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The effect of GM1 ganglioside on the recovery of concentrations of dopamine (DA) in the striatum, following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was studied in mice of various ages. At the start of the study, the mice were 8 weeks, 6, 12 and 20 months old. Mice from each age group received MPTP for 5 days, followed by either GM1 ganglioside or saline for 4 or 8 weeks. Animals older than 8 weeks, that did not receive GM1 showed no spontaneous recovery of striatal levels of DA in the striatum, over either 4 or 8 weeks. Animals that received GM1 showed varied amounts of recovery of levels of DA in the striatum. The young animals (8 wk old) had the most pronounced effect from GM1. With increasing age, the magnitude of the effect of GM1 became attenuated and recovery had a longer latency. The results suggest that GM1 can be effective in at least partially restoring MPTP-depleted levels of DA in the striatum, even in aged mice.

Tyrosine hydroxylase immunohistochemical analysis was performed on tissue sections through the pallidal complex from Nemistrina monkeys which had been made hemi-parkinsonian by intracarotid MPTP infusion 8-12 months earlier. The side contralateral to the MPTP infusion showed a dense dopaminergic innervation of the pallidum (both internal and external segments), but particularly the internal pallidum. The side of the brain ipsilateral to the MPTP infusion showed a remarkable sparing of the pallidal dopaminergic innervation, despite almost total loss of the dopaminergic innervation of the caudate and putamen. These results support the view that in the primate, the nigropallidal projection is mostly distinct from the nigrostriatal projection. It is also suggested that perhaps the sparing of pallidal dopamine at least in part may contribute to some of the recovery of function observed in some monkeys following exposure to MPTP.

The immunohistochemical localization of Met-enkephalin (Enk) was examined in the brains of normal monkeys (Macaca nemistrina), monkeys made parkinsonian by systemic MPTP administration and sacrificed while symptomatic, and monkeys exposed to low doses of MPTP over several months and sacrificed while asymptomatic for a gross parkinsonian motor disorder. The animals that had severe parkinsonian features had a large number of intensely Enk-immunoreactive perikarya in the putamen. Normal control animals had no Enk-immunoreactive perikarya while asymptomatic animals had small numbers of lightly to moderately stained perikarya in the putamen. Symptomatic animals also showed the most intense Enk immunoreactivity in the lateral globus pallidus (LGP) while the asymptomatic animals showed LGP Enk immunoreactivity intermediate between that seen in symptomatic and normal animals. These results suggest an increase in putamen Enk synthesis and LGP Enk content in animals with massive striatal dopamine depletions (greater than or equal to 97%) and which actively show parkinsonian features. Animals with slightly less striatal dopamine depletion and with no parkinsonian symptoms, had increased activity in this system but not to the extent seen in symptomatic animals.

Extracellular single unit activity was recorded in the dorsal lateral caudate nucleus of awake cats and the responses of these neurons to somatosensory, visual and auditory stimuli were assessed. Recordings were obtained when animals were normal and when they were symptomatic for a Parkinson-like syndrome as a result of exposure to the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In normal animals, 22% of recorded neurons responded to tactile stimulation of the face, 7% had auditory responses, 6% had visual responses, and 6% were multimodal. The post-MPTP period was divided into an 'early' period, in which cats had received several MPTP injections but still remained asymptomatic, and a 'late' period, in which cats had severe motor and sensorimotor impairments. Unit responsiveness was essentially normal in the 'early' period but grossly abnormal in the 'late' period. When animals were symptomatic, only 6% of sampled neurons had responses to somatosensory stimulation, 0.8% had auditory responses and no cells were found with visual responses. Those cells that did respond to somatosensory stimulation did so in a non-specific fashion. Symptomatic animals had 93-96% depletion of dorsal striatal dopamine and extensive loss of substantia nigra pars compacta neurons. The results suggest that sensorimotor and motor abnormalities that accompany severe loss of striatal dopamine are at least in part due to a dopamine-dependent loss of sensory processing abilities of striatal neurons.

