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The present paper deals with the computational simulation of a pile of thin sheets. The sheets are not laminated or glued, but they interact by frictional contact. In general, it is not possible to perform a full-scale finite element contact computation for piles containing thousands of sheets; the problem size becomes too large, and numerical solution methods suffer from severe convergence problems due to the large number of strongly coupled contact conditions. In this paper, a macroscopic material model is presented for the two-dimensional case. The pile of sheets is homogenized by introducing an effective anisotropic constitutive law, which is motivated by formulations of the theory of elasto-plasticity. This macroscopic material law models the behavior of a pile of sheets, allowing for no tensile stresses in the direction normal to the sheets and obeying Coulomb’s law of friction in the tangential contact plane. Applying this macroscopic material model, an equivalent homogeneous body can be treated using much coarser discretizations. Computational results for the problems are provided, and a comparison with simplified contact computations is done.

Visual habit formation in monkeys, assessed by concurrent visual discrimination learning with 24-h intertrial intervals (ITI), was found earlier to be impaired by removal of the inferior temporal visual area (TE) but not by removal of either the medial temporal lobe or inferior prefrontal convexity, two of TE's major projection targets. To assess the role in this form of learning of another pair of structures to which TE projects, namely the rostral portion of the tail of the caudate nucleus and the overlying ventrocaudal putamen, we injected a neurotoxin into this neostriatal region of several monkeys and tested them on the 24-h ITI task as well as on a test of visual recognition memory. Compared with unoperated monkeys, the experimental animals were unaffected on the recognition test but showed an impairment on the 24-h ITI task that was highly correlated with the extent of their neostriatal damage. The findings suggest that TE and its projection areas in the ventrocaudal neostriatum form part of a circuit that selectively mediates visual habit formation.

Rationale: The ameliorative effects of levodopa (l-3,4-dihydroxy-phenylalanine) on the motor impairment in Parkinson’s disease patients is well established, but characterization of its effects on the associated cognitive deficits is still incomplete. Objective: The present study determined the effect of different doses of levodopa on performance on a test of working memory in MPTP-treated rhesus monkeys, an animal model of Parkinson’s disease. Methods: Four MPTP-treated monkeys and their age-matched controls with the same experimental history as the MPTP-treated monkeys were tested on a spatial delay response task. Each daily session consisted of five trials at each of seven randomly presented delays (0, 10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five different conditions. In the first condition, control and MPTP-treated animals performed the task without levodopa. In the second condition, both groups were tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in which the doses of levodopa were increased to 250 and 500 mg, respectively, only the MPTP-treated animals were tested. In the final condition, the MPTP-treated animals where retested without levodopa. Results: Significant improvement was observed at all doses tested (range 100–500 mg). Conclusions: Levodopa can ameliorate memory impairments in this parkinsonian model.

Opiate receptor avidity, roughly equivalent to the ratio of unoccupied receptor density to the receptor dissociation constant (B′max/KD), was measured in four MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys and nine normal controls with positron emission tomography (PET) and 6-deoxy-6-β-[ 18 F ]fluoronaltrexone (cyclofoxy, CF), a μ- and κ-opiate receptor antagonist. Although the MPTP-lesioned monkeys were dopamine deficient as measured with [ 18 F ]- l -fluorodopa ([ 18 F ]-DOPA) and PET [Doudet et al., 6-[ 18 F ]- l -DOPA imaging of the dopamine neostriatal system in normal and clinically normal-MPTP-treated rhesus monkeys, Exp. Brain Res. 78 (1989) 69–80], they had clinically recovered from the acute motor effects of MPTP exposure. Opiate receptor avidity was found to be reduced by 30–35% in the opiate-receptor rich areas of caudate, anterior putamen, thalamus, and amygdala of the MPTP-lesioned animals. The results suggest that opiate pathways make a significant contribution to the adjustment of cortico–striatal–thalamic pathway activity and thereby to behavior in rhesus monkeys following dopamine loss.

Administration of either a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), or a muscarinic antagonist, scopolamine, produces dose-related impairments in performance of a visual recognition memory task, delayed non-matching to sample (DNMS) with lists of 20 symbols, in rhesus monkeys. In the present study, low doses of these two drugs, which were ineffective when given alone, significantly impaired performance when given in combination. Moreover, the effect was greater than additive, indicating a synergistic interaction. These results suggest that interactions between cholinergic and glutamatergic systems play an important role in regulation of visual recognition memory.

