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Biomedical subjects

S Boyce

Publications and source records attributed to S Boyce.

At least 55 records · Page 3Linked to original sources
PubMed1995

Antinociceptive activity of the tachykinin NK1 receptor antagonist, CP-99,994, in conscious gerbils.

1. The ability of CP-99,994, and its less active enantiomer, CP-100,263, to inhibit spontaneous behaviours and hyperalgesia induced by central infusion of the NK1 receptor agonist, GR73632 or intraplantar injection of formalin was investigated in rats and gerbils. 2. GR73632 (3 pmol, i.c.v.)-induced foot tapping in gerbils was dose-dependently inhibited by CP-99,994 (0.1-1 mg kg-1, s.c.), but not by CP-100,263 (10 mg kg-1, s.c.) using pretreatment times up to 60 min. The centrally active dose-range for CP-99,994 was increased to 1-10 mg kg-1 s.c. with a higher challenge dose of GR73632 (30 pmol, i.c.v.). 3. In gerbils, intrathecal (i.t.) injection of GR73632 (30 pmol) elicited behaviours (licking, foot tapping or flinching and face washing) which closely resembled, but which was less specifically localized than, behaviours seen in animals injected with formalin (0.1-5%) into one hindpaw. 4. In rats, CP-100,263, but not CP-99,994 (up to 30 mg kg-1), inhibited the early phase response to intraplantar injection of 5% formalin (ID50 = 13.9 mg kg-1). The late phase was inhibited by both compounds (ID50 values 36.3 and 20.9 mg kg-1, respectively). In gerbils, there was marginal evidence for enantioselective inhibition of the early phase induced by formalin (2%). The ID50 values were 6.2 mg kg-1 for CP-99,994 and 13.4 mg kg-1 for CP-100,263. 5. Intrathecal injection of GR73632 (30 pmol) caused thermal hyperalgesia in igerbils which was inhibited enantioselectively by s.c. administration of CP-99,994 (ID50= 2.46 mg kg-1), but not by CP-100,263 (30 mg kg-1).6. In gerbils, intraplantar injection of formalin (0.1%) caused thermal hyperalgesia which was inhibited by CP-99,994 (ID50= 1.1 mg kg-1, s.c.). There was a nonsignificant trend for an anti-algesic effect of CP-100,236 (estimated ID50 = 8.2 mg kg-1, s.c.).7 These findings support the proposal that NK1 receptor antagonists may be useful in the clinical management of pain and reinforce the need to dissociate specific and nonspecific antinociceptive effects of available compounds.

Animals↗
PubMed1995

Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach.

Recent studies have shown that there are two isoforms of cyclooxygenases. The constitutive form, cyclooxygenase 1 (COX-1), is believed to be involved in the maintenance of physiological functions. A second isoform, cyclooxygenase 2 (COX-2), has been shown to be induced in inflammation. In the present study, the pharmacology of a selective inhibitor of COX-2, L-745,337 (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indano ne), is described. L-745,337 has IC50 values of 23 +/- 8 nM and > 10 microM for the inhibition of prostaglandin E2 production in whole-cell assays for COX-2 and COX-1, respectively. This compound inhibited carrageenan-induced rat paw edema and rat paw hyperalgesia with ID50 values of 2.00 and 0.37 mg/kg, respectively. In an endotoxin-induced pyresis assay in the rat, L-745,337 significantly reversed the pyretic responses (ID50 = 3.75 mg/kg). L-745,337 did not cause visible gastric lesions in rats at up to 30 mg/kg (4 hr after dosing). In a fecal 51chromium (51Cr) excretion assay to detect gastrointestinal integrity in rats and primates, L-745,337 had no effect at doses up to 100 mg/kg (rat) or after chronic dosing at 20 mg/kg per day for 5 days (primates). In contrast, oral administration of indomethacin, diclofenac or flurbiprofen resulted in substantial increase in fecal 51Cr excretion and/or frank gastric ulceration (rats). L-745,337 significantly inhibited the prostaglandin E2 levels in the inflammatory exudates from the rat pleural cavity after injection with carrageenan but did not inhibit prostaglandin E2 levels in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

L-745,337: a selective inhibitor of cyclooxygenase-2 elicits antinociception but not gastric ulceration in rats.