6-[18F]Fluoro-L-DOPA (FDOPA) is an L-DOPA analog that is used to assess the functional integrity of central dopaminergic systems in vivo with positron emission tomography (PET). FDOPA metabolites from putamen of normal and MPTP-treated monkeys were characterized to correlate FDOPA metabolism changes with those of the endogenous dopamine system. In MPTP-lesioned putamen, 6-[18F]fluorodopamine and dopamine levels were less than 2% those of controls. Increases in endogenous dopamine metabolism were reflected by similar increases in 6-[18F]fluorodopamine metabolites. These results suggest that changes in the central dopamine system biochemistry can be monitored in vivo with FDOPA and PET.

Striatal neurochemistry and motor activity were assessed in cats treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and killed either when symptomatic for a Parkinson-like motor disorder or six weeks later, when showing significant motor recovery. The results of striatal neurochemical analyses showed distinct regional differences in susceptibility to MPTP-induced damage, with dorsal striatal regions generally more severely affected than ventral striatal regions. Symptomatic animals had more severe dopamine loss in all striatal regions than did recovered animals. The dorsal lateral caudate, the cat's sensorimotor striatum, had the largest dopamine depletion in the symptomatic animals (99%) and the least recovery in recovered animals (94% depletion). In contrast, the nucleus accumbens had a 94% dopamine depletion in symptomatic animals and only a 34% depletion in recovered animals. In addition to increases in dopamine levels and dopamine utilization in the striatum in recovered animals, significant increases in serotonin levels and serotonin utilization were also observed. Therefore, motor recovery may have been due to either or both of these neurochemical changes. The fact that the cat develops Parkinson-like motor symptoms but that they are not persistent may make this an interesting model in which to study the role of dopamine in motor function and to study compensatory mechanisms of the damaged dopamine system.

Schneider and Kovelowski (1990) showed that chronic low-dose N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to monkeys caused cognitive dysfunction without significant motor impairment on tasks thought to be related to the caudate-frontal axis. The cognitive difficulties were similar to those seen in monkeys with frontal lesions, normal young monkeys, and normal young children. The caudate-frontal dysfunction is consistent with the cognitive difficulties that are thought to exist in children with attention deficit disorder (ADD). The caudate-frontal dysfunction is also consistent with the distribution of decreased cerebral blood flow and, presumably, decreased metabolism that has recently been found in children with ADD. In monkeys given chronic low-dose MPTP, pilot neurochemical studies have suggested abnormalities in dopamine and norepinephrine metabolism, the two neurotransmitters most frequently linked with ADD. We suggest that chronic low-dose MPTP induced cognitive dysfunction in primates may not only be a model for the cognitive disturbances that accompany Parkinson's disease but may also aid in understanding the cognitive dysfunction seen in children with ADD.

Chronic low-dose MPTP exposure was previously found to impair cognitive performance in monkeys. These monkeys developed deficits in performance of delayed response and delayed alternation tasks but maintained performance on visual pattern discrimination. This, along with other subtle behavioral changes, occurred in the absence of gross parkinsonian motor symptoms. The present study reports the results of neurochemical and neuropathological examination of the brains of these animals. Chronic low-dose MPTP exposure resulted in profound decreases in caudate dopamine (DA) levels and slightly less severe depletions in the putamen. Increases in striatal HVA/DA ratios suggest an increase in DA turnover in these areas. In contrast to striatal DA depletions, we found significant increases in striatal serotonin levels without an associated increase in serotonin turnover. At the cortical level, we found inconsistent changes in frontal cortical DA levels and variable decreases in norepinephrine levels. Since the most profound and consistent deficits were in the nigrostriatal dopamine system, we suggest that most of the behavioral consequences of chronic low-dose MPTP exposure stem from the striatal dopamine depletion. We also suggest that the maintenance of motor function in the presence of massive striatal DA depletions may be due to less impairment of putamen DA vs. caudate DA, by an increase in striatal DA turnover, a compensatory increase in serotonin availability, or a combination of these and possibly other as yet undetermined compensatory mechanisms. Furthermore, we propose the present model utilizing chronic low-dose exposure to MPTP as a model for the early, compensated form of Parkinson's disease.

Following identification of an unusual cluster of cases of malignant melanoma among laboratory employees at this national facility, several studies were done to provide further understanding and solutions to the problem. This paper discusses the Laboratory's response, including the educational campaign and institution of self-examinations. Experience with the melanoma surveillance program to date reinforces its validity.

Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.

