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Biomedical subjects

M Hadjiconstantinou

Publications and source records attributed to M Hadjiconstantinou.

At least 73 records · Page 4Linked to original sources
PubMed1990

Dopamine receptors and sensorimotor behavior in MPTP-treated mice.

The contributions of dopamine (DA) receptor subtypes to sensorimotor behavior was studied in MPTP-treated mice. All DA antagonists studied produced akinesia and catalepsy in control and MPTP-treated mice. The rank order of potency was haloperidol greater than SCH 23390 much greater than L-sulpiride. Combined subthreshold doses of SCH 23390 and L-sulpiride induced marked motor impairments. Dose-response curves for each drug were shifted to the left in the MPTP-treated mice, suggesting behavioral supersensitivity. Pretreatment with the selective D1 agonist SKF 38393 or the selective D2 agonist quinpirole either alone or in subthreshold combination also prevented cold swim-induced motor deficits in the MPTP-treated animals. Haloperidol and SCH 23390 also produced somatosensory neglect in both control and MPTP-treated mice, with haloperidol greater than SCH 23390. Again, a shift of the dose-response curves to the left was observed in the MPTP-treated animals. L-Sulpiride, or another D2 antagonist spiperone, had only minimal effects on somatosensory orientation in both control and MPTP-treated mice. Our studies suggest that both D1 and D2 receptors participate in the expression of motor behavior, while D1 receptors appear to be predominantly responsible for somatosensory orientation.

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

Dopamine receptor plasticity following MPTP-induced nigrostriatal lesions in the mouse.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) destroys dopamine-containing nigrostriatal neurons and increases the apparent Bmax of both D1 and D2 binding sites in the striatum. However, the changes of Bmax occur at different intervals after the lesion. Up-regulation of D2 sites becomes evident about 3 weeks after the lesion and lasts for about 3 months. In contrast, about 3 months are required for the up-regulation of D1 sites and increased binding is still evident after 5 months.

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

Ethylcholine aziridinium ion depletes acetylcholine and causes muscarinic receptor supersensitivity in rat retina.

Three weeks after a single intravitreal injection of ethylcholine aziridinium ion (AF64A), there was a significant depletion of retinal acetylcholine (ACh) content. The depletion was accompanied by an increase of [3H]quinuclidinyl benzilate binding sites and a greater than control conversion of myo-[3H]inositol to inositol monophosphate following incubation with ACh. These changes are consistent with receptor supersensitivity due to AF64A-induced denervation.

Acetylcholine↗
PubMed1990

Aromatic L-amino acid decarboxylase is modulated by D1 dopamine receptors in rat retina.

Aromatic L-amino acid decarboxylase (AAAD) activity of rat retina increases when animals are placed in a lighted environment from the dark. The increase of activity can be inhibited by administering the selective dopamine D1 receptor agonist SKF 38393, but not the selective D2 agonist quinpirole, or apomorphine. Conversely, in the dark, enzyme activity can be enhanced by administering the selective D1 antagonist SCH 23390 or haloperidol, but not the selective D2 antagonist (-)-sulpiride. Furthermore, in animals exposed to room light for 3 h, the D1 agonist SKF 38393 reduced retinal AAAD activity, and this effect was prevented by prior administration of SCH 23390. In contrast, quinpirole had little or no effect when administered to animals in the light. Kinetic analysis indicated that the apparent Vmax for the enzyme increases with little change in the apparent Km for the substrate 3,4-dihydroxyphenylalanine or the cofactor pyridoxal-5'-phosphate. We suggest that dopamine released in the dark tonically occupies D1 receptors and suppresses AAAD activity. When the room light is turned on, D1 receptors are vacated and selective D1 agonists can either prevent the rise of AAAD or reverse light-enhanced AAAD activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Hypoxia-induced neurotransmitter deficits in neonatal rats are partially corrected by exogenous GM1 ganglioside.

