Biomedical subjects

R H Roth

Publications and source records attributed to R H Roth.

At least 55 records · Page 3Linked to original sources

PubMed1997

Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine.

The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function. Behavioral deficits and decreased dopamine utilization remained after phencyclidine treatment was stopped, an indication that these effects were not simply due to direct drug effects. The data suggest that repeated administration of phencyclidine in monkeys may be useful for studying psychiatric disorders associated with cognitive dysfunction and dopamine hypofunction in the prefrontal cortex, particularly schizophrenia.

Animals↗

PubMed1997

Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: modulation by the isomers of HA966.

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hyperdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of rats and monkeys were examined, because HA966 has been shown previously to attenuate stress- or drug-induced activation of dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotonin utilization was also increased in PFC. Pretreatment with either R-(+)HA966 (15 mg/kg, i.p.) or S-(-)HA966 (3 mg/kg, i.p.) partially blocked PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin turnover in PFC. PCP (0.3 mg/kg, i.m.) exerted regionally selective effects on the dopaminergic and serotonergic innervation of the monkey frontal cortex, effects blocked by pretreatment with S-(-)HA966 (3 mg/kg, i. m.). Importantly, these data demonstrate that in the primate, PCP has potent effects on dopamine transmission in the frontal cortex, a brain region thought to be dysfunctional in schizophrenia. In addition, a role for S-(-)HA966 as a modulator of cortical monoamine transmission in primates is posited.

Action Potentials↗

PubMed1997

Mesoprefrontal dopaminergic neurons: can tyrosine availability influence their functions?

The dopamine (DA) neurons projecting to the prefrontal cortex (PFC) are thought to be involved in working memory, stress response, and the pathogenesis of schizophrenia. In this commentary, we review the current evidence supporting a precursor tyrosine dependence of these mesoprefrondal DN neurons. Several studies in rats employing different experimental paradigms [i.e. experimental diabetes and early-treated phenylketonuria (PKU) model] have shown that reduced tyrosine levels in brain can affect markedly the physiology and functions of these DA neurons. However, supplemental tyrosine is effective in enhancing functional transmitter outflow from mesoprefrontal DA neurons only under conditions where their physiological activity is enhanced and DA synthesis and release are uncoupled from intrinsic regulatory controls. Recent studies in humans have also suggested that variations in brain tyrosine levels can affect significantly higher cortical functions subserved by the PFC. In early-treated PKU patients with mildly reduced tyrosine levels, marked impairments in cognitive functions dependent on the dorsolateral PFC could be detected. In drug-treated schizophrenic patients, supplemental tyrosine was shown to have a disruptive effects on the smooth-pursuit eye movement performance task. Furthermore, tyrosine administration was effective in restoring impaired working memory in humans following cold stress paradigm, as assessed by a computer-based delayed matching to-sample memory task. These human studies, together with the current evidence obtained from animal experiments, suggest that the functions of the mesoprefrontal DA neurons can, under certain circumstances, be readily influenced by the availability of the precursor tyrosine.

Animals↗

PubMed1997

Identification of novel variants of trkC mRNA transcripts in brain of African green monkeys.

The distinct biological effects of neurotrophins are mediated in part through their binding to the high-affinity neurotrophin receptors represented by the Trk family of receptor tyrosine kinases. Using the technique of reverse transcriptase-polymerase chain reaction (RT-PCR), we cloned several partial cDNAs encoding trkA, trkB, and trkC from fetal brains of African green monkeys. Southern analysis of PCR products showed that the ventral tegmental area of adult monkey and ventral midbrains of fetal monkeys of E59, E81, E91, and E150 days of gestation expressed all three trk gene transcripts, whereas only trkB and trkC mRNAs were detectable in the adult substantia nigra. The nucleotide sequences of the cloned monkey trk cDNAs are highly homologous to their human counterparts, and we detected a splice variant of trkC that has recently been described in humans, but not in rodents. Moreover, sequencing of trkC cDNAs derived from four fetal monkey midbrains revealed two novel variants with single nucleotide substitution. A missense mutation (AAT to AGT) was identified in the codon corresponding to codon 361 of the deduced human TrkC sequence, converting an encoded Asn to Ser. The second variant involves a silent transition at the third nucleotide of the codon Gly 362 (GGC to GGA). Furthermore, three of the four potential alleles involving these two trkC variants were detected in these monkeys, indicating that a segregation of multiple trkC alleles occurs in a geographically contained population of feral monkeys.

Animals↗

PubMed1997

Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson's disease.

This article gives a brief overview of the current understanding of the life cycle of the dopamine molecule, covering dopamine synthesis, storage, release, receptor and autoreceptor interactions, and reuptake. Special consideration is given to biochemical changes that occur in the nigrostriatal dopamine system in Parkinson's disease and how gene therapy may provide a new strategy for reversing parkinsonian biochemical deficits.

