action potential (AAP) without affecting the resting membrane potential (RMP) or the Vmax of phase 0 (Vmax 0). The velocity of change in voltage decreased at the beginning of the repolarization, causing an increase in the action potential duration (APD), but it was not modified at negative voltages. Nimodipine 4.2 X 10(-6) M reduced the AAP without affecting RMP or Vmax 0. The velocity of change in voltage increased at the beginning of the repolarization, causing a decrease in the APD, but was not modified at negative voltages. Ethanol 5.3 X 10(-2) M exerted actions similar to those of nimodipine. Simultaneous exposure to ethanol and nimodipine resulted in changes not different from those obtained with each of the two compounds. The MP remained unchanged when the preparations were exposed to ethanol and BAYK simultaneously. In summary, ethanol and nimodipine exerted similar actions on the atrial MP while BAYK had opposite actions. The effects of ethanol and BAYK cancelled each other.

This is a brief summary of our research on the prevention or reduction of the effects of brain damage. I believe that the results contain a number of exciting promises. At this time, the greatest hope for effective remedial interventions comes from the choline and metyrapone studies. However, I am also reminded of the components a psychiatrist who worked with children in the heart of Philadelphia made some 20 years ago at a conference on mental retardation. He said that the most significant contribution to the elimination of mental retardation in his city would be the elimination of lead-based paints from the walls of ghetto apartments, an intervention second only in effectiveness to the elimination of the ghettos themselves. The importance of early interventions with individuals suffering brain damage, either general or specific, is clearly recognized. In research now well underway, Yong Shen, William Smotherman, and I have found encouraging results indicating that both short- and long-term effects of hypoxia induced by clamping the rat's umbilical cord can be attenuated by the prior administration of a calcium L channel antagonist. If those results are upheld in further studies, the principles of prevention of damage described in this article for the adult may prove to be even more potent in the young.

In order to test the possible effectiveness of peripheral interventions with the adrenergic system for the alleviation of certain disorders that typically follow bilateral hippocampal lesions, rats with bilateral lesions of the hippocampus, the overlying neocortex, or sham operations were tested at two postoperative times in the Morris water maze, a frequently used "spatial task." Half of the animals in all groups were exposed to the adrenergic manipulations, i.e., a chronic, 7-day, systemic bretylium regime (5 mg/kg) and, in addition, a peripheral injection of norepinephrine (4 micrograms/kg) 30 min before the start of each training day. The other half received saline chronically and a single saline injection before each training day. Five days of training were given at each of the two training periods. The first began 7 days after surgery while the second began 33 days after surgery. As expected, the hippocampally lesioned animals were severely impaired in the task. The adrenergic treatment produced enhanced performances in the rats with hippocampal lesions at both training sessions, although the improvement was greatest at the later period. Although the animals receiving the pharmacologic treatment located the general area of the hidden platform better than the saline-treated animals with hippocampal lesions, the treated animals were still impaired, swimming directly to the hidden platform on fewer trials than did animals in the other groups.

Rats with large electrolytic lesions of the septal area were given the calcium channel antagonist nimodipine (70 micrograms/kg, ip) or its vehicle on the day of surgery and for 3 subsequent days. They were tested for emotionality and compared to control rats for 10 days beginning on the third day after surgery. Forty days after surgery all animals were trained in a two-way active avoidance task for 120 trials. Nimodipine reduced the hyperemotionality found after septal lesions as early as the first test day, and increased the rate of recovery toward control levels on subsequent days. Both septal-lesion groups exhibited more avoidance responses than controls, even though the intertrial crossings were enhanced only in rats with septal lesions that did not receive nimodipine.

In rats, sectioning the fimbria-fornix leads to a decrease in cells reactive for acetylcholinesterase and choline acetyltransferase, as well as other types of cells, in the medial septal area that project to the hippocampus. In this study cells in the medial septal area were stained for acetylcholinesterase reaction product or by a Nissl method two weeks after unilateral section of the fimbria-fornix. Counts were made of cells on each side of the midline by independent observers. The counts of the cells on the two sides of the brain were compared in rats that had been given nimodipine (70 μg/kg) just after the lesion and for 7 additional days and in rats that had been given only the vehicle for an equivalent amount of time. The number of cells reactive for acetylcholinesterase was reduced in the medial septal area on the side of the brain in which the forebrain fornix was sectioned, but this occurred to a significantly less extent in the nimodipine-treated rats. No differences were noted in the number of cells on the two sides of the medial septal area when counted in Nissl-stained sections.