Positron emission tomography (PET) was carried out, with 18 F-DOPA as a ligand, in normal control monkeys and “parkinsonian” monkeys who had been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The following approaches were used in data analysis: ratio of 18 F accumulation in specific to nonspecific brain areas and 18 F-DOPA influx constant obtained using either the actual plasma 18 F-DOPA or the 18 F activity in a nonspecific brain area as the input function. The results from these analyses were compared to one another and to biological parameters relevant to dopaminergic function. The striatum/cortex ratio and the rate constant calculated from plasma 18 F-DOPA appeared to be the most sensitive analytic techniques.

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

The effect of scopolamine on visual recognition memory in rhesus monkeys was assessed with a delayed nonmatching-to-sample task employing trial-unique stimuli. During the acquisition phase, 40 sample stimuli were presented sequentially. During the test phase, these same stimuli were presented in the reverse order, each paired with a novel stimulus. The animal was rewarded for choosing the novel stimulus in each pair. Two versions of this design were used. In Task 1, scopolamine (10.0 or 17.8 micrograms/kg) was administered 20 min prior to acquisition, which was followed immediately by the test phase. In Task 2, the drug was administered immediately after acquisition, which was followed 20 min later by the test phase. Performance was impaired in a dose-related manner in Task 1, but not at all in Task 2, indicating that the effects of scopolamine on performance cannot be attributed to an impairment either in the retrieval of stored information or in the attentive or perceptual discriminative processes needed for such retrieval, or, by implication, for storage. In addition, the forgetting curves for scopolamine in Task 1 were parallel to those of the control sessions; i.e., the curves did not diverge with increasing delay intervals, indicating that scopolamine did not increase the rate of forgetting. Taken together, the results suggest that scopolamine interferes selectively with the initial storage of the information to be remembered.

In vivo biochemical microdialysis in primate brain would greatly expand our understanding of functional neuronal systems. This work describes our efforts to establish a microdialysis system in primate brain. Seven anesthetized rhesus monkeys underwent magnetic resonance imaging (MRI) with the head fixed in a compatible stereotaxic frame. This allowed stereotaxic localization of the caudate nucleus and putamen. Guide cannulae were implanted and fixed to the skull. Microdialysis probes made from polyethylene and fused silica were inserted into the caudate and putamen through the guide cannulae and perfused at the rate of 1.3 microliters/min. The putamens were approached horizontally, while the caudate nuclei were reached via a 30 degrees-45 degrees angle from the vertical. Postdialysis MRI and histologic evaluation proved that all probes accurately arrived at the predetermined region. Our data show that MRI guided stereotaxis allows accurate placement of dialysis probes and that implantation of guide cannulae is a reliable and convenient way to perform repeated brain microdialysis procedures.

In 2 Fallbeispielen wird von den Autoren auf die Moglichkeit der Behandlung der Meralgia paraesthetica mit Akupunktur hingewiesen. Bei beiden Patienten konnten die bis dahin bestehenden therapieresistenten chronischen Schmerzen und Paraesthesien im Bereich der Oberschenkelausenseiten unter Akupunkturbehandlung schnell und anhaltend beseitigt werden. Der symptomatischen Therapie mus der Ausschlus von malignen Erkrankungen bzw. vertebrogenen Ursachen fur das Symptomenbild der Meralgia paraesthetica nocturna vorausgehen.

Single neurons in the ventral striatum of primates carry signals that are related to reward and motivation. When monkeys performed a task requiring one to three bar release trials to be completed successfully before a reward was given, they seemed more motivated as the rewarded trials approached; they responded more quickly and accurately. When the monkeys were cued as to the progress of the schedule, 89 out of 150 ventral striatal neurons responded in at least one part of the task: (1) at the onset of the visual cue, (2) near the time of bar release, and/or (3) near the time of reward delivery. When the cue signaled progress through the schedule, the neuronal activity was related to the progress through the schedule. For example, one large group of these neurons responded in the first trial of every schedule, another large group responded in trials other than the first of a schedule, and a third large group responded in the first trial of schedules longer than one. Thus, these neurons coded the state of the cue, i.e., the neurons carried the information about how the monkey was progressing through the task. The differential activity disappeared on the first trial after randomizing the relation of the cue to the schedule. Considering the anatomical loop structure that includes ventral striatum and prefrontal cortex, we suggest that the ventral striatum might be part of a circuit that supports keeping track of progress through learned behavioral sequences that, when successfully completed, lead to reward.