L-745,337 [5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indan one] a selective cyclooxygenase-2 inhibitor reversed hyperalgesia induced by carrageenan in rats without causing gastric ulceration at doses 100 times those causing antinociception. In contrast, piroxicam and indomethacin produced ulcerations at antinociceptive doses. These findings demonstrate that L-745,337 possesses antinociceptive activity but has a reduced liability for gastric ulceration.

Analgesics↗
PubMed1994

Sources of health insurance and characteristics of the uninsured. Analysis of the March 1993 Current Population Survey.

This Issue Brief/Special Report examines the extent of health insurance coverage in the United States, the characteristics of the uninsured population by employment status, firm size, industry, income, location, family type, gender and age, race and origin, and education, as well as how the uninsured population has changed over the last several years. Eighty-three percent of nonelderly Americans and 99 percent of elderly Americans (aged 65 and over) were covered by either public or private health insurance in 1992, according to EBRI tabulations of the March 1993 Current Population Survey (CPS). The March 1993 CPS is the most recent data available on the number and characteristics of uninsured Americans. In 1992, 17.$ percent of the nonelderly population--or 38.5 million people--were not covered by private health insurance and did not receive publicly financed health assistance. This compares with 36.3 million in 1991 (16.6 percent), 35.7 million in 1990 (16.5 percent), 34.4 million in 1989 (16.1 percent, and 33.6 million in 1988 (15.9 percent). The most important determinant of health insurance coverage is employment. Nearly two-thirds of the nonelderly (62.5 percent) have employment-based coverage. Workers were much more likely to be covered by employment-based health plans than nonworkers (71 percent, compared with 40 percent). A primary reason for the increase in the number of uninsured between 1991 and 1992 is a decline in employment-based coverage among individuals (and their families) working for small firms. Forty-two percent of the additional 2.2 million individuals without coverage between 1991 and 1992 were in families in which the family head worked for an employer with fewer than 25 employees. The number of children who were uninsured in 1992 was 9.8 million, or 14.8 percent of all children. This compares with 9.5 million and 14.7 percent in 1991. The increase in the number and proportion of uninsured children was partially offset by an increase in the proportion of children with Medicaid. In 12 states and the District of Columbia, more than 20 percent of the population was uninsured in 1992 (table 3). These states and their uninsured rates were Nevada (26.6 percent), Oklahoma (25.8 percent), Louisiana (25.7 percent), Texas (25.7 percent), the District of Columbia (25.5 percent), Florida (24.2 percent), Arkansas (23.5 percent), California (22.2 percent), South Carolina (20.8 percent) and Alabama (20.1 percent).

Adolescent↗
PubMed1994

Employment-based health benefits: analysis of the April 1993 Current Population Survey.

The April 1993 CPS differs from the March 1993 CPS in a number of respects. The April 1993 CPS supplement surveys only workers, whereas the March CPS examines the noncash benefits received by all Americans. The April CPS asks workers about health coverage in the week in which the questions were fielded, whereas the March CPS asks about coverage in the preceding year. In April 1993, there were 112.5 million civilian American workers between the ages of 18 and 64 with jobs. Eighty-two million (73 percent) of them worked for an employer that sponsored a health insurance plan, and 65 million (58 percent of all workers) participated in their employer's health plan. About one-third of workers at firms with fewer than 10 employees had employers who offer health benefits; about one-quarter of all of the workers in these firms participated in their employer's plan. Conversely, 94 percent of workers at firms with more than 1,000 employees had an employer who sponsored health benefits, and over 77 percent of these workers participated in their employer's plan. There are 16.5 million American workers whose employers sponsored health benefits but who did not participate in these benefits. Over one-half of these workers (8.5 million) chose not to be covered. Another 36 percent of these workers (5.9 million) did not participate because they were ineligible or denied coverage. Over 66 percent of the ineligible workers did not participate because they were part-time, contract, or temporary workers. Another 26 percent had not yet completed a probationary period. Among the reasons that those who chose not to participate in their employer's coverage, the vast majority (75 percent) stated they were covered by another health care plan. Twenty-nine percent stated that they chose not to purchase coverage because it was too costly or that they did not need or want the coverage. In 1993, there were 16.7 million workers with no health insurance coverage. The vast majority of these workers (95 percent) were employed by private employers. Sixty-six percent of the workers with no health insurance coverage were self-employed or worked for firms with fewer than 100 employees.