The effects of ethanol and/or dihydropyridines (DHPs) on force of contraction of atrial muscle were studied. Guinea pig atrial strips superfused with Tyrode's solution (36 degrees C) were driven (1.5 Hz) while recording muscle tension. Bay K 8644 (BAYK) increased, while nimodipine or ethanol reduced, the peak tension developed and the maximum velocity of development of tension. The effects of ethanol were readily reversible, but those of the DHPs were not. The combined actions of ethanol and DHPs were the result of the synergism or antagonism of the drugs tested. The shorter duration of the action of ethanol resulted in the effect of DHPs being still evident well after the exposure to the drugs ended. In summary, ethanol and nimodipine exerted depressant actions on atrial contractile force, while BAYK had opposite effects. The different mechanisms of action may explain the different duration of the effects of ethanol (physical agent) and DHPs (receptor-binding chemicals).

In this paper we review the temporal pattern of excessive grooming in the hour or so following the central injection of ACTH1-24 in the rat. Changes in the grooming pattern after specific neuropharmacological manipulations of dopaminergic and opiate-related systems are presented which indicate a differential sensitivity of the grooming responses at different times after injection. The grooming affected by dopaminergic antagonists and opiate agonists and antagonists occurs in the last 30 min of the observation period while that found earlier is unaffected. It is also the grooming in this last 30 min of the observation period term tolerance to central administration of ACTH1-24. In contrast lesions of the central nervous system that affect excessive grooming, i.e., the substantia nigra and the hippocampus, reduce grooming throughout the observation period. The present analysis has provided evidence for dopamine/opiate insensitive and sensitive systems in excessive grooming, and thus temporal aspects are of extreme importance to the understanding of central neuropeptide influences on behavior.

The actions and interactions of dihydropyridines (DHPs) and ethanol on sinus node (SN) automaticity were studied using rat sinoatrial preparations superfused with Tyrode's solution at 37 degrees C. Intracellular microelectrodes were used to monitor SN rate (SNR). The automaticity of the SN was not affected by nimodipine 10(-10) M, but it was depressed by a higher concentration of this calcium antagonist (10(-8) M). The racemic compound (+/-)Bay K 8644 had a dose-dependent biphasic chronotropic action: At 10(-8) M it decreased the SNR, while at 10(-7) M it increased the SNR. The negative component was blocked by atropine. A small concentration of ethanol (1.8 x 10(-2) M) had a positive chronotropic effect on the SN, and this action was blocked by nimodipine 10(-10) M. This small concentration of ethanol did not modify the chronotropic effects of either of the DHPs. A higher concentration of ethanol (5.3 x 10(-2) M) did not by itself affect the SNR, but it antagonized the chronotropic actions of the two DHPs.

Sixteen rats were tested for 10 min in an open field on postoperative Days 6--7, 11--12, 19--20, and 38--39, under two conditions of illumination. Septal lesions produced alterations in activity, rearing, and grooming that changed over the repeated tests. Septal rats initially had low activity scores that increased over testing to a level higher than that of controls, low rearing behavior that increased over sessions but always remained below control levels, and low grooming scores that became equivalent to controls by postoperative Days 38--39. These findings indicated that repeated testing given only postoperatively in an open field resulted in hyperactivity, decreased rearing, but no differential effect in grooming. The time course of change in these three behaviors was not identical.

The suppression of corticosterone synthesis with metyrapone (25 mg/kg) reduced the hyperactivity and altered the exploratory activity of hippocampally lesioned animals (HPC) in the open field to the level of cortical and sham controls (Experiment 1). In a second experiment, corticosterone (600 micrograms/kg) pretreatment 2 h, but not 1 h, before metyrapone partially restored the hyperactivity of HPC animals that had been decreased by the corticosteroid-suppressant drug. Alterations in exploratory behavior induced by metyrapone were also prevented by corticosterone pretreatment. The results suggest that the suppression of corticosterone in hippocampally lesioned animals produces a normalization of behavior that can be prevented by pretreatment with corticosterone.