Cognitive deficits which may occur following chronic low-dose exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in monkeys who remained motor asymptomatic for parkinsonism throughout the study. The tasks used to assess cognitive functioning are those which have proved in the past to be sensitive to disruption of frontal cortical and or striatal integrity (delayed response and delayed alternation) or sensitive to inferior temporal lobe dysfunction (visual pattern discrimination). Since Parkinson's disease patients have been described as exhibiting frontal signs, we were interested to examine whether MPTP-treated monkeys might exhibit deficits on frontally-mediated tasks, without the confound of motor disturbances. We found that macaque nemistrina monkeys exposed to cumulative doses of 14.94-75.42 mg of MPTP over periods ranging from 5 to 13 months never developed parkinsonian motor signs. However, all 4 animals examined showed significant post-MPTP deficits in delayed response and delayed alternation performance, while visual pattern discrimination performance remained intact. These animals also developed other behavioral problems including irritability and decreased attentiveness. These results show that MPTP can cause specific cognitive deficits independent of the motor deficits which can be produced by this toxin.

A complex syndrome consisting of locomotor hyperactivity and a cervical choreoathetoid dyskinesia was produced in rats after 7 to 10 days administration of 3-3 -iminodipropionitrile. Attenuation of motor abnormalities after lesions of the basal ganglia (BG) but not cortical lesions suggests the importance of descending BG influences in this syndrome. Responses of this syndrome to pharmacologic manipulations further argues for BG involvement. This syndrome may be a possible animal model of human hyperkinetic basal ganglia disorders.

The neurophysiological basis of behavior and psychiatric disorders is for the most part unknown. However, over the years dysfunction of the dopaminergic system and, specifically, the basal ganglia have been implicated in many complex behaviors and psychiatric disorders. Evidence is presented in support of a basal ganglia role in sensory gating in the CNS and suggests a possible mechanism by which basal ganglia dysfunction may result in complex behavioral disturbances. Using schizophrenia as an example, this paper suggests that such disorders may to a certain extent represent a complex dysfunction of sensory filtering mechanisms in the brain. The suggestion is that the basal ganglia, acting as an active sensory information gating station, maintain the normal flow of afferent information to both ascending and descending structures. When this gating system is dysfunctional, unmodulated afferent information leads to inappropriate behavioral responses.

Tyrosine hydroxylase immunohistochemical analysis of the dorsal raphe nucleus (DRN) of severely parkinsonian MPTP-treated cats and cynomolgus monkeys revealed a marked loss of catecholaminergic neurons in this region. Cell loss was more extensive in the ventral portion of the nucleus with a relative sparing of neurons in the dorsal-most portions of the DRN. These results demonstrate that catecholaminergic neurons other than those in the ventral mesencephalon and the locus ceruleus are affected by the toxic effects of MPTP.

Three patients with pericarditis following therapeutic irradiation for malignant tumors were studied at autopsy. In one subject, death occurred five days after the last dose of radiation. The pericardial involvement was characterized by fibrinous exudation. This was more marked in degree over the right side of the heart than the left and corresponded with the field of irradiation. In the remaining two patients, two and four courses of radiation had been applied, the interval between the last dose and death being seven weeks in one patiet and 1 1/2 years in the other. The lesions were those of organizing pericarditis.

The relationship between severity of dopa-induced parkinsonian symptoms and the latency and severity of dopa-induced dyskinesias was studied in monkeys exposed to the toxin MPTP. Levodopa and D-2 receptor agonist-induced dyskinesias appeared early, between 2 and 12 days after initiation of dopa therapy in severely parkinsonian animals. In these animals, it was difficult to find a dose of L-dopa which had beneficial effects clinically and no dyskinesia-producing effects. These animals were all found to have massive (greater than or equal to 95%) striatal dopamine loss. A monkey with mild parkinsonian symptoms never developed dyskinesias similar to those produced in the severely affected animals. Stereotypies could be induced in this animal with excessively high doses of L-dopa or the dopamine D-2 receptor agonist, LY-171555. These movements were controlled by reducing the drug dose. This animal had less severe striatal dopamine loss (less than 80%) than the former group of monkeys. These results suggest that dopa dyskinesias in parkinsonian monkeys may be related to the extent of damage sustained by the nigrostriatal system.

