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J R Sladek

Publications and source records attributed to J R Sladek.

At least 19 recordsLinked to original sources
PubMed2005

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, autosomal recessive disease resulting from mutations in the CLN2 gene with consequent deficiency in its product tripeptidyl peptidase I (TPP-I). In the central nervous system (CNS), the deficiency of TPP-I results in the accumulation of proteins in lysosomes leading to a loss of neurons causing progressive neurological decline, and death by ages 10-12 years. To establish the feasibility of treating the CNS manifestations of LINCL by gene transfer, an adeno-associated virus 2 (AAV2) vector encoding the human CLN2 cDNA (AAV2CUhCLN2) was assessed for its ability to establish therapeutic levels of TPP-I in the brain. In vitro studies demonstrated that AAV2CUhCLN2 expressed CLN2 and produced biologically active TPP-I protein of which a fraction was secreted as the pro-TPP-I precursor and was taken up by nontransduced cells (ie, cross-correction). Following AAV2-mediated CLN2 delivery to the rat striatum, enzymatically active TPP-I protein was detected. By immunohistochemistry TPP-I protein was detected in striatal neurons (encompassing nearly half of the target structure) for up to 18 months. At the longer time points following striatal administration, TPP-I-positive cell bodies were also observed in the substantia nigra, frontal cerebral cortex and thalamus of the injected hemisphere, and the frontal cerebral cortex of the noninjected hemisphere. These areas of the brain contain neurons that extend axons into the striatum, suggesting that CNS circuitry may aid the distribution of the gene product. To assess the feasibility of human CNS delivery, a total of 3.6 x 10(11) particle units of AAV2CUhCLN2 was administered to the CNS of African green monkeys in 12 distributed doses. Assessment at 5 and 13 weeks demonstrated widespread detection of TPP-I in neurons, but not glial cells, at all regions of injection. The distribution of TPP-I-positive cells was similar between the two time points at all injection sites. Together, these data support the development of direct CNS gene transfer using an AAV2 vector expressing the CLN2 cDNA for the CNS manifestations of LINCL.

Aminopeptidases↗
PubMed2000

Oligodendrocyte-type 2 astrocyte-derived trophic factors increase survival of developing dopamine neurons through the inhibition of apoptotic cell death.

Survival of embryonic dopamine (DA) neurons is extremely low (5-20%) following transplantation. Strategies to increase this survival are critical to the future of transplantation for Parkinson's disease. We demonstrate here that a factor(s) released from striatal oligodendrocyte-type 2 astrocytes (SO2A) greatly improves the survival and phenotype expression of mesencephalic DA neurons in culture while simultaneously decreasing the presence of apoptotic nuclear profiles, as detected by the TUNEL method and bisbenzamide/tyrosine hydroxylase double labeling. This SO2A-derived trophic factor(s) has minimal effects on glia and no effect on nondopaminergic mesencephalic neurons. The developmental period during which this SO2A trophic effect occurs (E14-18) coincides with the period when mesencephalic grafts are undergoing the highest rates of apoptosis, i.e., immediately following implantation. Therefore, SO2A-derived trophic factor(s) offers great potential for the augmentation of grafted DA neuron survival.

Animals↗
PubMed2000

Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatment.