The effects of a 5-day ganglioside (GM1) treatment (30 mg/kg) on body weight and water intake subsequent to medial septal lesions were evaluated for 44 consecutive days. In addition, activity, rearing, and repetitive motor acts were measured on postsurgery days 5, 10, 40, and 60. The rate of increase in the body weights of rats with medial septal lesions treated with GM1 was equivalent to that of controls, while untreated rats with such lesions had reduced body weights. Rats with medial septal lesions treated with GM1 also exhibited movement times and frequency of repetitious motor acts similar to those of control rats by postsurgery day 60. No differences were found in water intake between any of the groups. Rats with medial septal lesions, whether treated with GM1 or not, had equivalent frequencies of rearings that were lower than control rats. This study emphasizes that even brief regimes of GM1 administration can exert behavioral changes in brain-damaged rats well after the treatment was administered, i.e. 40-60 days after surgery.

Rats with unilateral lesions of either the supracallosal regions (including the dorsal cingulate cortex) and the fimbria-fornix either on the same (S) or the opposite (O) sides of the brain were studied in a 16-hole open field without pharmacologic intervention and, subsequently, after 0.1 and after 1.0 mg/kg scopolamine HBr. Their performances were compared with those of unoperated control animals subjected to the same testing regime. Certain of their behaviors were compared with those of a larger number of animals with bilateral hippocampal destruction (and their control groups) from prior studies. Unilateral lesions of fimbria-fornix and supracallosal afferents to the hippocampal formation produced a decrease in hole poking activity relative to control animals. A further decrease in hole-poking behavior, coupled with increased locomotion, was observed in rats with fimbria-fornix and cingulate cortex lesions on opposite sides of the brain (group O). The smaller dose of scopolamine accentuated these effects. Indeed, the behavior of group O after scopolamine treatment was similar to animals with large bilateral hippocampal lesions. The large dose of scopolamine induced stereotyped rearing or hole poking in the brain-damaged animals but not in the control group. These findings suggest that both the fimbria-fornix and the supracallosal pathway is necessary for normal hippocampal function and that the behavioral deficit is greater when these structures are damaged on the opposite sides of the brain.

Following a unilateral electrolytic lesion in the ventral rat mesencephalon, changes in the immunocytochemical distribution of the neuron-specific B-50, neurofilament (NF) protein and glial fibrillary acidic (GFAP) proteins were studied around the lesion after 0, 3, 10 and 28 days. At all recovery times, the controls displayed on immunostaining with anti-B-50 and anti-neurofilament antibodies, a characteristic pattern of synaptic and neuritic localization of these antigens, whereas anti-GFAP staining revealed a distribution typical for astrocytes. The lesion was characterized by a center of coagulated material that exhibited immunoreactivity to B-50 (BIR) and NF (NFIR), but never GFAP-immunoreactivity. From 3 days on, the center became surrounded by disintegrating cells which were unreactive to the antibodies. The antigen distribution changed temporally, predominantly at the lesion rim. By 10 and 28 days postlesion, additional BIR was observed as punctuate dots in fibers and membranes of neurons. Enhanced NFIR was detected in fibers and cell bodies. Many astrocytes were detected around the lesion rim, forming by 28 days postsurgery a barrier between the lesion cavity and the uninjured tissue. Our study shows that distribution changes in B-50, NF and GFAP around the lesion may indicate local degenerative and adaptative processes as a temporal response to brain trauma.

Rats were prepared with radio frequency lesions of the dorsolateral or ventromedial regions of the substantia nigra. Other rats were prepared as operated and unoperated controls for each type of lesion. Their behavior was evaluated in an open field at postoperative days 2, 7, 10, and 15. Three types of behavioral changes were observed over time: those noticeable for a brief period, i.e., a few days, after the lesion (rotational behavior), those lasting 7-10 days after the lesion (turning preferences) and those lasting through the end of the experiment that may be permanent (enhanced locomotion). The early effect of the medioventral lesions was pronounced contralateral rotation while the early effect of the dorsolateral lesion was ipsilateral rotation. This effect of the dorsal lateral lesions was reversed on test days 7 and 10. Lesion-induced turning changes associated with forward locomotion were observed on these two test days as well. By 15 days after surgery the only demonstrable effect of either lesion was enhanced locomotion. The results are discussed in terms of various theories of substantia nigra regulation of motor activities.