Corpus Striatum↗

PubMed1997

Severe long-term 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the vervet monkey (Cercopithecus aethiops sabaeus).

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces parkinsonian neurochemical and functional deficits in human and non-human primates. The utility of MPTP-induced parkinsonism in monkeys as an animal model of Parkinson's disease would be greater if it produced a persistent and stable behavioural syndrome so that the effects of novel therapeutic treatments can be accurately assessed. Further, the claim that many species including primates spontaneously recover from MPTP is a significant difference from idiopathic Parkinson's disease. This experiment focused on the long-term (six months) persistence of behavioural deficits in severely and moderately parkinsonian monkeys. The severity of the syndrome was based on a quantitative and objective measure of parkinsonism. Adult male African green (vervet) monkeys (Cercopithecus aethiops sabaeus) were treated with MPTP (cumulative dose 2.5 mg/kg over five days), and six were saline-control treated. MPTP-treated subjects were examined in two groups: those that were severely parkinsonian ("severe" group, n = 11) and those that were moderately impaired ("moderate" group, n = 5) the month after treatment. Summary factor scores were examined reflecting abnormal ("parkinsonian") behaviour and normal "healthy" behaviour. Subjects that displayed severe parkinsonism the month after MPTP were found to show stable and severe parkinsonism for the time period studied. In contrast, the group of animals that initially were moderately parkinsonian did not show a stable deficit during the study. These data suggest that the initial severity of the deficit is an important predictor of outcome. None the less, stable parkinsonism can be observed in severely parkinsonian subjects despite variability in the severity of the impairment in response to MPTP treatment. Two moderately and three severely affected subjects were studied for more than six months and they appeared to show equivalent scores at six months compared with between 11 to 19 months after MPTP administration. MPTP-treatment in the vervet monkey can result in persistent long-term deficits and therefore provides an excellent phenomenological as well as neuropathological model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1997

Delta 9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966.

The present study examined delta 9-tetrahydrocannabinol (THC)-induced alterations in monoamine transmission in the rat forebrain as well as the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on the monoamine response to THC. Activation of dopamine (DA) and norepinephrine (NE) but not serotonin (5-HT) turnover in the prefrontal cortex (PFC) was observed after THC (5 mg/kg i.p.) administration. Both enantiomers of HA966 completely prevented the effects of THC on PFC DA turnover and partially blocked the THC-induced rise in NE metabolism. The cognitive consequences of THC exposure were also examined. THC significantly impaired spatial working, but not reference, memory in rats, and this effect was ameliorated by HA966. Thus, HA966 prevents the THC-induced increases in PFC DA turnover and impairments of prefrontal cortical working memory function. Furthermore, these data suggest that cognitive impairments displayed by marijuana self-administering humans may be related to PFC DA hyperactivity and that HA966 may prevent this effect.

Animals↗

PubMed1997

Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys.

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.

Animals↗

PubMed1997

Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat.

Repeated ingestion of phencyclidine by humans induces enduring schizophrenic symptomatology, particularly cognitive dysfunction. In the presently described series of experiments, the neurochemical and cognitive consequences of subchronic phencyclidine administration in the rat were explored. Repeated phencyclidine exposure led to a selective reduction in basal and stress-evoked dopamine utilization in the prefrontal cortex. In addition, rats previously subchronically-treated with phencyclidine were impaired on performance of a spatial working memory task in a delay-dependent manner. Importantly, these dopaminergic and cognitive deficits were observed after withdrawal from phencyclidine, and as such, the neurochemical and behavioral effects were due to drug-induced neurobiological changes rather than direct drug effects. These biochemical and behavioral data show that repeated phencyclidine administration induces prefrontal cortical cognitive deficits in rats, as in humans, and offer a biochemical perspective of the neural substrate underlying this cognitive impairment: inhibition of mesocortical dopamine neurons. Thus, these data may have relevance to psychiatric disorders involving prefrontal cortical dopaminergic hypoactivity and cognitive dysfunction, as has been hypothesized in schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

(S)-(-)-HA-966, a gamma-hydroxybutyrate-like agent, prevents enhanced mesocorticolimbic dopamine metabolism and behavioral correlates of restraint stress, conditioned fear and cocaine sensitization.

This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 and 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilization in both the medial prefrontal cortex and nucleus accumbens, in contrast to the positive enantiomer. Conditioned fear increased dopamine metabolism in both the core and shell subdivisions of the nucleus accumbens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induced increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppressed fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization without altering the acute motoric response elicited by cocaine. The highest dose of (S)-(-)-HA-966 (5 mg/kg i.p.) blocked acute cocaine-induced locomotion but resulted in sedation. In addition, the highest dose of (S)-(-)-HA-966 tested suppressed weight gain in control rats, unlike its enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been proposed to act at the gamma-aminobutyric acid (GABA)B receptor, we examined the ability of (S)-(-) and (R)-(+)-HA-966 to displace [3H]-(-)-baclofen from cortical membranes to assess GABAB receptor binding. Neither enantiomer significantly altered [3H]-(-)-baclofen binding at relevant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the baclofen binding site on the GABAB receptor.