Despite widespread use of the primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, there is a paucity of data concerning the relationship between striatal dopaminergic function and behavior over time. This study examines the relationship between markers of dopamine neuron integrity and dopaminergic metabolic activity in striatal subregions with the degree of parkinsonian disability in 32 monkeys treated with MPTP one year earlier. Based on the parkinsonian summary score during the month following MPTP treatment, each monkey was assigned to one of four severity categories. We called these categories "Severe", "Moderate", "Mild" and "Asymptomatic". Monkeys in the Severe category were behaviorally stable, and loss of dopamine concentration was greater than 98% in all subregions of striatum one year after MPTP treatment. This value was not significantly different from the level of depletion, reported previously, at one to two months after MPTP in Severe monkeys, and apparently this loss of striatal dopamine is beyond the level from which effective compensations can occur. The parkinsonian disabilities in monkeys of other severity groups (Moderate, Mild, Asymptomatic) improved significantly over the year, despite having mean dopamine depletion of 75-99% in different subregions of striatum at one to two months after MPTP treatment. At one year after MPTP treatment, the mean dopamine depletions in different subregions of caudate nucleus and putamen had diminished in Asymptomatics (21-81%), Milds (35-96%), and Moderates (86-97%). Dopamine loss in nucleus accumbens was relatively spared compared with most striatal subregions, yet in Severe monkeys the decrease in this region reached 96%. In addition, at one year after MPTP treatment, there was a significant linear relationship between parkinsonian behavioral severity category and dopamine concentration, and homovanillic acid concentration and homovanillic acid/dopamine ratio in the striatum. The re-establishment of dopamine levels and homovanillic acid/dopamine ratios was most pronounced in putamen, ventromedial caudate nucleus and nucleus accumbens. Thus the small difference in striatal dopamine loss that distinguishes monkeys with widely different behavior at one to two months after MPTP increases over time. We suggest that the milder the initial loss, the greater capacity there is for regeneration or sprouting of dopamine terminals, which is reflected in marked increases in dopamine levels and modest elevations of metabolic activity (homovanillic acid/dopamine ratio). With greater initial losses, there is less capacity to increase terminal density, which is reflected later by smaller increases in striatal dopamine levels and more marked increases in metabolic activity. It appears that 5-10% of normal striatal dopamine levels is sufficient for overtly normal motor performance in non-human primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Spontaneous blink rates correlate with dopamine levels in the caudate nucleus of MPTP-treated monkeys.

Previous studies have suggested a dopaminergic regulation of eye blink rates in human and nonhuman primates. Blockade of either dopamine (DA) D1 or DA D2 receptors or DA depletion induced by the dopaminergic neurotoxin MPTP both decrease spontaneous eye blink rates in monkeys. MPTP-induced decreases in blink rates can be reversed by administration of the full efficacy D1 agonist dihydrexidine, which has also been found to have dramatic antiparkinsonian effects in MPTP-treated animals. Increases in blink rates can also be induced by D1 and D2 agonists in normal animals. In the current study, we have investigated whether blink rates correlate with concentrations of DA or HVA and/or HVA:DA ratios in specific brain regions in MPTP-treated monkeys. Furthermore, the potential relationship between the severity of behavioral indices of parkinsonism and blink rates were examined. We found that (1) blink rates significantly correlate positively with concentration of DA and inversely with HVA:DA ratios in the rostral portion of the ventromedial body of the caudate nucleus (CD), but not other subcortical regions, and (2) that severity of parkinsonism was inversely correlated with blink rate. These data support a dopaminergic regulation of blink rate and suggest that the ventromedial region of the body of the CD may be critically involved in regulation of blink rate.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons.

To enhance the current therapeutic benefit of dopamine (DA) neuron grafts in Parkinson's disease, strategies must be developed that increase both DA neuron survival and fiber outgrowth into the denervated striatum. Previous work in our laboratory has demonstrated that dopaminergic neurons grow to greater size when co-grafted with striatal cell suspensions and display extensive tyrosine hydroxylase-positive (TH+) projections, but no conclusion could be reached concerning enhancement of survival of grafted DA neurons. The aim of the present study was to characterize further the potential trophic effects of striatal co-grafts on grafted mesencephalic DA neuron survival. Unilaterally lesioned male Fischer 344 rats were grafted with either a suspension of mesencephalic cells or with both mesencephalic and striatal cell suspensions. Co-grafts were either mixed together or placed separately into the striatum. Lesioned rats receiving no graft served as controls. Rotational behavior was assessed following amphetamine challenge at 2 weeks prior to grafting and at 4 and 8 weeks following grafting. Only rats receiving co-grafts of nigral and striatal suspensions separated by a distance of 1 mm showed significant behavioral recovery from baseline rotational asymmetry. Both mixed and separate striatal co-grafts were associated with a doubling of DA neuron survival compared with solo mesencephalic grafts. In the mixed co-graft experiment, DA neurite branching appeared enhanced and TH-rich patches were observed, whereas with co-grafts that were separated, TH+ innervation of the intervening host striatum was increased significantly. These results provide the first evidence suggesting that nigral-striatal co-grafts, particularly those placed separately and in proximity to each other, increase both DA neuron survival and neurite extension from the mesencephalic component of the grafts.

