Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum.

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography.

Galanin-(1-16) modulates 5-HT1A receptors in the ventral limbic cortex of the rat.

The aim of the present study was to evaluate whether galanin-(1-16) of the rat and porcine type and rat galanin-(1-29) can modulate the 5-HT1A receptors, using [3H]8-OH-DPAT as a radioligand, in membrane preparations from the ventral limbic cortex of the rat. Galanin-(1-16) produced a concentration dependent increase in the Kd value of [3H]8-OH-DPAT binding sites with a maximal effect of approximately 61% at 30 nM without changing the Bmax values. The galanin antagonist M35 blocked these effects.

Modulation of [(35)S]GTPgammaS binding to chinese hamster ovary cell membranes by D(2(short)) dopamine receptors.

Rat dopamine D(2short) expressed in Chinese hamster ovary (CHO) cells were characterized by means of activation of [(35)S]-guanosine 5'-O-(gamma-thiotriphosphate) ([(35)S]GTPgammaS) binding and inhibition of [(3)H]raclopride binding. Among 18 dopaminergic ligands studied dopamine, NPA, apomorphine and quinpirole were full agonists in activation of [(35)S]GTPgammaS binding, while seven ligands were partial agonists with efficacies from 16 to 69% of the effect of dopamine and seven ligands were antagonists having no effect on the basal level of [(35)S]GTPgammaS binding, but inhibited dopamine-dependent activation in a dose-response manner. Despite the different efficacies, the potencies of all 18 ligands to modulate [(35)S]GTPgammaS binding revealed a good correlation with their potencies to inhibit [(3)H]raclopride binding in the CHO cell membranes.

Subchronic toluene exposure in low concentrations produces signs of reduced dysfunction in the 6-hydroxydopamine lesioned nigrostriatal dopaminergic system of the rat.

The effect of a subchronic (4-week) exposure to low concentrations of toluene (40 or 80 parts per million, ppm) on the brain dopaminergic system has been examined in a rat model of Parkinson's disease. A unilateral lesion of the substantia nigra (SN) dopamine (DA) nerve cells was performed by injection of a low dose of 6-hydroxydopamine (6-OH DA). The peak activity of contralateral rotational behavior induced by apomorphine was significantly decreased after exposure to 80 ppm toluene.

Galanin modulates 5-hydroxytryptamine functions. Focus on galanin and galanin fragment/5-hydroxytryptamine1A receptor interactions in the brain.

The reciprocal interactions between galanin and 5-HT1A receptors in the rat brain are presented. Galanin and its NH2-terminal fragments antagonize 5-HT1A receptor-mediated transmission at the postjunctional level, whereas galanin receptor activation mimics the inhibitory action of 5-HT1A receptor activation at the soma-dendritic level, leading to reductions of 5-HT metabolism and release. These interactions have been shown in both receptor binding studies and functional studies.

Pharmacological characterization of dopamine-stimulated [35S]-guanosine 5'(gamma-thiotriphosphate) ([35S]GTPgammaS) binding in rat striatal membranes.

Functional activation of dopamine receptors in the crude membranes from rat striatum was studied by a [35S]-guanosine 5'-O-(gamma-thiotriphosphate) ([35S]GTPgammaS) binding assay. Binding of [35S]GTPgammaS could be characterized with a dissociation constant (Kd) = 14.6+/-0.

Possible involvement of G-proteins in the regulation of striatal dopamine D2 receptor affinity by cholecystokinin octapeptide.

A G(i)-protein antibody AS/7 at 1:10 dilution significantly increased the K(d) values of the D2 agonist [3H]N-propylnorapomorphine (NPA) binding sites in the rat striatal membranes, and coincubation with sulphated cholecystokinin octapeptide (CCK-8; 1 nM) did not further increase the K(d) values. A GTP analogue guanylyl-imidodiphosphate (GMP-PNP) at 100 microM markedly increased the K(d) values of the [3H]NPA binding sites in the rat forebrain sections, and coincubation with CCK-8 (1 nM) again did not produce a further increase in the K(d) values. The present results indicate that abnormal activity of G-proteins abolished the ability of CCK-8 to reduce the D2 receptor affinity in the brain.

Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected fibroblast cells.