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored.

The authors demonstrate a way to treat meralgia paresthetica ("jeans disease") with acupuncture. Two patients with therapy-resistant chronic pain and paresthesia of the lateral thigh became free of symptoms quickly and remained under acupuncture therapy. Gynecological, vertebral and urological factors must be excluded before any kind of symptomatic therapy is begun. The advantages and disadvantages of acupuncture are discussed.

Our previous studies demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various rodent models of amnesia, through activation of the somatostatin neuronal system. To extend the antiamnesic action of FK960 to nonhuman primates, FK960 was evaluated for its ability to reverse the deficits in visual recognition memory produced by muscarinic cholinergic receptor blockade by scopolamine or N-methyl-D-aspartate receptor blockade by dizocilpine (MK-801) in four rhesus monkeys performing a computer-automated version of delayed nonmatching to sample, with a list length of 20 trial-unique graphic symbols. Furthermore, the effects of FK960 were compared with those of physostigmine, a cholinesterase inhibitor. Doses of FK960 (1, 3.2, 10, 32,100, 320 or 1000 microg/kg) injected i.m. 30 min before testing minimally affected visual recognition memory when administered alone. FK960 (1, 3.2, 10 or 32 microg/kg) significantly antagonized the deficits in visual recognition memory produced by scopolamine (10 microg/kg); the same doses of the drug minimally affected the deficits produced by dizocilpine (32 microg/kg). Similarly, physostigmine (3.2, 10 or 32 microg/kg) significantly and dose-dependently restored the visual recognition memory deficits produced by scopolamine (10 microg/kg) but not those produced by dizocilpine (32 microg/kg). From these results, we conclude that FK960 improves deficits in recognition memory associated with central cholinergic hypofunction in nonhuman primates, and we suggest that the therapeutic potential of this drug for patients with dementia should be evaluated.

Extracellular levels of acetylcholine in inferior temporal cortex (IT), perirhinal cortex (PR), and dentate gyrus (DG) of the hippocampus were monitored using in vivo microdialysis in rhesus monkeys performing two behavioral tasks. Performance on a visual recognition task was associated with 26%, 41% and 24% increases in acetylcholine overflow in IT, PR and DG, respectively, compared with pre-test baseline levels. Performance on a memory-independent task was associated with increases in acetylcholine release of 24%, 34% and 7% above baseline in IT, PR and DG, respectively. The PR-DG differences were significant, but the others were not. The results provide biochemical evidence for cerebral cholinergic system activation during visually mediated behavior in non-human primates, and are consistent with the view that such activation is a prerequisite for visual recognition memory.

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl-D-asparate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1-10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficity following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2-32 micrograms/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 micrograms/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 micrograms/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

Strychnine-insensitive glycine binding sites have recently been shown to positively modulate N-methyl-D-aspartate (NMDA) receptors. In the present study, the effects on recognition memory of D-cycloserine, a partial agonist at the glycine modulatory site on the NMDA receptor, were evaluated in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trail-unique graphic symbols. Single administration of D-cycloserine (100-1000 micrograms/kg i.m.) facilitated DNMS performance significantly with an inverted U-shaped dose-response curve when given 30 min before testing. To assess further the possible neural mechanisms, D-cycloserine was evaluated for its effects on the memory impairments after blockade of the glycine sites by HA-966, N-methyl-D-aspartate receptors by MK-801, or cholinergic receptors by scopolamine. D-Cycloserine completely reversed the visual recognition memory deficits produced by HA-966 (3.2 mg/kg i.m.). D-Cycloserine also dose-dependently and significantly restored the memory deficits produced by MK-801 (32 micrograms/kg i.m.). In addition, D-cycloserine produced a partial, though significant, improvement on the recognition memory deficits after cholinergic blockade with scopolamine (10 micrograms/kg i.m.). From these results, we propose that D-cycloserine has a cognition-enhancing property in non-human primates and that it may have a potential value in treating dementias. Furthermore, the present results provide new evidence for the important role for the glycine sites in the regulation of recognition memory.