Rats were injected systemically with either saline, apomorphine, or one of four doses of DPI (3,4-dihydroxyphenylamino-2-imidazoline) and the levels of dopamine and DOPAC determined in the nucleus accumbens and the caudate regions. DPI reduced dopamine and DOPAC levels in the nucleus accumbens, while apomorphine did not. On the other hand, apomorphine reduced the levels of dopamine and DOPAC in the caudate but not the nucleus accumbens. DPI largely was without effect in the caudate. The results are discussed in terms of possible specificity of the two dopamine agonists in the two forebrain regions.

Intact male rats exhibited more grooming in unfamiliar testing chambers than in their home cages. Hypophysectomized rats showed a much reduced increase in grooming in these testing chambers. Intraventricular injections of antiserum to adrenocorticotropic hormone to intact rats decreased the grooming usually observed in the novel situation, whereas a similar injection of control serum did not produce this effect. Peripheral injections of the antiserum did not affect grooming. Since intraventricularly injected adrenocorticotropic hormone induces excessive grooming, these results suggest that the increased grooming observed in the novel environment may be at least partly due to the release of this hormone directly into the cerebral ventricular system.

Large bilateral aspiration lesions of the hippocampus in rats lead to a variety of changes in spontaneous behavior measured in an open field/hole board, relative to sham and neocortically lesioned controls. These changes include increased locomotion, and decreased grooming frequency and rearing bout duration. When animals were injected with the dopamine (DA) agonist 3,4-dihydroxyphenylamino-2-imidazoline (DPI: 0.5, 1.0 and 5.0 microgram) into the nucleus accumbens one week after surgery, the behavior of hippocampally lesioned rats was restored to levels not different from control lesioned rats. Haloperidol injections (0.05, 0.1 and 0.5 microgram) into the caudate nucleus were not able to do this. Further, DPI injected into the caudate month after surgery was also able to attenuate some of the effects of hippocampal damage. On the other hand, haloperidol injections into the nucleus accumbens did not influence behavior. The results are interpreted in terms of hippocampal lesion-induced alteration of a balance in basal ganglia DA systems, indicated by modified response to pharmacological intervention and which mediate the behavioral effects of the lesion.

Kainic acid is an analog of glutamate. The CA3-4 field of the hippocampus is extremely sensitive to its toxic properties. Intracerebroventricular injection of of nontoxic doses of kainic acid in rats produces behaviors similar to morphine withdrawal. Lesion of CA3-4 abolishes this response to kainic acid. Destruction of CA3-4 blocks the ability of Met-enkephalin, ketocyclazocine, and 5-hydroxytryptophan, but not sodium valproate or ice water to induce withdrawal-like behaviors. The actions of kainic acid, endorphins, and ketocyclazocine are blocked by naloxone and enhanced by opiate agonists. Sodium valproate, ice water, and withdrawal itself are released by naloxone and blocked by opiate agonists. Similar discriminations by CA3-4 lesions and challenge by naloxone and morphine may indicate that two neural circuits exist through which withdrawal-like behaviors are evoked. The hippocampal circuit is not directly involved in dependence, but may modulate withdrawal. Withdrawal-like behaviors are observed in rats in situations where behavior is blocked. These withdrawal-like behaviors are reminiscent of verbal reports of anxiety. In particular, wet-dog shakes in these situations may be analogous to shuddering. In humans, monosodium glutamate intolerance is associated with shuddering.

Rats were given sham, cortical, or hippocampal lesions and sacrificed 7 or 28 days following surgery. Levels of norepinephrine, dopamine, and the major dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA), were assayed in 3 brain regions. At day 7 there was a decrease in dopamine utilization and a decrease in norepinephrine levels in the nucleus accumbens after hippocampal damage but both of these measures returned to normal levels by day 28. In the neostriatum HVA levels decreased at day 7 after hippocampal damage. The utilization of dopamine in the neostriatum was decreased at day 28 in animals that received neocortical lesions but this was not observed in animals with hippocampal destruction. No effects of any lesion at any day were found in the olfactory tubercle region, the third brain region analyzed. It is thought that the removal of hippocampal and neocortical input to the basal ganglia influences catecholamine function reflected in the loss and subsequent recovery of dopamine utilization.