The immunohistochemical localization of monoamine oxidase-B in normal cat brain was examined. The enzyme was localized in both neural and nonneural elements of the cat brain. Neurons in the hypothalamus (lateral, dorsal, ventromedial, dorsomedial, and supraoptic nuclei), raphe system, dorsal tegmental nucleus, locus ceruleus, Kölliker-Fuse nucleus, dorsal parabrachial region, and central tegmental field were positive. No substantia nigra pars compacta, retrorubral, or ventral tegmental neurons stained positively. Glial cells (astrocytes) stained positively for monoamine oxidase-B in many regions of the central nervous system, however, there was a significantly greater number of monoamine oxidase-B-positive glial cells in the substantia nigra pars compacta than in other adjacent dopaminergic regions. Because nigra compacta neurons are specifically damaged by the neurotoxin MPTP and because the toxicity of the drug is expressed only in the presence of monoamine oxidase-B, it is possible that the preferential loss of substantia nigra pars compacta neurons in the cat brain may be related to the regional and cellular localization of monoamine oxidase-B.

Tardive dyskinesia is a disabling movement disorder, caused by antipsychotic medications, that occurs frequently and is not responsive to treatment. It is not known how the brain damage underlying tardive dyskinesia produces abnormal movement. We propose that altered sensory flow to motor systems results in this syndrome. Verification of such a mechanism could lead to early detection and improved treatment of tardive dyskinesia.

Both anatomical and physiological studies have shown that pause neurons (PNs) in the medial pontine reticular formation project to two groups of burst neurons (BNs) involved in the genesis of horizontal saccadic eye movements: The excitatory burst neurons (EBNs), which lie rostral to the abducens nucleus, and the inhibitory burst neurons (IBNs), which lie caudal to the abducens. This study is concerned with the projection from PNs to a group of vertical BNs in the nucleus of the H field of Forel (H FF) in the caudomedial subthalamus. Three anatomical methods were used to demonstrate this connection. First, intra-axonal horseradish peroxidase (HRP) injection into physiologically identified PN axons demonstrated axonal branching and axonal terminations in and around the H FF. Second, micro-injection of the tracer Phaseolus vulgaris leucoagglutinin (PHA-L) into the pontine PN region labelled terminal axons and boutons in the nucleus of the H FF. Third, extracellular pressure injection of HRP into H FF yielded retrogradely labelled pontine PN neurons. These anatomical results confirmed the termination of PNs in areas controlling rapid vertical eye movements as physiologically demonstrated by Nakao et al.: Exp. Brain Res. 70:632-636, '88). This work points to the major role of pontine PNs in the synchronization of BN activity in rapid eye movements in all directions.

The effects of bilateral globus pallidus lesions were observed in rats trained to perform a somatosensory/proprioceptive guided forelimb reaching task. Postlesion reaching became very inaccurate, characterized by gross abnormalities in limb and body posture. Postural abnormalities and paw use deficits were not observed in other situations. These results suggest that pallidal damage does not result in a simple motor deficit but interferes with motor performance when movements depend upon somesthetic and proprioceptive feedback.

Neuronal activity was recorded in 7 awake cats (3 animals 11-15 years and 4 animals 1-3 years of age) to determine if the ability of caudate neurons to process facial somatosensory information was impaired in aged animals. Proportionately fewer neurons responded to somatosensory stimuli and facial receptive fields were larger in the aged cats. In addition, proportionately fewer caudate neurons responded to cortical activation, there were fewer excitatory responses and spontaneous firing decreasing in aged cats. These results provide additional evidence that excitability of caudate neurons is reduced in aged cats.

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces substantia nigra pars compacta (SNc) cell death in several species including the mouse, dog and monkey. MPTP is presently shown to cause apparent nigral cell death in the SNc of the cat as noted by a long-lasting decrease in tyrosine-hydroxylase (TH)-like cell staining. A transient loss of TH-like staining is also observed in the ventral tegmental area, locus coeruleus and retrorubral area. These latter areas appear normal 1.5-5.0 months after MPTP administration. The caudate nucleus (CD) showed a greater TH depletion than the nucleus accumbens (ACC) and only recovered slightly over time. After 7 days of MPTP, an apparent axonopathy, characterized by lightly staining fibers with large TH-positive varicosities, is seen in the CD and to a lesser extent, in the ACC. These findings demonstrate that MPTP is toxic to the cat's nigrostriatal dopaminergic system and suggests that the cat is a good intermediate species in which to study the responses of dopaminergic neurons to MPTP.