1. The results of neuropsychological, neuropharmacological, and neurophysiological experiments have implicated the ventral striatum in reward-related processes. We designed a task to allow us to separate the effects of sensory, motor, and internal signals so that we could study the correlation between the activity of neurons in the ventral striatum and different motivational states. In this task, a visual stimulus was used to cue the monkeys as to their progress toward earning a reward. The monkeys performed more quickly and with fewer mistakes in the rewarded trials. After analyzing the behavioral results from three monkeys, we recorded from 143 neurons from two of the monkeys while they performed the task with either juice or cocaine reward. 2. In this task the monkey was required to release its grip on a bar when a small visual response cue changed colors from red (the wait signal) to green (the go signal). The duration of the wait signal was varied randomly. The cue became blue whenever the monkey successfully responded to the go signal within 1 s of its appearance. A reward was delivered after the monkey successfully completed one, two, or three trials. The schedules were randomly interleaved. A second visual stimulus that progressively brightened or dimmed signaled to the monkeys their progress toward earning a reward. This discriminative cue allowed the monkeys to judge the proportion of work remaining in the current ratio schedule of reinforcement. Data were collected from three monkeys while they performed this task. 3. The average reaction times became faster and error rates declined as the monkeys progressed toward completing the current schedule of reinforcement and thereby earning a reward, whereas the modal reaction time did not change. As the duration of the wait period before the go signal increased, the monkeys reacted more quickly but their error rates scarcely changed. From these results we infer that the effects of motivation and motor readiness in this task are generated by separate mechanisms rather than by a single mechanism subserving generalized arousal. 4. The activity of 138 ventral striatal neurons was sampled in two monkeys while they performed the task to earn juice reward. We saw tonic changes in activity throughout the trials, and we saw phasic activity following the reward. The activity of these neurons was markedly different during juice-rewarded trials than during correctly performed trials when no reward was forthcoming (or expected). The responses also were weakly, but significantly, related to the proximity of the reward in the schedules requiring more than one trial. 5. The monkeys worked to obtain intravenous cocaine while we recorded 62 neurons. For 57 of the neurons, we recorded activity while the monkeys worked in blocks of trials during which they self-administered cocaine after blocks during which they worked for juice. Although fewer neurons responded to cocaine than to juice reward (19 vs. 33%), this difference was not significant. The neuronal response properties to cocaine and juice rewards were independent; that is, the responses when one was the reward one failed to predict the response when the other was the reward. In addition, the neuronal activity lost most of its selectivity for rewarded trials, i.e, the activity did not distinguish nearly as well between cocaine and sham rewards as between juice and sham rewards. 6. Our results show that mechanisms by which cocaine acts do not appear to be the same as the ones activated when the monkeys were presented with an oral juice reward. This finding raises the intriguing possibility that the effects of cocaine could be reduced selectively without blocking the effects of many natural rewards.

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinson's patients, the MPTP-treated primates display spatial deficits.

Both acetylcholine and glutamate are now thought to play important roles in memory. Recent evidence suggests that the interaction of these two neurotransmitters may be important for some forms of memory, and that acetylcholine, in particular, may function to facilitate glutamate activity by coordinating states of acquisition and recall in the cortex and hippocampus.

Both N-methyl-D-aspartate (NMDA) and cholinergic receptors are thought to participate in processes of learning and memory. The effects of the noncompetitive NMDA antagonist ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) MK-801 on recognition memory in rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample DNMS were compared to those of the cholinergic compounds physostigmine and scopolamine. In the sample phase of the test, 20 symbols were presented sequentially every 30 sec on a color monitor fitted with a touch-sensitive screen. These symbols were then presented again in the same order as before, but each symbol was now paired with a different novel symbol. A monkey was rewarded with a food pellet if it touched the symbol in the sample phase and the previously unseen symbol in the choice phase. Physostigmine (3.2, 10 and 32 micrograms/kg), scopolamine (3.2, 10, 17.8 and 32 micrograms/kg) or MK-801 (3.2, 10 and 32 micrograms/kg) was injected i.m. 20, 20 and 30 min before testing, respectively. The highest doses of both MK-801 and scopolamine significantly impaired performance. In addition, scopolamine, but not MK-801, prolonged response latency, whereas MK-801, but not scopolamine, increased response bias. Physostigmine produced a small but significant increase in correct responses at the intermediate dose, but not at the highest dose. These results suggest that both the glutamatergic and the cholinergic systems participate in visual recognition memory in monkeys, though probably by different mechanisms.