Exposure of 7-day-old rats to 7% oxygen/balance nitrogen for 2 h results in selective changes of cholinergic, serotonergic, and dopaminergic neuronal markers in the frontal cortex, hippocampus, and striatum when evaluated 3 weeks after the insult. There is also about a 15% deficiency in brain weight. Treatment with GM1 ganglioside, 50 mg/kg i.p., for 2 days before and for 3 weeks after the hypoxic insult partially corrects the neurodevelopmental abnormalities including the deficiency in brain weight. We conclude that GM1 ganglioside might have therapeutic potential for treating suspected neonatal hypoxia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Treatment with GM1 ganglioside reverses dopamine D-2 receptor supersensitivity induced by the neurotoxin MPTP.

Treatment of mice with the neurotoxin MPTP to destroy nigrostriatal dopaminergic neurons results in up-regulation of D-2 receptors in the striatum when studied after 30 days. Administration of GM1 ganglioside after inducing the lesion prevents D-2 receptor up-regulation. The ganglioside has no apparent effect when administered to normal animals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

GM1 ganglioside-induced recovery of nigrostriatal dopaminergic neurons after MPTP: an immunohistochemical study.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice results in the loss of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the mouse striatum and a loss of cells containing tyrosine hydroxylase (TH)-immunoreactivity from the substantia nigra. The cells that remained in the nigra after MPTP treatment were smaller in diameter than normal cells. Treatment with GM1 ganglioside beginning 24 h after establishing the MPTP lesion resulted in partial restoration of DA and DOPAC content in the striatum and an increase in the diameter of the TH-immunoreactive nigra cells. It appears, therefore, that treatment of MPTP-intoxicated mice with GM1 ganglioside results in the partial restoration of both the biochemistry and morphology of dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Angiotensin II stimulates phosphoinositide turnover in the rat myometrium.

Angiotensin II (AII) activates rat myometrium phospholipase C resulting in the hydrolysis of phosphoinositides. The response to AII is concentration- and time-dependent, and it is blocked by saralasin. During pregnancy there is a loss of responsiveness to AII at the site of placental implantation that appears to return during parturition.

Angiotensin II↗
PubMed1989

Continued administration of GM1 ganglioside is required to maintain recovery from neuroleptic-induced sensorimotor deficits in MPTP-treated mice.

Injection of a dose of haloperidol that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. Chronic GM1 ganglioside administration improves the behavioral impairments, partially restores striatal dopamine (DA) content and prevents DA D-2 receptor up-regulation. Discontinuation of GM1 ganglioside treatment results in a time-dependent decline of striatal DA content to pretreatment pathological levels, return of haloperidol-induced sensorimotor deficits and a rise of DA D-2 receptor density in the striatum. Apparently, continuous administration of GM1 ganglioside is necessary to maintain the biochemical and behavioral recovery in the MPTP-treated mouse. These observations may provide useful cues for understanding the mechanism of action of GM1 ganglioside.

Animals↗
PubMed1989

Gestational alterations in phospholipase C coupled muscarinic response.

In the pregnant rat, carbachol-induced phosphoinositol hydrolysis by myometrium at the placental attachment region progressively decreased toward term, whereas hydrolysis was relatively stable in the myometrium of the non-attachment region. Tritium-quinuclidinyl benzilate binding increased in the myometrium of non-attachment regions as pregnancy progressed. At placental attachment sites binding remained relatively stable until parturition when it increased. Apparently the myometrium associated with the placental attachment site is less sensitive to cholinergic influence during pregnancy compared with the non-attachment site when evaluated by muscarinic activation of phospholipase C or ligand binding.

Animals↗
PubMed1989

Dissociation between biochemical and behavioral recovery in MPTP-treated mice.

Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and somatosensory neglect in MPTP-treated mice. These neuroleptic-induced sensorimotor impairments are exhibited soon after MPTP treatments and coincide with a decrease in both striatal DA and DOPAC levels. DA and DOPAC content gradually return to near-control levels over a 3-5 month period. Interestingly, while the haloperidol-induced somatosensory deficits declined in parallel with the rise in DA and DOPAC levels, the motor deficits persisted for up to 5 months after MPTP administration. These data suggest subtle differences in the neurochemical mediation of these behaviors and that the persistence of neuronal impairments may not necessarily be revealed by near-normal transmitter levels.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Modulation of retinal aromatic L-amino acid decarboxylase via alpha 2 adrenoceptors.