Animals↗
PubMed1998

Upregulation of striatal D2 receptors in the MPTP-treated vervet monkey is reversed by grafts of fetal ventral mesencephalon: an autoradiographic study.

Although neural transplantation holds promise as a treatment for Parkinson's disease, parkinsonian primates have generally exhibited inconsistent and incomplete recovery of motor functions following intrastriatal grafting of fetal ventral mesencephalon. One possible contributing factor to this variable response is lack of appropriate integration of donor neurons with host striatal circuitry with the result that there is insufficient dopamine release and postsynaptic dopamine receptor activation. This issue was examined by measuring the effect of transplanting fetal ventral mesencephalon to the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP) monkeys on striatal D2 receptor binding. One year after receiving MPTP, D2 receptor binding was upregulated in the dorsal and ventral striatum of African green monkeys. Grafting of fetal ventral mesencephalon to the dorsal striatum of MPTP-treated monkeys 9 months before sacrifice, eliminated the D2 receptor upregulation in dorsal, but not ventral, region. Dopamine concentration in dorsal striatum of grafted MPTP-treated monkeys was significantly higher than in that region of MPTP-treated non-grafted monkeys. In addition, dopamine concentration was significantly higher in dorsal compared to ventral striatum of grafted MPTP-treated monkeys. These data, in addition to those from a previous autoradiographic study on dopamine uptake site density in these monkeys, strongly supports the hypothesis that ectopically placed ventral mesencephalon not only produces, but maintains the release of sufficient levels of dopamine to restore postsynaptic dopamine transmission in regions influenced by graft-derived dopamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model.

The majority of investigations into the degree of restoration of neural circuitry following transplantation of the embryonic ventral mesencephalon to the striatum have focused upon the particular neurochemical subtypes of the fibers exchanged between graft and host. Visualization of neurites of specific neurotransmitter type while informative regarding the specificity of graft-host interactions, vastly underrepresents overall synaptogenesis as it may occur in the grafting situation. The present approach of using a molecular marker characteristic of all normal, functional synapses provides broader information about the synaptic remodeling that occurs after tissue grafting. Synaptophysin (SY), an integral membrane protein of the synaptic vesicle, is a reliable marker of nerve terminal differentiation. Immunohistochemical staining with antibodies directed against SY and the dopamine synthetic enzyme tyrosine hydroxylase (TH) was used to assess overall synaptic differentiation as well as the relationship between SY immunoreactivity and the distribution of grafted dopamine (DA) neurons and processes in mesencephalic grafts and mesencephalic-striatal co-grafts implanted in the striatum of MPTP-treated African green monkeys. Grafted embryonic cerebellar tissue was used as a comparison graft type that does not normally exchange prominent direct projections with striatum. Dense pericellular arrays of SY-positive terminals were associated with TH-positive neurons in mesencephalic grafts. In mixed mesencephalic-striatal co-grafts, TH-positive fiber patches within the striatal portion of the graft demonstrated a high degree of correspondence with SY immunoreactivity. In contrast, grafts of cerebellar tissue did not display the same pattern of prominent pericellular arrays of SY staining. These observations suggest that functional synapses are abundantly present within grafted mesencephalon, and that these contacts are enriched in areas of the graft occupied by DA neurons. Implantation of an inappropriate striatal target, the cerebellum, results in visibly diminished innervation. The pattern of SY labeling observed suggests that tissue grafts are extensively innervated, probably both from extrinsic and intrinsic sources, and that the pattern and density of this innervation corresponds to the appropriateness of the graft-host interaction.