Animals↗

PubMed1996

Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stress-induced impairment.

The anxiogenic benzodiazepine inverse agonist FG7142 increases dopamine turnover in rodent prefrontal cortex but not in other dopamine terminal field areas. FG7142-induced increases in prefrontal cortical dopamine receptor stimulation impair prefrontal-dependent, but not nonprefrontal-dependent, cognitive tasks in rats and monkeys. The degree of impairment correlates with levels of prefrontal cortical dopamine turnover in rats and can be blocked in rats and monkeys with dopamine receptor antagonists, suggesting that increased dopamine turnover is directly related to the cognitive deficits. The current study examined nondopaminergic drug effects on FG7142-perturbed biochemistry and cognition. Both the noradrenergic alpha-2 agonist clonidine and the glycine/NMDA antagonist (+)HA966 prevented the FG7142-induced increase in dopamine turnover in rodent prefrontal cortex. Infusion of (+)HA966 into the ventral tegmental area (VTA) also blocked this increase in dopamine turnover, indicating that critical modulatory effects of (+)HA966 on FG7142-induced changes in dopamine turnover are occurring at the level of mesoprefrontal dopamine neuron cell bodies. Systemic (+)HA966 and clonidine, but not propranolol or D-cycloserine, prevented FG7142-associated spatial working memory deficits in rats and monkeys. These results support the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning, with excessive dopamine turnover leading to cognitive impairment. These studies also provide evidence for the regulation of prefrontal cortical dopamine turnover and cognition by multiple neurotransmitter systems and suggest that the VTA is an important regulatory site for these effects.

Animals↗

PubMed1996

Sensitization to the locomotor activating effects of cocaine following cocaethylene-preexposure.

The present study assessed the ability of cocaethylene to induce sensitization to the behavioral activating effects of cocaine in the male Sprague-Dawley rat. Preexposure to cocaethylene (15 or 25 mg/kg) significantly enhanced the locomotor activating effects of a subsequent cocaine (15 mg/kg) challenge injection. In addition, acute intraperitonecal administration at several doses (10, 15, or 25 mg/kg) confirmed previous reports of increased bioavailability of cocaine in brain and plasma relative to cocaethylene. These data are discussed in terms of previous work in which a significant augmentation of cocaine-induced locomotor activity was not observed following cocaethylene preexposure.

Analysis of Variance↗

PubMed1996

Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat.

Exposure to mild stress is known to activate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) metabolism in the anteromedial prefrontal cortex (m-PFC). Neuroanatomical site(s) providing afferent control of the stress activation of the m-PFC monoaminergic systems is at present unknown. The present study used a conditioned stress model in which rats were trained to fear a substartle-threshold tone paired previously with footshock and assessed for behavioral, neuroendocrine, and neurochemical stress responses. Bilateral NMDA-induced excitotoxic lesioning of the basolateral and central nuclei of the amygdala was performed before or after training. Pretraining amygdala lesions blocked stress-induced freezing behavior, ultrasonic vocalizations, adrenocortical activation, and dopaminergic metabolic activation in the m-PFC. Post-training amygdala lesions blocked stress-induced m-PFC DA, 5-HT, and NE metabolic activation. Post-training amygdala lesions also blocked stress-induced freezing and defecation, and greatly attenuated adrenocortical activation. These data provide evidence of amygdalar control of stress-induced metabolic activation of the monoaminergic systems in the m-PFC, as well as amygdalar integration of behavioral and neuroendocrine components of the rat stress response. These results are discussed in terms of possible relevance to stress-induced exacerbation of schizophrenic symptoms and the pathophysiology of posttraumatic stress disorder.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.

Analysis of Variance↗

PubMed1996

Tyrosine enhances behavioral and mesocorticolimbic dopaminergic responses to aversive conditioning.