Stereotaxic maps of the trigeminal ganglion of rat, cat and monkey are presented. Each ganglion drawing is a composite from means of coordinates from several ganglions sampled. Depth coordinates are supplied in relation to both the dorsal surface of each ganglion and the cranial bone directly underlying the ganglion.

Immunohistochemical analysis of tyrosine hydroxylase (TH)-containing neurons in the cat ventral mesencephalon revealed a marked loss of substantia nigra pars compacta neurons and moderate losses of TH-positive neurons in the ventral tegmental area, retrorubral or A8 region, and in the substantia nigra pars lateralis of cats treated with the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The pattern and magnitude of cell loss in these ventral mesencephalic regions parallels that previously reported for the MPTP-treated monkey. These results further support the use of the cat as a model for studying the pathology to catecholaminergic neurons induced by MPTP.

GM1 ganglioside (GM1) has in the past been reported to promote regenerative sprouting and functional recovery in both central and peripheral nervous systems. The present experiments were performed in order to investigate whether GM1 might have any therapeutic effect on young mice who had been exposed to the Parkinson-producing neurotoxin MPTP. GM1 caused moderate to dramatic increases in striatal dopamine levels, depending upon duration of exposure to GM1, in animals previously exposed to MPTP. Furthermore, the effects of GM1 on enhancing striatal dopamine levels were apparent when GM1 administration was delayed until 3 days after the last MPTP injection was given and these effects were not reversed when GM1 was withdrawn. Tyrosine hydroxylase (TH) immunohistochemistry of the striatum demonstrated increased numbers of TH-positive fibers and TH-positive terminal fields in GM1-treated animals as compared to animals that received only MPTP. TH immunohistochemistry of the substantia nigra revealed little or no loss of parts compacta neurons in the MPTP-treated mice. On the basis of these observations, GM1 appears to increase the dopamine content of the striatum by promoting or stimulating regenerative sprouting of dopaminergic terminals and perhaps collateral sprouting from remaining intact fibers in the MPTP model of Parkinsonism in the young mouse. We suggest that GM1 ganglioside may hold some promise as a potential adjunct in the treatment of Parkinson's Disease.

Single-unit activity was recorded in the caudate nucleus and entopeduncular nucleus in cats during ingestion. In both nuclei, ingestion-related neurons were of two types: those with no facial somatosensory receptive field and an ingestion-related response, and those with a facial somatosensory field and an ingestion response. Neurons in both regions contained cells with conditioned responses to the noise produced by the solenoid that delivered milk. No caudate neurons and only 3% of entopeduncular neurons were phasically related to jaw muscle activity. These results indicate that neurons in both input and output regions of the basal ganglia in the cat have complex ingestion-related response characteristics with little relationship to specific orolingual movements.

Electrical stimulation of the substantia nigra in cats elicits jaw movements. A variety of tests were performed to assess the contribution of current spread to this phenomenon. The results of these tests strongly suggest that stimulation-evoked movements are not due to activation of the substantia nigra but rather are the result of current spread to adjacent structures.

Orofacial sensorimotor function was assessed in patients with Parkinson's disease and in age-matched controls. Tests were designed to assess sensory function, motor abilities, and the integration of sensory information for the performance of specific movements. Patients with Parkinson's disease and normal subjects both made more errors with increasing age; however, overall, patients with Parkinson's disease made significantly more errors in our tests than did normal subjects. Interestingly, patients with Parkinson's disease showed greater deficits in tests of sensory function and sensorimotor integration than in tests of motor function. These results suggest that one aspect of Parkinson's disease consists of complex deficits in the utilization of specific sensory inputs to organize and guide movements. The results are further discussed in relation to a proposed sensory gating or filtering schema of basal ganglia motor functioning.