Animals↗
PubMed1998

Efferent synaptic connections of dopaminergic neurons grafted into the caudate nucleus of experimentally induced parkinsonian monkeys are different from those of control animals.

This study investigated the question of whether grafted dopamine cells in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys form synapses and, if they do, whether their postsynaptic targets were the same as those in control monkeys or in previous studies in rats. Electron-microscopic single immunostaining was performed for tyrosine hydroxylase on vibratome sections prepared from the head of the caudate nucleus of controls and MPTP-treated African green monkeys (Cercopithecus aethiops sabaeus) that received a graft. Furthermore, correlated light- and electron-microscopic double immunostaining was carried out for tyrosine hydroxylase and calbindin in the same brain area of MPTP-treated plus grafted animals. In control monkeys, the majority (97%) of dopamine boutons terminate on spines that were also synaptic targets of immunonegative boutons forming asymmetric synaptic contacts: synaptic triads. In MPTP-treated, grafted animals, the majority of transplanted dopamine cells terminate on dendritic shafts (67%) and somata (32%), and only a few (1.33%) form axospine synapses. The results of the double immunostaining experiments indicated that these newly formed axosomatic and axodendritic synapses are associated with calbindin-immunoreactive, medium-sized, spiny striatonigral projection neurons. These observations indicate that: (1) dopamine from transplanted embryonic tissue acts via synaptic contacts on host neurons; (2) the primary synaptic targets of transplanted dopamine cells are not spines but dendrites and somata of host neurons; (3) these target neurons are the same as in control animals; and (4) comparing these observations with results of control and grafted rats, there are major species differences between rats and monkeys in the dopamine innervation of both control and transplanted animals.

Animals↗
PubMed1998

In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector.

An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopamine-depleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded TH after stereotactic injection for periods up to 134 days, with biochemical effects consistent with dopamine biosynthetic enzyme expression. A subsequent experiment was carried out in six more severely depleted and parkinsonian monkeys. Several TH/aadc-treated monkeys showed elevated levels of dopamine near injection tracts after 2.5 months. Two monkeys that received a beta-galactosidase expressing vector showed no change in striatal dopamine. Behavioral changes could not be statistically related to the vector treatment groups. Toxicity was limited to transient fever in several animals and severe hyperactivity in one animal in the first days after injection with no associated histological evidence of inflammation. This study shows the successful transfection of primate neurons over a period up to 2.5 months with suggestive evidence of biochemical phenotypic effects and without significant toxicity. While supporting the idea of an in vivo gene therapy for Parkinson's disease, more consistent and longer lasting biochemical and behavioral effects will be necessary to establish the feasibility of this appraoch in a primate model of parkinsonism.

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

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↗
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↗
PubMed1995

The detrimental effect of levodopa on behavioral efficacy of fetal dopamine neuron grafts in rats is reversible following prolonged withdrawal of chronic dosing.

In previous studies, we observed that chronic levodopa treatment resulted in impaired morphology and function of grafted dopamine neurons in rats. To begin to better understand how levodopa treatment might influence dopamine neurons, we examined whether subsequent discontinuation of chronic levodopa treatment might allow for recovery of graft efficacy. Function of embryonic mesencephalic tissue grafts was assessed by monitoring rotational behavior elicited by amphetamine in lesioned, grafted rats initially treated for 6 weeks with levodopa followed by a 6 week drug-free period. As observed previously, control grafted animals, but not levodopa treated animals, showed behavioral improvement. However, following a 6 week withdrawal period, the levodopa animals demonstrated a significant reduction in amphetamine rotations which was reminiscent of control animals. This suggests that grafted neurons can recover functionally after levodopa treatment is withdrawn, which may be of significance in clinical transplantation trials.