Aromatic L-amino acid decarboxylase (AAAD) activity of the rat retina increases when animals are placed in a lighted environment from the dark. The rise of activity can be inhibited by administering alpha 2 adrenoceptor agonists. In the dark, the enzyme activity can be made to increase by administering alpha 2 adrenoceptor antagonist drugs. Kinetic analysis indicates that the maximum velocity of the enzyme increases with little change of the Km for the substrate L-3,4-dihydroxyphenylalanine or the cofactor pyridoxal-5'-phosphate. The rise of activity in the light and in the dark after alpha 2 antagonists can be blocked by administering cycloheximide, suggesting that protein synthesis is needed for the response. We speculate that epinephrine released in the dark from a subpopulation of retinal amacrine cells onto alpha 2 receptors suppresses AAAD activity that is associated with dopaminergic amacrines.

Animals↗
PubMed1989

Pharmacological characterization of rat retinal dopamine receptors.

The dopamine (DA) D-1 and D-2 receptors coupled to adenylate cyclase in the rat retina were characterized pharmacologically. In confirmation of reports using other neural tissues, activation of D-1 receptors with DA, apomorphine or SKF 38393 resulted in activation of adenylate cyclase and enhanced accumulation of cyclic AMP (cAMP). The response to DA was blocked by SCH 23390, a D-1 receptor antagonist. D-2 receptors negatively coupled to adenylate cyclase were demonstrated by preincubating retina with SCH 23390 and then with DA or apomorphine. D-2 receptor responses were also elicited with quinpirole or bromocriptine, D-2 receptor agonists, in the absence of SCH 23390. (+)-Butaclamol, but not (-)-butaclamol, blocked the D-2 receptor-induced decrease of cAMP. Moreover, I-sulpiride was more active than d-sulpiride in reversing the DA-induced inhibition of cAMP accumulation. D-1 and D-2 receptor responses were also evident in forskolin-activated retina. The intraocular injection of pertussis toxin prevented the fall of cAMP and enhanced the rise of cAMP by DA, indirectly implicating the need for a guanine nucleotide regulatory protein in the process. Our results demonstrate that retinal tissue contains DA receptors that are similar to those found in brain and they imply that therapeutic agents that interact with the receptors in brain might interact with the receptors in retina.

Adenylyl Cyclases↗
PubMed1989

Pharmacological characterization of the muscarinic receptors mediating phosphoinositide hydrolysis in rat myometrium.

Activation of rat uterine myometrial muscarinic receptors with a variety of agonists results in increased phosphatidylinositol metabolism. Activation with carbachol is concentration- and time-dependent and is most apparent by following the accumulation of inositol monophosphate although there are small but significant increases of inositol bisphosphate and inositol trisphosphate. Carbachol stimulation of phospholipid turnover is greatest in the upper third of the uterus. The carbachol-induced increase of inositol monophosphate is antagonized by atropine and by the selective M-3 muscarinic receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide. Pirenzepine, a selective M-1 receptor antagonist is less active, whereas gallamine and 11-2[[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, selective M-2 receptor antagonists, are minimally effective suggesting that muscarinic M-3 receptors modulate phospholipid turnover in the rat myometrium. Displacement of tritium-quinuclidinyl benzilate binding by muscarinic antagonists also supports the presence of M-3 receptors in the uterus. Incubation with phorbol 12, 13-dibutyrate significantly reduced the accumulation of inositol monophosphate induced by carbachol implying that protein kinase C might modulate the responsiveness of the M-3 receptors in the rat uterus. Our results suggest that the intracellular concentration of calcium required for the contraction of the rat myometrium may be modulated, in part, through M-3 muscarinic receptors coupled to phospholipase C-activated turnover of phosphoinositides.

Animals↗
PubMed1988

Administration of GM1 ganglioside eliminates neuroleptic-induced sensorimotor deficits in MPTP-treated mice.

Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. GM1 ganglioside treatment eliminates all of these behavioral impairments and also partially restores striatal dopamine content. These observations suggest that the MPTP-treated mouse may be a valuable model for studying mechanisms underlying parkinsonism and that administration of GM1 ganglioside may be an effective therapy.

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