Adult↗
PubMed1993

Anxiolytic-like and antinociceptive effects of MK-801 accompanied by sedation and ataxia in primates.

Anxiolytic-like and antinociceptive activities of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine) were compared with sedative and ataxic side effects in primates. Administration of MK-801 (0.1 mg/kg) caused taming in cynomolgus monkeys and increased tail withdrawal latencies in squirrel monkeys; both effects were accompanied by sedation and ataxia. These findings are discussed in relation to the possible therapeutic uses of NMDA antagonists and differences in the behavioural effects of such compounds in primate and rodent species.

Analgesics↗
PubMed1993

Antinociceptive activity of NK1 receptor antagonists: non-specific effects of racemic RP67580.

1. Release of substance P in the dorsal horn is considered a primary event in the perception of pain. The profile of racemic RP67580, a non-peptide antagonist at the NK1 (substance P) receptor, was examined in a range of antinociception tests on rodents. 2. At doses up to 30 mg kg-1, s.c. racemic RP67580 exhibited antinociceptive activity in writhing and formalin paw tests in mice and gerbils. Acetic acid induced writhing and the licking response to formalin were reduced to 40-50% of the level observed in vehicle-treated animals (P < 0.05). However, this agent was not active in mouse tail flick, rat paw pressure or rat and guinea-pig formalin paw tests. 3. Like racemic RP67580, the calcium channel blockers nifedipine (30 mg kg-1, i.p.) and verapamil (10 or 20 mg kg-1, s.c.) inhibited the response to formalin by approximately 60% in gerbils (P < 0.05 compared with vehicle-treated animals). 4. Evidence for calcium channel antagonist activity of RP67580 was obtained in vitro. Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 +/- 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (IC50 = 298 nM) and depressed high threshold calcium currents in neurones cultured from rat cortex (10% inhibition at 10 microM). 5. These findings indicate that the acute antinociceptive effects of RP67580 may not be attributable to a specific interaction with NK1 receptors and may be mediated via calcium channel blockade.

Analgesics↗
PubMed1993

The pathophysiologic changes following bile aspiration in a porcine lung model.

Aspiration of bile is an underpublicized aspiration syndrome. Using a porcine lung model, the physiologic response and the histopathology of lung tissue were evaluated after the intratracheal instillation of sublethal doses of bile. Twenty-one domestic swine (11 to 19 kg) were the studied population. Three groups of five swine were evaluated: a control group received intratracheal physiologic saline (pH 7.45); study group 1 received strained gastric contents (pH 2.24); and study group 2 received strained bile (pH 7.19). All animals received the solutions at 0.5 ml/kg intratracheally. Lungs of six additional animals were studied (two gastric, two bile, and two physiologic saline) after aspiration by scanning electron microscopy (SEM). A seventh untreated animal was used as the SEM control. The physiologic data were analyzed using analysis of variance for repeated measures. The SEM and histopathologic results were graded by an observer blinded to the groups and were analyzed using the analysis of variance (ANOVA) and Scheffe tests. The group with bile aspiration was consistently characterized by significant deterioration of PaO2, the alveolar-arterial (A-a) gradient, shunt fraction, and static compliance (p < 0.01); and the light histopathologic and SEM findings demonstrated pathologic changes in the bile-exposed lung (p < 0.05) greater than the gastric- or saline-exposed lungs. It is concluded that bile aspiration produces a severe chemical pneumonitis leading to noncardiac pulmonary edema.

Animals↗
PubMed1993

Sources of health insurance and characteristics of the uninsured. Analysis of the March 1992 Current Population Survey.