Animals↗
PubMed1994

The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.

Six Rhesus monkeys between 24 and 29 years of age received unilateral transections of the fornix. Three monkeys then received intraventricular transplants of polymer-encapsulated baby hamster kidney (BHK) fibroblasts that had been genetically modified to secrete human nerve growth factor (hNGF). The remaining three monkeys received identical grafts except the cells were not modified to secrete hNGF. Monkeys receiving the fornix transection and control grafts displayed extensive reductions in the number of choline acetyltransferase- (57-75%) and p75 NGF receptor- (53%) immunoreactive medial septal neurons ipsilateral to the lesion/implant. In contrast, monkeys receiving transplants of encapsulated hNGF-secreting cells display only a modest loss of choline acetyltransferase- (0-36%) and p75 NGF receptor-(7-22.4%) immunoreactive septal neurons. Additionally, all monkeys receiving the hNGF-secreting implants, but none receiving control implants, displayed robust sprouting of cholinergic fibers within the septum ipsilateral to the transplant. Just prior to sacrifice, the capsules were retrieved and found to contain viable BHK cells releasing biologically relevant levels of hNGF. These data demonstrate that hNGF can provide trophic and tropic influences to aged primate basal forebrain neurons undergoing lesion-induced degeneration, supporting the contention that hNGF may prevent the degeneration of basal forebrain neurons in Alzheimer disease.

Aging↗
PubMed1994

trk-immunoreactivity in the monkey central nervous system: forebrain.

Neurotrophins such as nerve growth factor (NGF) mediate their effects through interactions with high-affinity tropomycin-related kinase (trk) receptors. The present study employed a polyclonal antibody to characterize the distribution of trk-immunoreactive neurons within the nonhuman primate brain. Both young adult and aged cebus and rhesus monkeys displayed trk-immunoreactive neurons within all subdivisions of the basal forebrain. Colocalization studies revealed that between 66% and 76% of trk-immunoreactive basal forebrain neurons also expressed immunoreactivity for the low-affinity p75 NGF receptor, an excellent marker for cholinergic basal forebrain cells. In this experiment, most single-labeled basal forebrain neurons contained only trk immunoreactivity, whereas 4% of basal forebrain neurons expressed only the low-affinity p75 NGF receptor. Scattered trk-immunoreactive neurons also were observed within the caudate nucleus and putamen. Although dual-localization studies with choline acetyltransferase (ChAT) were not performed, striatal neurons codistributed with ChAT-immunoreactive cells, and both types of cells were similar in size and morphology. This suggests that trk immunoreactivity is expressed within cholinergic interneurons within the primate striatum. Finally, lightly stained trk-immunoreactive neurons were observed within the stratum oriens of the hippocampal formation and within the hypothalamus. These data indicate that both cholinergic and, possibly, noncholinergic forebrain neurons express the protein for the high-affinity trk receptor, which transduces the signal mediating the trophic effects of neurotrophins. In addition, the pattern of trk immunoreactivity was preserved in two aged (26 and 29 years old) rhesus monkeys, suggesting that the expression of trk, for the most part, is sustained throughout the lifetime of the organism.

Acetylcholine↗
PubMed1994

Novel radioligands for the dopamine transporter demonstrate the presence of intrastriatal nigral grafts in the MPTP-treated monkey: correlation with improved behavioral function.

This preliminary study demonstrates by in vitro autoradiography the value of novel radiolabeled cocaine analogs to characterize the neurochemical identity and measure the density and growth of fetal ventral mesencephalic cells transplanted to the caudate nucleus of the adult MPTP-treated monkey. Two cocaine derivatives were used, one with extremely high affinity for both dopamine and serotonin transporters and one which was selective for the dopamine transporter. The results suggest that the transplantation procedure was able to increase the density of transporter sites in most of the caudate nucleus, although the proportion of dopaminergic and serotonergic fibers may have been altered from normal.

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