Locomotor activity was measured in mice with lesions restricted to the neocortex, in animals with hippocampal damage, and in sham-operated control mice of the selectively bred high and low open-field activity lines developed by J. C. DeFries. Postoperatively, the high-activity animals with hippocampal lesions showed reduced activity relative to those with only neocortical damage, and their postoperative activity levels were uncorrelated with those obtained preoperatively. Testing the animals under reduced illumination enhanced locomotor activity, with the greatest increase demonstrated by high-activity mice with hippocampal damage. While increases in activity under low illumination did occur in the low-activity line, no significant group differences were observed. Amphetamine did not affect locomotor behavior of the high-activity control animals, whereas doses of 1.0 and 10.0 mg/kg reduced the activity of the low-activity mice. High-activity mice with hippocampal damage evidenced a significant increase in locomotor behavior after the 10.0 mg/kg dose. These results emphasize that the behavioral effects of brain lesions and pharmacological manipulations cannot be adequately assessed without regard to genotype of the animals under investigation.

Peptides derived from ACHT and alpha-MSH are known to exert trophic influences on peripheral and central nervous structures. Age-related brain diseases may in part be related to loss of neural plasticity. Melanocortins improve adaptional abilities of the nervous system. Chronic treatment with melanocortins may counteract age-related brain pathology.

The effects of dorsal, ventral, and near-total hippocampal lesions upon both rhythmic and stress-induced corticosterone secretion in adult male rats were examined. All hippocampally-damaged, cortically-damaged, and intact rats showed rhythmic corticosterone secretion as measured in 4 blood samples for each animal taken at 6-h intervals at least 1 week apart. There were no significant differences among the groups. In addition, there were no significant differences in the amount of stress-induced corticosterone across experimental groups.

Adult Binghamton Heterogeneous (HET) stock mice were administered one of three doses of diazepam (0.1, 2.5, or 5.0 mg/kg) immediately followed by a second injection of either the slow calcium channel blocker, nimodipine (Bay e 9736), or its vehicle. Hypothermic responses and muscular incoordination were measured twenty and sixty minutes later as assessed by changes in rectal temperature and motoric activity on a rotating rod. Nimodipine (5 mg/kg) alone did not significantly affect body temperature or motor coordination. However, when administered in combination with the two highest doses of diazepam, nimodipine significantly potentiated the hypothermic response produced by these doses both twenty minutes and sixty minutes post-injection. Administration of high doses of diazepam (2.5 and 5.0 mg/kg) resulted in significant motor incoordination at both observation periods, but this effect was not potentiated by nimodipine.

Ethanol and verapamil are both known to affect the transmembrane movement of Ca2+ in several biological systems. Both ethanol and verapamil have negative chronotropic actions on the isolated sinus node. The following study was designed to determine if these actions were synergistic. Studies on sinoatrial (SA) node-atrial preparations from rats pair-fed either sucrose or ethanol liquid diets showed that the preparations from the ethanol rats were more sensitive to verapamil. Studies on SA node-atrial preparations from control rats showed that acutely administered ethanol (20 mg/dl, 40 mg/dl) reduced spontaneous beating. In addition, verapamil had a greater negative chronotropic effect in the presence of ethanol (20 mg/dl, 40 mg/dl) than it did alone. It is hypothesized that the ethanol-verapamil interaction is mediated through a reduction in transmembrane Ca2+ movement.

Previous studies have shown that peripheral injections of the codeinone RX 336-M can induce excessive grooming in rats in an age-dependent fashion. The present experiment demonstrates that codeine, itself, also induces excessive grooming but with apparent equal effectiveness at all ages tested. Because of the structural similarity between codeine and morphine, the effects of intraperitoneally administered morphine were examined as well. Morphine was found to produce a temporal course of excessive grooming quite different from that produced by codeine. Morphine did not affect grooming in the first half (30 min) of the observation period, but accentuated it, briefly, for the next 30-45 min. Intraventricular administration of codeine at doses of 0.3 or 1.0 microgram/3 microliter had no effect on grooming in animals previously shown to demonstrate excessive grooming in response to either dose.

Animals were pretreated with 6-OHDA or ascorbate vehicle injected into the nucleus accumbens and tested 10 days later for excessive grooming induced by intracerebroventricular injection of ACTH1-24. The animals pretreated with 6-OHDA showed a significant decrease in excessive grooming produced by the neuropeptide and this reduction was seen only in the last 30 minutes of a 60-min test session. The results suggest an interaction of ACTH with dopamine systems on the onset and maintenance of excessive grooming.