Eighty-three percent of nonelderly Americans and 99 percent of elderly Americans (aged 65 and over) were covered by either public or private health insurance in 1991, according to EBRI tabulations of the March 1992 Current Population Survey (CPS). The March 1992 CPS is the most recent data available on the number and characteristics of uninsured Americans. In 1991, 16.6 percent of the nonelderly population--or 36.3 million people--were not covered by private health insurance and did not receive publicly financed health assistance. This number compares with 35.7 million in 1990 (16.6 percent), 34.4 million in 1989 (16.1 percent), and 33.6 million in 1988 (15.9 percent). The most important determinant of health insurance is employment. Nearly two-thirds (64 percent) of the nonelderly have employment-based coverage. Workers were much more likely to be covered by group health plans than nonworkers (71 percent versus 40 percent). Even though workers and members of their families were more likely to be covered by health insurance than nonworkers, 85 percent of the uninsured lived in families headed by workers in 1991, primarily because most people lived in families headed by workers. More than 60 percent of uninsured were in families headed by full-year workers with no unemployment. Nearly all persons who were covered by an employment based-plan received at least some contribution to that plan from their employer. The estimated average annual contribution among those receiving a contribution to employee or family plans was $2,129. Although many individuals in poor families are covered by public health plans, that coverage is far from universal. In 1991, only 52 percent of the nonelderly with income below the poverty line were covered by a public plan--49 percent by Medicaid. The number of children who were uninsured in 1991 was 9.5 million, or 14.7 percent of all children, compared with 9.8 million or 15.3 percent of all children in 1990. Twenty-three percent of children were covered by public health insurance, with 21 percent being covered by Medicaid. In 11 states and the District of Columbia, more than 20 percent of the population was uninsured in 1991. These states and their uninsured rates were the District of Columbia (30.3 percent), Texas (25.3 percent), New Mexico (24.5 percent), Louisiana (23.8 percent), Florida (23.5 percent), Mississippi (22.1 percent), Oklahoma (22.1 percent), Nevada (21.8 percent), California (21.7 percent),Arizona (21.1 percent), Alabama (20.6 percent), and Idaho (20.6 percent).

Adult↗
PubMed1993

Cardiorespiratory response to walking in trained and sedentary pregnant women.

In order to test whether trained (n = 10) and sedentary (n = 29) pregnant women have different responses to weight-bearing exercise in the second trimester (range 23 to 28 weeks of gestation), subjects walked continuously on a treadmill for 26 minutes: at low intensity for 10 minutes, then an intermediate stage, followed by moderate intensity for 10 minutes. In the trained group, the mean heart rate was lower (p < 0.02) with both low [104.0 +/- 4.5 (SD) versus 117.4 +/- 2.3 bpm] and moderate intensity exercise (128.4 +/- 5.7 versus 145.2 +/- 2.9 bpm) and the associated mean stroke volume was higher (105 +/- 16 versus 84 +/- 17 ml; 103 +/- 15 versus 86 +/- 18 ml, respectively) (p < 0.02). The mean cardiac output, blood pressure and oxygen consumption were the same in the two groups (p > 0.02) at the same absolute workloads. The potential implications of these findings for exercise prescriptions for pregnant women, research evaluation and exercise testing are discussed.

Adult↗
PubMed1992

Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.

Animals↗
PubMed1992

A 2-deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Implications for the neural mechanisms that mediate dopamine agonist-induced dyskinesia.

