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Biomedical subjects

A J Hunter

Publications and source records attributed to A J Hunter.

At least 73 records · Page 4Linked to original sources
PubMed1997

Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment.

For an understanding of the aberrant biology seen in mouse mutations and identification of more subtle phenotype variation, there is a need for a full clinical and pathological characterization of the animals. Although there has been some use of sophisticated techniques, the majority of behavioral and functional analyses in mice have been qualitative rather than quantitative in nature. There is, however, no comprehensive routine screening and testing protocol designed to identify and characterize phenotype variation or disorders associated with the mouse genome. We have developed the SHIRPA procedure to characterize the phenotype of mice in three stages. The primary screen utilizes standard methods to provide a behavioral and functional profile by observational assessment. The secondary screen involves a comprehensive behavioral assessment battery and pathological analysis. These protocols provide the framework for a general phenotype assessment that is suitable for a wide range of applications, including the characterization of spontaneous and induced mutants, the analysis of transgenic and gene-targeted phenotypes, and the definition of variation between strains. The tertiary screening stage described is tailored to the assessment of existing or potential models of neurological disease, as well as the assessment of phenotypic variability that may be the result of unknown genetic influences. SHIRPA utilizes standardized protocols for behavioral and functional assessment that provide a sensitive measure for quantifying phenotype expression in the mouse. These paradigms can be refined to test the function of specific neural pathways, which will, in turn, contribute to a greater understanding of neurological disorders.

Animals↗
PubMed1997

Photothrombotic lesions of the rat cortex impair acquisition of the water maze.

Photochemical induction of a thrombosis produces lesions of the cortex of reproducible area and depth, and it has been suggested that this may provide a relatively noninvasive model of the human condition of stroke. The cognitive effects of photothrombotic lesions centred at two different positions were assessed in rats using the Morris water maze test for spatial learning and memory, and it was demonstrated that profound deficits in acquisition of this task were produced by bilateral lesions of the frontal cortex. These effects were in the absence of overt motor deficits, and there was no significant correlation between lesion volume and functional deficits. Flunarizine (2 mg/kg) did not attenuate this ischaemic damage and had no effect on the functional deficits. This model has distinct advantages over more invasive global models of ischaemia and may also provide greater understanding of the functional role of the mammalian neocortex.

Animals↗
PubMed1997

Differential expression of c-fos, Hsp70 and Hsp27 after photothrombotic injury in the rat brain.

In situ hybridization and immunohistochemistry were used to examine the expression of c-fos, Hsp70 and Hsp27 following photothrombotic injury in the right fronto-parietal cortex of the rat. C-fos mRNA and protein were detected in the entire cerebral cortex on the lesioned side. Hsp70 mRNA accumulation was observed only adjacent and peripheral to the site of the lesion. At 1 h after photothrombotic injury, Hsp70 expression delineates the area of necrosis at 24 h after photothrombotic injury. Hsp27 protein was observed in the ipsilateral cerebral cortex with the exception of the deep layers of the cingulate cortex. In addition, while c-Fos immunoreactivity was localized in cell nuclei, Hsp27 immunoreactivity was detected in the cytoplasm of astrocytes. These results demonstrate that unilateral cortical injury induces changes in gene expression that vary according to cell type and brain region.

Animals↗
PubMed1997

Dissociation of effects of glutamate receptor antagonists on excitotoxic and hypoxic neuronal cell death in a novel rat cortical culture system.

A novel in vitro cell culture model has been developed to investigate the mechanisms of delayed neuronal cell death following exposure to excitatory amino acids and hypoxia. Medium change damages cortical cells possibly leading to preselection of the neuronal population. This model allowed compounds to be administered in the absence of a medium change. In this system, the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801, attenuated the neurotoxic effects of overnight exposure to glutamate and NMDA completely, and partially protected neurones exposed to alpha-amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA). The non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, did not attenuate the effects of glutamate or NMDA but blocked the excitotoxic effects of AMPA completely. These results suggest partial involvement of NMDA receptor activation in AMPA-induced toxicity. By contrast, hypoxia-induced neuronal degeneration in this model was attenuated by either NMDA or non-NMDA antagonism, which confirms previous reports that the mechanisms of hypoxic and excitotoxic neurodegeneration in these in vitro models are not identical. A number of other compounds, which have been reported previously as neuroprotective in vitro and in vivo, including the calcium channel antagonists, SB 201823, flunarizine, and nifedipine, and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, L-NAME, demonstrated no significant neuroprotective effects in this in vitro system. In common with other in vitro models that include a change of medium, these data suggest that this system does not have predictive validity for the identification of novel neuroprotective agents in vivo.

Animals↗
PubMed1997

Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anaesthetized cat.