Performance of three rhesus monkeys on a test of one-trial stimulus-reward association, in which recall intervals ranged from 0.5 to 6.5 min, was evaluated during nondrug-control conditions and following administration of the muscarinic-receptor blocker scopolamine. During control sessions, performance averaged 78% correct responses. Following administration of 10.0 and 17.8 μg/kg of scopolamine, performance fell significantly, to 69% and 63% correct responses, respectively. This dose-dependent impairment in recall was similar to the impairment we reported previously in recognition. Although the results thus failed to support a suggestion derived from behavioral electrophysiological findings that stimulus-reward association might be more vulnerable to scopolamine than stimulus recognition, they provide additional evidence for a cholinergic contribution to cognitive memory.

The accumulation of 3-O-methyl-6-[18F]fluoro-L-DOPA (18F-30M-DOPA) in the brain from the circulation is responsible for most of the nonspecific background during 18F-DOPA positron emission tomography scanning. To increase the sensitivity of 18F-DOPA for imaging presynaptic dopamine systems, we took advantage of 18F-30M-DOPA's rapid clearance from the brain (T1/2 approximately 15-20 min). The infusion of the unlabeled amino acid L-phenylalanine, starting 75 min after 18F-DOPA administration, prevents 18F-30M-DOPA entrance into the brain through competition at the large amino acid transport system of the blood brain barrier. This method produces high specific-to-nonspecific contrast images of 18F accumulation beginning 15-30 min after onset of amino acid infusion and better sensitivity to small changes in 18F-DOPA uptake while still allowing for kinetic analysis of the data in the early time points. Kinetic and anatomical data were found to be strongly correlated.

Carbamazepine is one of the most potent anticonvulsants against completed amygdala-kindled seizures, with no impact, however, on the development of these seizures in the rat. Based on this observation and the finding that lidocaine-kindled seizures produce marked increases in behavioral aggression in the rat,1–3 we wished to examine whether carbamazepine would be able to block these aggressive responses, presumably in the absence of its ability to block the local anesthetic seizure. Contrary to our expectations, carbamazepine was highly effective in blocking the development of both lidocaine-and cocaine-kindled seizures.4–7

The sensitivity of 18F-DOPA positron emission tomography for imaging presynaptic dopamine systems is limited by the amount of specific-to-nonspecific accumulation of radioactivity in brain. In rhesus monkeys, we have been able to increase this ratio by taking advantage of the lag time between 18F-DOPA injection and the formation of its main metabolite, the amino acid 18F-fluoromethoxydopa, the entrance of which into brain is responsible for most of the brain's nonspecific radioactivity. By infusing an unlabeled amino acid, L-phenylalanine, starting 15 min after 18F-DOPA administration, we preferentially blocked the accumulation of 18F-fluoromethoxydopa by preventing its entrance into brain through competition at the large neutral amino acid transport system of the blood-brain barrier. This method appears as reliable as the original and more sensitive, as demonstrated by the comparison of normal and MPTP-treated animals under both conditions.

To assess the contributions of the basal forebrain cholinergic nuclei to visual recognition memory in macaques, we compared the effects of lesions of (a) the nucleus basalis of Meynert, (b) the medial septal and diagonal band nuclei, and (c) all nuclei combined on performance of delayed nonmatching-to-sample with trial-unique stimuli. Whereas monkeys with the separate lesions did not differ from each other or from normal control animals, those with combined lesions showed a significant impairment. With time and extended practice, however, the performance of the animals with combined lesions recovered to normal levels. During the recovery period, these monkeys showed an initially increased sensitivity to scopolamine that later dissipated, at which time they also failed to show the improvement that follows physostigmine administration in normal animals. Postmortem assessment of cortical choline acetyltransferase activity revealed that only the group with combined lesions had significant depletion of this enzyme. The results suggest that (1) the basal forebrain cholinergic system participates in mnemonic processes in primates and that (2) extensive damage to this system is necessary before impairments in recognition memory, even transient ones, can be observed.

Kinetic modeling of the PET tracer 6-[18F]fluoro-l-dopa ([18F]Dopa), used to measure presynaptic dopamine function, requires the accurate determination of the plasma input curve. We have developed a new method that uses alumina extraction preceded by cation and anion exchange resins to determine the parent compound, [18F]Dopa and its critical metabolite 3-O-methyl-6-[18F]fluoro-l-dopa. Using this method we found that carbidopa increases the plasma input of [18F]Dopa while decreasing the rate of metabolite formation, and that previous drug treatment can significantly effect [18F]Dopa metabolism.