Tyrosine hydroxylase immunohistochemical examination of the mesencephalon of severely parkinsonian MPTP-treated macaque fascicularis monkeys revealed a marked loss of substantia nigra pars compacta (SNc) neurons in both medial and central portions of the nucleus with a relative sparing of neurons in the dorsal-most portions of the substantia nigra. These animals also sustained 20-65% loss of neurons in the substantia nigra pars lateralis area, ventral tegmental area (A-10), and the retrorubral area (A-8 cell group, and the parabrachialis pigmentosus region). These animals all had extreme striatal dopamine depletions. A monkey which received several small doses of MPTP and yet remained asymptomatic for a motor disorder (although it had demonstrable behavioral performance deficits) had only a loss of ventral SNc neurons, with no appreciable cell loss in associated ventral mesencephalic dopamine areas and no loss of striatal dopamine. These data suggest that the effects of MPTP are not as selective as originally thought and, more importantly, indicate that MPTP-induced parkinsonism in the primate may be more analogous to idiopathic Parkinson's disease, where cells other than SNc cells are affected. Furthermore, the present findings suggest that only certain mesencephalic dopamine neurons are susceptible to MPTP-induced damage. The unique characteristics of these neurons need to be elucidated.

Anatomical studies utilizing wheat germ lectin-bound horseradish peroxidase demonstrated direct connections between the pontine parabrachial region and the substantia nigra pars reticulata and to a lesser extent, the entopeduncular nucleus as well as a number of other forebrain regions including the amygdala, hypothalamus, thalamus, bed nucleus stria terminalis and substantia innominata. The pontine parabrachial region was also shown to receive direct inputs from the spinal trigeminal system and to send axons to areas surrounding trigeminal and hypoglossal motor areas. Once the anatomical connections were determined, electrophysiological studies were undertaken to investigate some of the functional aspects of these connections between the pontine parabrachial, basal ganglia and trigeminal systems. Extracellular single unit recordings were obtained from 228 cells in the dorsal pontine parabrachial region of the cat. These cells were tested for responsiveness to trigeminal sensory stimulation and activation of basal ganglia outputs (i.e. substantia nigra and entopeduncular nucleus). Twenty-two percent of pontine parabrachial cells responded to only trigeminal stimulation; 4% responded to entopeduncular nucleus only; 37% responded to substantia nigra only, and 28% responded to both substantia nigra and trigeminal stimulation. Furthermore, 43% of pontine parabrachial cells with both substantia nigra and sensory response had the sensory response altered by a preceding stimulus to the substantia nigra. Thus, the substantia nigra is shown to exert influences on both the spontaneous activities and afferent responses of pontine parabrachial neurons. The significance of these findings are discussed in relation to the importance of descending basal ganglia influences and ascending influences from the pontine parabrachial region on various sensorimotor activities.

The effects of acute administration of amphetamine on membrane potentials and evoked postsynaptic potentials of caudate neurons in cats were assessed using intracellular recording. High doses of amphetamine (0.5 mg/kg, i.v.) produced a reversible depolarization of the cell membrane in 78% of cells tested. Low doses (0.1 mg/kg) had no effect on the resting membrane potential. Long-lasting increases in amplitude of both excitatory and inhibitory components of evoked postsynaptic potential sequences were observed after both high and low doses of amphetamine. These changes were more evident to cortical than to substantia nigra or to intralaminar thalamic stimulation. These results were shown to be independent of the peripheral autonomic actions of amphetamine. These effects appear to be mediated by the ability of amphetamine to alter catecholaminergic mechanisms in the caudate nucleus and suggest that increased dopamine release may have a facilitatory effect on both excitatory and inhibitory synaptic transmission.

There is a sizeable literature concerning basal ganglia (BG) functioning that is based on data from experiments employing a method of analysis that is traditionally used with other motor areas. A brief review of this literature is presented and the following conclusion is reached: as compared to the success of traditional methodologies in elucidating the workings of other motor systems, their use in BG investigations has proven disappointing. A possible reason for the shortcomings of traditional analyses in BG research is discussed. The remainder of this review concerns an alternative approach to the study of the BG that follows from consideration of a variety of clinical and experimental findings. The literature suggests that sensory aspects of BG functioning must be taken into account to fully appreciate the role of this system in motor control. A review of the literature concerning the latter suggests two points: The BG function as sensory analyzer for motor systems. That is, the BG convert sensory data from a form that is receptor oriented to a form that is relevant for guiding movement. The BG ultimately affect movement by gating sensory inputs into other motor areas rather than by directly affecting these areas. This sensory-based model of BG functioning explains a number of apparent discrepancies in the literature. In addition, seemingly anomalous findings are reconciled with the overwhelming evidence that the BG are a motor system. In particular, the suggestions of a BG role in attention and cognition are viewed as being intrinsic rather than orthogonal to the role of the BG in movement.