Intravenous infusion of glyceryl trinitrate (GTN) into migraineurs induces an immediate headache followed by migraine. We studied the effect of GTN (0.25 microgram kg-1 min-1) on local cerebrovascular laser Doppler flux (rCBFLDF), artery diameter and NO concentration (selective NO microelectrode) in the pial middle cerebral artery perfusion territory of the anaesthetized cat, at rest and during cortical spreading depression (SD). GTN infusion induced a significant increase in pial artery diameter, rCBFLDF, and NO concentration. Following termination of infusion, NO concentrations remained significantly elevated above controls for 60 min, other parameters returned to baseline within 10 min (p < 0.05, ANOVA, post hoc Dunnett's multiple comparison procedure). Two hours after termination of infusion KCl-evoked SD was initiated. GTN-treated animals exhibited significantly (p < 0.05, Kruskal-Wallis) elevated SD-induced NO release compared to controls. All other parameters remained unaffected. Our results demonstrate that GTN induces a prolonged increase in local NO concentrations and enhances SD-induced NO release.

Anesthesia↗
PubMed1997

Furosemide inhibits regenerative cortical spreading depression in anaesthetized cats.

Ionic perturbations occur during cortical spreading depression (SD), a phenomenon implicated in migraine pathophysiology. We studied the effect of 0.2, 2 and 20 mg kg-1 i.v. (n=4) furosemide on cortical direct current (d.c.) potential, cerebrovascular laser Doppler flux (rCBF[LDF]), artery diameter and NO concentration in the parietal cortex of the anaesthetized cat during repetitive SD. In vehicle-treated animals (n=4), SD activity was sustained for 50+/-1.8 min. However, duration of SD activity was significantly reduced when compared to vehicle to 39+/-6.6 (n=4), 34+/-8.5 (n=4) and 27.3+/-11.3 min (n=4), at 0.2, 2 and 20 mg kg-1 i.v. furosemide respectively. It is hypothesized that the mechanism of inhibition of SD d.c. activity by furosemide may be through alterations in cortical ion buffering capacity or inhibition of cell swelling in neurones or glia. These mechanisms may represent potential novel drug targets in future migraine therapy.

Analysis of Variance↗
PubMed1997

The effects of SB 206284A, a novel neuronal calcium-channel antagonist, in models of cerebral ischemia.

The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.

Animals↗
PubMed1997

Comparison of the cardiovascular effects of the novel 5-HT(1B/1D) receptor agonist, SB 209509 (VML251), and sumatriptan in dogs.

The systemic cardiovascular effects of a novel 5-hydroxtryptamine (5-HT)(1B/1D)-receptor agonist were investigated in the anaesthetised dog. SB 209509 (VML 251) was more potent than sumatriptan in producing increases in carotid vascular resistance after intravenous administration and was similar in potency to sumatriptan after sequential intraduodenal administration at 30-min intervals. In open-chest dogs, sequential intravenous administration of SB 209509 or sumatriptan produced marked increases in carotid vascular resistance without changing coronary vascular resistance. In contrast to sumatriptan, after administration of high doses of SB 209509 (>790 nmol/kg), a reduction in coronary vascular resistance was observed. After a single bolus intraduodenal dose of SB 209509 (260, 520, or 790 nmol/kg), increases in carotid vascular resistance could be detected over a 5-h period. Sumatriptan (i.d.), 2.4 micromol/kg but not 700 nmol/kg, produced a sustained effect similar to the effects of SB 209509 (790 nmol/kg). In all experiments, SB 209509 and sumatriptan had minimal effects on arterial blood pressure or heart rate but produced marked changes in carotid vascular resistance over the same concentration range. SB 209509 was rapidly absorbed after intraduodenal administration in conscious dogs and had good bioavailability. These data indicate that SB 209509 is a potent 5-HT(1B/1D)-receptor agonist that is rapidly absorbed from the duodenum. The effects of SB 209509 are long lasting and selective for the carotid vascular bed.

Animals↗
PubMed1996

Motor dysfunction in a photothrombotic focal ischaemia model.

The study of behavioural deficits resulting from cerebral infarction in animal models of stroke has in the past taken second place to histological assessment. This is particularly true of the photothrombotic lesion model. Most tests currently used to measure motor deficits use a scoring system to quantify parameters such as beam walking. The present study set out to characterise a simple and objective assessment for motor impairment in the photothrombotic cortical lesion model. Rats were assessed on a number of motor function tests, i.e. gross locomotor activity, rotarod, and grip strength. After the establishment of stable baselines, cortical photothrombotic lesions were induced, after which the animals were re-tested for a further 18 days. The presence of cortical photothrombotic lesions significantly imparied the rats' performance on the rotarod and grip-strength tests. The deficit observed with the grip-strength task appeared 24 h postsurgery, but was much reduced by day 18 postsurgery. The rotarod test revealed an effect that took longer to establish, but which was more persistent. Gross locomotor activity was not affected. These data suggest that bilateral photothrombotic lesions of the prefrontal cortex produce deficits that can be detected by rotarod and grip-strength tasks.