Several penicillins and penicillin-related compounds were tested for their ability to produce epileptiform activity in rat neocortex. (1) Alterations in the side chain of penicillin G decreased epileptogenic capability in all the compounds tested in this study: Phenoxymethylpenicillin produced a primary focus but no mirror focus, suggesting a dissociation of the mechanisms underlying these two processes. Ampicillin, 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid produced little or no epileptiform activity. All these compounds have free amino grounds and are amphoteric. (2) Breaking the beta lactam ring of penicillin G (potassium penicillin G penicilloate) eliminated epileptogenic capability. (3) Potassium salts of penicillin or its derivatives (potassium penicillin G, propicillin, potassium 6-aminopenicillanic acid, potassium penicillin G penicilloate) consistently suppressed cortical activity, regardless of the ability of the compound to produce spike discharges. Thus, mechanisms underlying these two properties can be dissociated. (4) Antibiotic activity of penicillins bears no relationship to epileptogenic capability.

The purpose of the present study was to assess the effects of ganglioside treatment on changes in emotional, activity, and avoidance behaviors following septal brain damage. Rats were treated with GM1-gangliosides either before and after septal lesions, or only after septal lesions and tested for emotionality on 10 consecutive days beginning on the second day after surgery. The ganglioside treatment decreased the emotionality of rats with septal damage on the first test day, and enhanced their rate of recovery to control levels of emotionality. Septal rats treated with gangliosides had activity, rearing, and avoidance behaviors equivalent to nontreated septal rats; however, lesioned rats treated with GM1 showed reduced intertrial crossings during avoidance conditioning. These results suggest that the changes in emotional behavior of septal rats treated with GM1 occur shortly after the lesion.

Systemic injection of GDEE (glutamate diethyl ester), an antagonist of glutamate and aspartate receptors, induces stretching and yawning in rats. This was not accompanied by excessive grooming. Coupled with previous work these findings give evidence that a glutamatergic mechanism is involved in stretching and yawning.

Male, adult mice of the Binghamton heterogeneous stock received one of two doses of ethanol (1.0 g/kg or 2.0 g/kg in saline) alone or in combination with the calcium (Ca2+) slow channel blocker, verapamil (5.45 mg/kg in 25% v/v ethanol in saline). Hypothermic responses and motor incoordination were assessed in terms of rectal temperatures and rotorod activity both 20 and 60 min after drug administration. Verapamil alone did not affect body temperature, but it potentiated ethanol-induced hypothermia at both post-administration test times. Both verapamil and ethanol impaired muscular coordination and these effects were additive at the two observation periods. Verapamil did not affect ethanol blood levels from 10 to 80 min after administration of the drugs. Since motor impairment was observed when verapamil was administered with only its ethanol vehicle, this suggests a powerful interactive effect between the two drugs.

An inexpensive input/output transfer system between a PDP-8/1 Digital Equipment Corporation computer and two operant stations is described. An interrupt facility is included. Slight modification of this interface will also permit it to work with the newer PDP-8 series computers.

Hippocampal, cortical and sham lesioned rats were trained to discriminate between two odors, in non-contingent, partially contingent, and perfectly contingent schedules. In the non-contingent situation both odors signaled shock with probability of 0.5. In the partially contingent situation one odor signaled shock with probability of 0.5 and the other "no shock" with probability of 1. In the perfectly contingent situation one odor signaled shock and the other "no shock" with probabilities of 1. In the non-contingent schedule none of the three surgical groups evidenced learning, in the partially and perfectly contingent cases the hippocampally lesioned animals performed so as to indicate greater learning of the aversion than did the cortically lesioned or the sham operated animals. It is suggested that the behavior of animals with hippocampal lesions is more sensitive to contingencies than that of normal animals.

Offspring from pregnant rats injected with 4mg/kg body weight colchicine on Embryonic Days 18, 19, and 20 were found to have isocortical and hippocampal structures greatly reduced in mass when examined at birth. Cells with pyknotic nuclei were found in Layers 5, 4, and 3 of the cerebral isocortex, the habenula, and anterior medial nuclei of the thalamus. Brains taken at Postnatal Days 22 and 132 were reduced in overall size, and had a 20-30% reduction of cells at the vertex of the neocortex with up to 50% reduction in the thickness of the corpus callosum. A decrease in activity, an increase in fearfulness and/or decreased tendency to explore, reduced error scores on the Hebb-Williams maze, poor performance on the Maier elevated maze, and a lessened sensitivity to sound-induced seizures were correlated with these anatomical changes.