A total of 676 dysplastic moles collected from 487 patients over a 1-year period were reviewed together with demographic data. The associated nevus in 642 cases (95%) had a superficial, or "acquired," pattern within the papillary dermis, in comparison with the nevus in the remaining 34 cases (5%), which showed a deep, or "congenital," pattern. The dysplasia was graded in severity as mild, moderate, or severe (on a scale of 1 to 3). When patients with mild to severe dysplastic melanocytic nevi were compared with those patients showing atypical intraepidermal melanocytic hyperplasia (also called in situ malignant melanoma) or early invasive malignant melanoma associated with dysplasia, a progression of ages was noted. The average ages in the five diagnostic groups were as follows: 34.8 years, mild dysplasia (group 1); 35.1 years, moderate dysplasia (group 2); 41.5 years, severe dysplasia (group 3); 44.4 years, in situ malignant melanoma (group 4), and 46.9 years, early invasive malignant melanoma (group 5). Statistical analysis revealed that the two younger groups differed significantly in age from the three older groups. Men and women had an equal proportion of acquired and congenital pattern nevi, but men were older in each category and had more severe dysplasia, a greater tendency toward truncal lesions, and more regressive changes. Biopsy of trunk lesions was done in 275 cases (80%), of extremity lesions in 60 cases (17%), and in head and neck sites in 9 cases (3%).(ABSTRACT TRUNCATED AT 250 WORDS)

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent dopaminergic neurotoxin, was administered to cats systemically for 5 to 7 days. This treatment produced a behavioral syndrome characterized by akinesia, ataxia, bradykinesia, and feeding difficulties, lasting for several weeks. During this period of severe behavioral impairment, caudate and nucleus accumbens dopamine and norepinephrine concentrations were quite depleted. Behavioral recovery ensued over the next several weeks as did some recovery of striatal catecholamines. MPTP destroyed the majority of substantia nigra pars compacta neurons while affecting a much lesser number of locus ceruleus and ventral tegmental neurons. These results demonstrated for the first time that MPTP can cause long-lasting deficits in nigrostriatal functioning in the cat and may provide a means for studying the apparently selective neurotoxic effects of MPTP as well as for understanding the pathophysiology of Parkinson's disease.

Wheat germ lectin-horseradish peroxidase was injected into the medial medullary reticular formation in 4 cats. Retrogradely labeled cell bodies were observed in the ipsilateral substantia nigra pars reticulata and bilaterally in the superior colliculus, oculomotor nucleus and fastigial nucleus of the cerebellum. The nigral projection to this reticular formation area, which receives diffuse afferents from cortex, cerebellum, oculomotor system and vestibular nucleus and projects to spinal cord, may be of some relevance in understanding the nigral role in postural, head- and eye-movement control.

Six adult Macaca fascicularis monkeys were trained to perform an instrumentally conditioned, visually-guided forearm reaching task for fruit juice reinforcement. Once animals were overtrained on this task, they were given intravenous injections of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (0.15 to 0.33 mg/kg). Animals were tested daily for performance in the previously learned behavioural task and were assessed daily for abnormalities in motor functioning. Monkeys developed deficits in operant task performance characterized by termination of responses after an initial series of responses and long pauses between responses. Once an animal stopped responding to the task, responses could often be reinitiated if the experimenter guided the monkey through the task. This type of performance deficit was seen both before and without the appearance of distinct parkinsonian motor signs. Animals which developed motor signs had extensive ventral mesencephalic cell loss while an animal with performance deficits but without motor signs had cell loss restricted to the ventral substantia nigra pars compacta. The results demonstrate that operant performance deficits can be observed in MPTP-treated monkeys independent of the appearance of motor deficits.

An inexpensive light weight head restraint device enabling horizontal rotational head movements is described. The restrainer provides sufficient stability to allow prolonged single unit recording and is compatible with conventional recording techniques.