Animals↗
PubMed1996

Effect of a thyrotrophin-releasing hormone analogue, RX77368, on AMPA-induced septal-hippocampal lesioned rats in an operant delayed non-matching to position test.

The aim of the present study was to determine the effect of a thyrotrophin-releasing hormone (TRH) analogue, RX77368, on performance of a working memory test, using a delayed non-matching to position (DNMTP) procedure, in (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced septal-hippocampal lesioned rats. Following a post-surgery recovery period, pretrained rats were tested once daily on DNMTP, 30 min post-administration of RX77368 (1.0 mg kg-1, i.p.) or saline. AMPA-induced lesions significantly reduced percent correct responses during the second week of testing. Comparison of percent correct responses between days 1 and 13 of testing showed that sham rats significantly improved DNMTP performance, whereas lesioned rats did not. RX77368 significantly reduced general locomotor activity in sham rats in activity boxes, but did not disrupt non-mnemonic measures, such as locomotion and motivation, in the DNMTP test. RX77368 increased percent correct responses in AMPA-lesioned rats on days 8-10 and 11-13. There was also a significant improvement in percent correct responses achieved between day 1 and 13 in RX77368-treated lesioned and sham rats. These results showed that: (i) septal-hippocampal lesioned rats did not improve over the testing period; and (ii) on test days when a significant impairment was present, RX77368 partially improved DNMTP performance.

Animals↗
PubMed1995

Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat--relationship to circling behaviour.

The ability of benzazepine D-1 dopamine agonists with varying efficacies in stimulating adenylate cyclase and to induce contralateral circling was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats, the benzazepines SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue), SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue), all produced contralateral circling. The rank order of efficacies (maximal effect, Emax) being, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 >> SKF 82958. In striatal slices from the intact hemisphere, dopamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclase activity. The rank order of efficacies being SKF 82958 (109%) = dopamine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 (67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylate cyclase activity, this effect did not reach statistical significance. In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenylate cyclase activity were lower (-25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denervated striatum was greater than observed in the intact striatum. The rank order of efficacies in the dopamine denervated striatum being SKF 82958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SKF 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepine derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circling and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 dopamine receptors and/or transduction systems other than adenylate cyclase.

Adenylyl Cyclases↗
PubMed1995

Short- and long-term changes in striatal and extrastriatal dopamine uptake sites in the MPTP-treated common marmoset.

The 'short-term' (15-30 days) and 'long-term' (18-42 months) effects of the systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on [3H]mazindol binding to dopamine uptake sites was investigated in the common marmoset. In the 'short-term' MPTP-treated group, [3H]mazindol binding was reduced in the caudate-putamen (by -82 to -98% with respect to controls), substantia nigra pars compacta (-71 to -84%), ventral tegmental area (-72%) and nucleus accumbens (-54%). [3H]Mazindol binding in the globus pallidus, frontal cortex and substantia nigra pars reticulata was much lower and was unaffected by MPTP treatment. In the 'long-term' MPTP-treated group [3H]mazindol binding was still greatly reduced in the substantia nigra pars compacta (by -76 to -89%), ventral tegmental area (-71%) and most of the caudate-putamen (-69 to -98%), although the reduction in [3H]mazindol binding in the nucleus accumbens (-27%) and rostroventral caudate nucleus (-69%) was less than in the 'short-term' MPTP-treated group. The motor deficits induced by MPTP treatment in the common marmoset are largely reversible with increasing survival times (Ueki et al., 1989, Neuropharmacology 28, 1089). In the present study, the apparent 'recovery' in [3H]mazindol binding in the rostroventral caudate nucleus and nucleus accumbens may indicate regeneration of dopamine neurone terminals in these regions and this may contribute to the behavioural recovery seen in this primate model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Matrix nonenzymatic glycosylation leads to altered cellular phenotype and intracellular tyrosine phosphorylation.