Independent groups of rats with hippocampal, neocortical, or sham lesions were observed 7, 14, or 28 days after surgery in an open field-hole board apparatus and in a smaller circular apparatus. In the circular apparatus, animals were observed after unilateral injection of the dopamine agonist, 3,4-dihydroxyphenylamino-2-imidazoline (DPI) or saline into nucleus accumbens. Behavioral changes in locomotion, exploration and grooming measured in the open field were consistent with those found previously after hippocampal damage, with each behavioral anomaly demonstrating a specific pattern of change after surgery. In general, the injection of DPI into nucleus accumbens produced greater behavioral change in animals with hippocampal damage than in animals with either neocortical or sham lesions. The drug-induced changes in the hippocampally lesioned rats made their behavior more like that of control animals. These results suggest that destruction of the hippocampus may induce alterations in dopaminergic mechanisms in nucleus accumbens which can be modified by appropriate pharmacologic intervention.

Although the research topics discussed in this chapter cover a substantial range of areas, methods, and behaviors, there is a consistent central issue: the alterations of brain and behavior subsequent to hippocampal lesions. The initial hypothesis that important secondary changes occur in the basal ganglia after hippocampal lesions has been sustained, at least in part, but other and unexpected results have been obtained that both clarify and mystify at the same time. The restoration of normal locomotion to animals with hippocampal damage by the application of a DAi agonist, DPI, to n. accumbens certainly supports our general idea, but the fact that membrane and transmitter changes in accumbens are transitory needs to be explained and perhaps related to alterations in DA receptor populations. The fact that intra-accumbens DPI can restore ACTH-induced excessive grooming at 28 days after hippocampal damage supports the idea that progressive changes are occurring in DA receptors in n. accumbens, but we need to know their nature more precisely. To do this, however, will probably require advances in our general knowledge of central DA receptors. One of the more interesting aspects of our observations is that the intra-accumbens administration of DPI restores normal behavioral patterns in several types of behaviors, especially locomotion and the excessive grooming response. These two behaviors are not closely linked in nature because large changes can occur in them independently, given appropriate conditions for testing. On the basis of available evidence both of these behaviors seem linked to activities in forebrain DA systems. This would further support the idea that the hippocampus modulates DA activities in basal ganglia systems. The results that suggest the presence of multiple sites for the central induction of grooming were also unexpected. As evidence mounts in support of this idea, it is likely that the one located in n. accumbens is more influenced by hippocampal destruction than the region(s) affected by icv neuropeptide administration. The interactions that take place in the basal ganglia can be extensive. Afferents from the entirety of the neocortical surface, the limbic system, and the projections from the brainstem DA cell groups meet in the striatum and ventral striatum. The efferents from this region not only reach motor cortical and subcortical sites but also project back onto diffusely projecting monoaminergic cells of the brainstem.(ABSTRACT TRUNCATED AT 400 WORDS)

Rats received lateral intracerebroventricular (icv) injection of sulfated or desulfated cholecystokinin octapeptide (CCK-8-S or CCK-8-D, respectively) and subsequent grooming behaviors were observed using a behavioral sampling technique. CCK-8-S (2.0 to 4.0 micrograms in 10 microliter) elicited a significant increase in grooming behaviors relative to the controls, but the relatively inactive CCK-8-D did not. Excessive grooming induced by CCK-8-S produced less grooming than did the adrenocorticotropic hormone fragment, ACTH1-24 (1.0 microgram in 10 microliter). An icv injection of CCK-8-S 3 h before the icv injection of ACTH1-24 inhibited the usual excessive grooming produced by the ACTH. Conversely, prior injection of ACTH1-24 abolished the increased grooming induced by CCK-8-S. Thus, the sulfated cholecystokinin octapeptide and ACTH1-24 exhibited short-term cross tolerance for excessive grooming. These results suggest that the colocalization of corticotropin releasing hormone and CCK-8 in neurons may have functional significance in connection with stress-related neuronal systems.