This study investigated the occurrence of primary and secondary complications following conservative versus surgical intervention in the treatment of midface and lower jaw fractures. Follow-up studies were undertaken on 81 patients who had been admitted to the above clinic with such fractures during their adolescence. It was found that more complications developed after surgical intervention.

Standard stereotactic procedures rely upon external cranial landmarks and standardized atlases for localization of subcortical neural regions. Magnetic resonance imaging permits the visualization of the neural structure of the brain in vivo. A stereotactic instrument compatible with a magnetic resonance unit was constructed and together with magnetic resonance imaging a procedure was developed that overcomes the limitations and inaccuracies of the traditional stereotactic methods and allows accurate and reliable localization of subcortical targets in the rhesus monkey brain.

Previous studies have shown that a variety of local anesthetics including procaine are self-administered at high rates by rhesus monkeys. In the present study two rhesus monkeys were given a mutually exclusive choice between various doses of intravenous cocaine and procaine. In almost all comparisons cocaine was preferred even when the procaine dose was 16 times that of cocaine. Other measures of performance such as rate of responding did not vary systematically with preference. These data provide further support for the idea that rate of responding under simple schedules of drug delivery is an unreliable measure of relative reinforcing efficacy. In addition, the consistent preference for cocaine over procaine in monkeys suggests that the infrequent abuse of procaine by humans may be related to its low reinforcing efficacy relative to drugs such as cocaine.

d-Glaucine is an alkaloid derived from Glaucium flavum, which is as effective as codeine as an antitussive. d, l-Glaucine. 1.5 phosphate is a synthetic compound related to d-glaucine. The ability of d, l-glaucine.1.5 phosphate to maintain responding in rhesus monkeys was assessed in 2 procedures. In the first responding was maintained under a fixed-ratio 10 schedule of codeine delivery during daily 3-hr sessions. When d, l-glaucine.1.5 phosphate (0.05-0.4 mg/kg) was substituted for codeine, responding was not maintained. In the second procedure, monkeys given 23-hr/day access to 0.5-1.0 mg/kg under a fixed-ratio schedule did not self-administer d,l-glaucine.1.5 phosphate above saline levels even after a 21-day period of programmed injections. Following the period of programmed injections, there were not signs of opiate withdrawal following the administration of naloxone. These results indicate that the abuse potential of d,l-glaucine.1.5 phosphate is low relative to codeine.

The effects of naloxone on visual recognition were evaluated in five macaques trained in delayed nonmatching-to-sample with trial-unique objects. In four of the five monkeys, naloxone yielded an inverted U-shaped dose-effect curve. For each of these four animals, as well as for all five animals as a group, at least one dose within a narrow range (0.32-3.2 mg/kg) produced a significant increase in the number of objects correctly recognized. Lower doses had little effect, while the highest dose (10.0 mg/kg) tended to disrupt performance.

The behavioral effects of acute IP administration of 1-alpha-acetylmethadol, its metabolites, 1-alpha-noracetylmethadol and 1-alpha-dinoracetylmethadol, and morphine were studied in the rat using behavior controlled by a fixed-interval schedule of food reinforcement. Administraiton of all compounds produced a dose-related decrease in response rate. The metabolites were approximately three to four times the potency of the parent compound which was approximately five times the potency of morphine. Data obtained from cumulative response records suggested that the onset of effects for the metabolites was more rapid than for the parent compound.

Rhesus monkeys were allowed to choose between intravenous injections of cocaine and food reinforcement for lever pressing. A choice trial was available every 15 minutes continuously for 8 days. The animals chose cocaine almost exclusively, which resulted in high cocaine intake, decreased food intake, weight loss, and marked behavioral toxicity. The study provides evidence of the reinforcing efficacy of cocaine.

The effects of orally administered delta-9-tetrahydrocannabinol (THC) were evaluated on two different learning abilities in monkeys. Visual recognition memory, known to depend on limbic system integrity, was tested by means of delayed nonmatching-to-sample and found to be significantly impaired by acute administration of 2 and 4 mg/kg THC given 1 or 2 h prior to testing. Performance was significantly impaired throughout a 21-day period of repeated administration of 4 mg/kg THC and also during a 3-5 day period that began 7-10 days after the last dose of THC. By contrast, 24-h concurrent discrimination learning, a task that monkeys with limbic lesions can perform normally, was not impaired by THC, even following doses as high as 16 mg/kg. These results suggest that THC interferes with recognition memory more than discrimination learning, possibly reflecting a selective action of THC on limbic mechanisms.

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.