The effect of matrix nonenzymatic glycosylation on signal transduction and the cellular phenotype was examined. Human microvascular endothelial cells were plated on control or glycated basement membrane-like matrix. Cells exhibited a decrease in their ability to adhere and spread on modified matrix. The pattern of intracellular tyrosine phosphorylation was examined by Western Immunoblotting; a band with 65 kDa mobility exhibited a marked reduction of tyrosine phosphorylation in cells adherent to modified matrix. Immunoprecipitation experiments provided evidence that this band is paxillin, a member of focal adhesion proteins. Immunoprecipitation with antibodies against focal adhesion kinase (pp125FAK), the enzyme that is thought to regulate paxillin tyrosine phosphorylation, also demonstrated a reduction in tyrosine phosphorylation of pp125FAK. To confirm these biochemical data, adherent cells were examined for the distribution of paxillin, using immunofluorescence microscopy; paxillin was seen in focal points peripherally located in cells on normal matrix, but lacked this pattern in cells on modified matrix. Actin filaments were also disorganized in cells plated on modified matrix. These data suggest that matrix nonenzymatic glycosylation can interfere with and potentially alter cellular phenotype and intracellular signaling.

Animals↗
PubMed1995

Image directed proton spectroscopy of gerbil brain at 7 tesla.

Image directed localized 1H NMR spectra were obtained at 7 T (300 MHz) from cubic volumes of less than 40 microL in the gerbil brain. Signals from cerebral metabolites commonly detected in other rodent species were easily assigned, and high resolution spectroscopy (360 MHz) of aqueous brain extracts assisted the tentative identification of partially overlapping resonances from lower concentration compounds like alanine, lysine, gamma-aminobutyrate, valine, leucine and isoleucine. Weak coupling at 7 T was manifest in the resolution of signals from the gamma-CH2 groups of glutamine and glutamate. Down-field of water, signals assigned to purine nucleotides were conspicuous in the extract spectra, but localized spectra acquired routinely in vivo, using selective excitation and gradient crushing (SUBMERGE) for water suppression, exhibited little or no signal from purines. When localized in vivo spectra were acquired without water suppression, however, or using a low power binomial excitation sequence rather than SUBMERGE, a broad signal appeared at the resonant frequency of purine aromatic protons. NMR experiments on the nucleotide adenosine 5'-monophosphate (AMP) in 90% glycerol/10% D2O solution demonstrated that pre-irradiation of the water signal even for less than 100 ms attenuated the nucleotide signal appreciably. This implies that the soft pulses required for selective excitation of water in sequences such as SUBMERGE induce spin-diffusion which eliminates or diminishes the signal from nucleotides in vivo.

Acetates↗
PubMed1995

Short and long-term changes in cerebral [14C]-2-deoxyglucose uptake in the MPTP-treated marmoset: relationship to locomotor activity.

The "short-term" (0.7 +/- 0.1 months post-MPTP) and "long-term" effects (36.7 +/- 4.4 months) of MPTP treatment on motor behaviour and [14C]-2DG uptake were investigated in the common marmoset. The subcutaneous administration of MPTP greatly reduced locomotor activity (-94% with respect to controls) and induced motor disability in the "short-term" MPTP-treated marmoset group. In the "long-term" MPTP group, MPTP treatment did not significantly affect locomotor activity (-27% with respect to controls) and there was partial recovery of motor disability. In the "short-term" MPTP group, there were increases in [14C]-2DG uptake in the GPl (+31 to +37%), SNc (+34 to +42%), VTA (+35%), LC (+23%), PPN (+19%) and in the VA (+19%), VL (+20%) and AM (+17%) thalamic nuclei. [14C]-2DG uptake was decreased in the STN (-15%). In the "long-term" MPTP group, [14C]-2DG uptake was increased in the GPl (+18%), SNc (+27%), VTA (+25%), PPN (+19%), ventral caudate nucleus (+18 to +23%), NAc (+22%), F.Ctx (+18%) and in the VA (+34%), VL (+28%), AV (+33%) and AM (+24%) thalamic nuclei. [14C]-2DG uptake was unchanged in the STN. The increase in metabolic activity of the surviving DA neurones and/or the reactive gliosis may account for the initial increase in [14C]-2DG uptake in the SNc and VTA. On the other hand, in the "long-term" MPTP-treated animals the increase in [14C]-2DG uptake in the SNc (though less than in the "short-term" MPTP group), ventral caudate and NAc may reflect the regenerative changes in the dopaminergic system in these areas. Despite the behavioural recovery, [14C]-2DG uptake remained elevated in the target areas for medial pallidal output (the thalamic nuclei and PPN). However, the attenuation of the changes in [14C]-2DG uptake in the GPl and STN of "long-term" MPTP-treated marmosets suggest that the striato-GPl and GPl-STN outputs closely reflect motor function in this primate model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset.

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D1 DA receptor selectivity), demonstrated high D1 DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) and SKF 75670 (3-CH3 analogue) further reduced locomotor activity (by -70 to -80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6-10 fold) and a reversal in motor disability (by -64 to -77%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D2 DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D1 DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D1 DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D1 DA receptors uncoupled to AC and/or a role for extrastriatal D1 DA receptors in mediating the behavioural response to D1 DA agonists.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease.

The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.

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