Tyrosine is a precursor in the biosynthesis of catecholamines and, when administered systemically, has been shown to enhance the in vivo rate of tyrosine hydroxylation in the medial prefrontal cortex. Additionally, exogenous tyrosine has been demonstrated to enhance the pharmacologically-induced increase in dopamine metabolism seen following administration of haloperidol or the anxiogenic B-carboline, FG-7142. In this report, we examine the effect of a physiologically relevant dose of tyrosine (25 mg/kg) on biochemical and behavioral consequences of aversive conditioning. Rats were conditioned to fear a tone by pairing it with footshock, so that when challenged with the tone alone, rats responded with immobility, defecation, and elevated dopamine metabolism in the medial prefrontal cortex and nucleus accumbens. When tyrosine was administered on the test day (tones alone), the rats displayed an even greater elevation of dopamine metabolism in the nucleus accumbens and prolonged immobility to the tone, compared to the saline/conditioned controls. Tyrosine did not alter mobility or dopamine utilization in the nucleus accumbens in nonconditioned controls. However, dopamine metabolism in the medial prefrontal cortex of nonconditioned rats treated with tyrosine was increased to levels similar to those in the conditioned groups. This may be accounted for by handling and by exposure to an unfamiliar environment necessary for nonconditioned controls. We conclude that exogenous tyrosine is able to 1) elevate stress-induced dopamine metabolism in the nucleus accumbens, 2) alter dopamine utilization in the medial prefrontal cortex of handled, nonconditioned controls, and 3) enhance fear-induced immobilization. These data suggest a role for dietary tyrosine in biochemical and behavioral responses to aversive stimuli.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Serotonergic lesions alter cocaine-induced locomotor behavior and stress-activation of the mesocorticolimbic dopamine system.

The aim of this study was to examine the effects of serotonergic lesions to the dorsal raphe on midbrain dopaminergic systems. 5,7-Dihydroxytryptamine lesions of the dorsal raphe resulted in a substantial loss of serotonin in the medial prefrontal cortex (about 75%) and the nucleus accumbens (about 50%), while no change in DA levels or DA metabolism were noted in either region at 12 days postlesion. A transient basal locomotor activation was noted in the lesioned animals compared to the sham controls 7 to 12 days after the lesions. The locomotor response to an acute dose of cocaine was also enhanced in 5,7-dihydroxytryptamine lesioned rats, however, no change in the time course or magnitude of the behavioral locomotor response to repeated cocaine administration was observed. Restraint for 30 min increased DA metabolism in both the NAS and mPFC of sham rats, as expected. However, in 5,7-dihydroxytryptamine lesioned rats, restraint stress enhanced the usual stress-induced increase in DA metabolism by about 50 and 150% in the medial prefrontal cortex and nucleus accumbens, respectively. Our results indicate the 5,7-dihydroxytryptamine lesions of the dorsal raphe lower serotonin in both the mPFC and NAS leading to an enhanced responsiveness of the DA projections in both regions. This effect may be explained by a loss of sensitivity of DA receptors in 5,7-dihydroxytryptamine denervated rats. This interpretation implies that the stimulated, but not basal, release of DA in the mPFC and NAS is dependent on serotonin tone.

5,7-Dihydroxytryptamine↗

PubMed1996

Effects of D2 dopamine receptor antagonists on Fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate.

Recent studies have reported that acute administration of dopamine D2 receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D2 antagonists in primate species. Since all clinically effective antipsychotic drugs share D2 receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D2 receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extra-pyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D2 receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested.

Animals↗

PubMed1996

Early gestational mesencephalon grafts, but not later gestational mesencephalon, cerebellum or sham grafts, increase dopamine in caudate nucleus of MPTP-treated monkeys.

The mechanism of the behavioral improvement observed in parkinsonian primates that receive intrastriatal transplants of fetal dopamine neurons has not been firmly established. Dopamine production by grafted neurons may be the basis of the behavioral recovery. Alternatively, stimulation of the host dopamine system by the transplant procedure itself may be central to the outcome. The present study examined whether dopamine concentration was raised in the caudate nucleus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate following grafting, and if so, whether the elevation was dependent on either (i) the introduction of the implantation cannula (sham), (ii) the brain region that was grafted, or (iii) the gestational age of fetal tissue that was grafted. Transplantation of early gestational age fetal ventral mesencephalon (embryonic days 40-50) was associated with significant elevation of caudate nucleus dopamine concentration to a mean of approximately 20% of control values in the vicinity (within 2 mm) of the graft, compared with more distant sites in the caudate nucleus. With early gestational age fetal ventral mesencephalon, the ratio of homovanillic acid/dopamine concentration near the graft site was normalized compared to the elevated value found in the caudate nucleus distant from the graft site. Grafts of later stage fetal ventral mesencephalon, or fetal cerebellum, or sham implantation did not increase dopamine concentration or lower homovanillic acid/dopamine ratio near the graft site. Biochemical and histochemical evidence suggests that host dopamine neurons terminating in the nucleus accumbens are not the source of the changes. Numerous tyrosine hydroxylase-positive neurons at the graft site were only observed in the MPTP-treated monkeys that received grafts of early gestational age fetal ventral mesencephalon. These data lend strong support to the hypothesis that dopamine derived from grafted dopamine neurons is the major basis for behavioral recovery observed following intrastriatal transplantation in our MPTP-treated monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