The neural mechanisms that underlie both the anti-parkinsonian effects of dopamine agonists and dopamine agonist-induced dyskinesia were studied in parkinsonian primates, using the regional brain uptake of [3H]2-deoxyglucose (2-DG). Parkinsonian symptoms were induced in monkeys by the administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Some of the animals received chronic dopamine replacement therapy for at least 3 mths, which resulted in the appearance of peak-dose dyskinesia. The remaining animals spent an equivalent period of time relatively unexposed to dopaminergic agents, receiving only therapeutic doses, and at no time showed any signs of dopamine agonist-induced dyskinesia. The 2-DG metabolic mapping technique was applied to all of these animals shortly following the administration of a dose of dopamine agonist which was sufficient to alleviate their parkinsonian symptoms and to induce dyskinesia in those prone to this complication. The 2-DG uptake technique permits the autoradiographic measurement of local cerebral glucose uptake which was used as an index of regional synaptic activity. The resultant autoradiographs were compared with those from a previous study which examined 2-DG uptake in parkinsonian and normal brains from animals which had not received dopamine agonists prior to the terminal 2-DG uptake procedure. The pattern of 2-DG uptake in the animals which received a dopamine agonist prior to the terminal procedure was strikingly different to both of the other groups. The most affected structure was the subthalamic nucleus which showed a dramatic increase in 2-DG uptake in animals exposed to dopamine agonist immediately prior to the terminal procedure, especially in the ventral tip of the nucleus. The medial pallidal segment also showed relatively greater levels of 2-DG uptake in the dopamine agonist group compared with the untreated parkinsonian state whereas, in contrast, the lateral pallidal segment showed decreased levels of 2-DG uptake. The parkinsonian animals which had been sacrificed after receiving a dopamine agonist were split into three groups on the basis of their response to the agonist. The first group had their parkinsonism reversed and appeared clinically normal. The remaining animals had their parkinsonism reversed by the dopamine agonist but showed dyskinesia at peak dose. These animals were allotted to two further groups depending on whether their dyskinesia was of a choreic or dystonic nature.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Weak antiparkinsonian activity of the D1 agonist C-APB (SKF 82958) and lack of synergism with a D2 agonist in primates.

The role of D1 receptors in motor control is poorly understood. In parkinsonian squirrel monkeys, the full D1 agonist C-APB (SKF 82958; 0.1-0.4 mg/kg s.c.) caused weak stimulation of locomotor activity. However, the motor stimulant effects of the D2 agonist (+)-PHNO (0.001 mg/kg s.c.) were not potentiated by C-APB (0.3 mg/kg). Differences between these observations and expectations from experiments using rodents are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates.

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.

Animals↗
PubMed1991

Collagen metabolism during healing of lacerated rabbit corneas.

We previously demonstrated that there are two waves of increased collagen synthesis following corneal laceration in rabbits. In the present study, we have examined whether increases in collagen synthesis and degradation result from increased amounts of mRNAs for collagen and collagenase, respectively. Rabbits were anesthetized by combined administration of ketamine (intramuscular) and pentobarbital (intravenous). A penetrating 8-mm incision was made at the center of each cornea. The lacerated corneas were allowed to heal for 0-49 days. The rabbits were then killed and the corneas excised. The total RNA was extracted from the tissue and subjected to slot-blot hybridization using 32P-labeled alpha 1(I) cDNA. The results indicate that there is a two-phase increase in the amount of alpha 1(I) mRNA in injured corneas and that the collagenase mRNA is elevated at most times throughout the healing period. However, the increase is collagenase mRNA may not fully account for the accelerated collagen degradation during corneal wound-healing. Thus, we propose that cells in the wound area may be directly involved in collagen degradation by phagocytosis. To examine our hypothesis, we cultured injured rabbit corneas in the presence or absence of leupeptin, a proteinase inhibitor. The tissues were then examined by electron microscopy. In the presence of leupeptin, lysosomes within fibroblasts or fibroblast-like cells in the wound area of the lacerated corneas healed for 2 and 3 weeks, contain collagen fibrils. In the absence of leupeptin no identifiable collagen was seen in the lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography.

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis).

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.

Animals↗
PubMed1990

Induction of chorea and dystonia in parkinsonian primates.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primates induced a parkinsonian syndrome that could be reversed by levodopa treatment. Animals quickly developed an apparent restlessness ("akathisia") of the lower limbs after as little as five doses. After 4-10 weeks of regular levodopa therapy, animals developed "peak dose" choreiform movements in the lower limbs that spread, with time, to involve the upper limbs and orofacial musculature. With further treatment (5-21 months), animals developed "peak dose" dystonia that variably involved the limbs and orofacial musculature. These conditions represent novel models of levodopa-induced chorea and dystonia in humans. They depend on the same underlying neuropathology and treatment regimen as their human counterparts. It is to be anticipated that these models of dyskinesia will be useful in determining the mechanisms underlying chorea and dystonia in humans and are ideally suited for experimental evaluation of new treatment strategies.

Animals↗