In membrane preparations from rat striatum, where adenosine A2A and dopamine D2 receptors are coexpressed, stimulation of adenosine A2A receptors was found to decrease the affinity of dopamine D2 receptors for dopamine agonists. We now demonstrate the existence of this antagonistic interaction in a fibroblast cell line (Ltk-) stably transfected with the human dopamine D2 (long-form) receptor and the dog adenosine A2A receptor cDNAs (A2A-D2 cells). In A2A-D2 cells, but not in control cells only containing dopamine D2 receptors (D2 cells), the selective adenosine A2A agonist 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethyl-carboxamido adenosine (CGS 21680) induced a 2-3-fold decrease in the affinity of dopamine D2 receptors for dopamine, as shown in competition experiments with dopamine versus the selective dopamine D2 antagonist [3H]raclopride.

The non-peptide neuropeptide Y Y1 receptor antagonist BIBP3226 blocks the [Leu31,Pro34]neuropeptide Y-induced modulation of alpha 2-adrenoceptors in the nucleus tractus solitarii of the rat.

The potential blockade of the neuropeptide Y (NPY) Y1 receptor agonist [Leu31,Pro34]NPY-induced modulation of the characteristics of alpha 2-adrenoceptor agonist [3H]p-aminoclonidine binding sites by a selective non-peptide NPY Y1 receptor antagonist BIBP3226, was studied in the nucleus tractus solitarii of the rat by means of quantitative receptor autoradiography. [Leu31,Pro34]NPY at a concentration of 10 nM significantly increased the Kd value of [3H]p-aminoclonidine binding sites in the nucleus tractus solitarii without influencing the Bmax, suggesting the existence of an antagonistic modulation by NPY Y1 receptors of alpha 2-adrenoceptors in the nucleus tractus solitarii. BIBP3226 at 100 nM fully blocked the [Leu31,Pro34]NPY-induced increase in Kd of the [3H]p-aminoclonidine binding sites.

Subacute toluene exposure increases DA dysfunction in the 6-OH dopamine lesioned nigrostriatal dopaminergic system of the rat.

The potential neurotoxicity of the solvent toluene to the nigrostriatal dopaminergic system was assessed in a rat model of Parkinson's disease. Rats, 1 day after a unilateral injection of 6-hydroxydopamine (6-OH DA) into the substantia nigra, inhaled air or different concentrations of toluene (80, 300 or 1000 ppm), 6 h/day for 3 days. The animals were sacrificed 2 days after the last exposure and biochemical measurements of catecholamines and 3,4-dihydroxyphenylacetic acid (DOPAC) were performed in the neostriatum and substantia nigra.

Regulation of dopamine D2 receptor affinity by cholecystokinin octapeptide in fibroblast cells cotransfected with human CCKB and D2L receptor cDNAs.

Alteration in dopamine (DA) and/or cholecystokinin (CCK) transmission in the CNS may be of relevance for schizophrenia. Previous findings in striatal membranes give indications of a modulation of DA D2 receptor affinity by CCKB receptor activation. In the present study receptor binding studies were performed in a mouse fibroblast cell line (L-hD2l/CCK), expressing both human D2 receptors (long form, D2L) and human CCKB receptors, and binding sites for [3H]CCK-8S (sulfated CCK octapeptide), the D2 agonist [3H]NPA and the D2 antagonist [3H]raclopride were found and characterized in saturation and competition experiments.

A single (-)-nicotine injection causes change with a time delay in the affinity of striatal D2 receptors for antagonist, but not for agonist, nor in the D2 receptor mRNA levels in the rat substantia nigra.

The in vitro and in vivo effects of (-)-nicotine on dopamine D2 receptors in the rat neostriatum have been studied using biochemical binding, in situ hybridization and immunocytochemistry. A single i.p.

Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors.

Behavioural and biochemical evidence for the existence of a powerful specific postsynaptic interaction between adenosine A1 and dopamine D1 receptors in the mammalian brain was found. Behavioural data showed that A1 receptor stimulation induced a decrease in the D1-induced motor activation in reserpinized mice and a decrease in the D1-dependent oral dyskinesia in rabbits. Biochemical data suggested that A1 receptor stimulation could produce a GTP-independent uncoupling of the rat striatal D1 receptor to the G protein.

Chronic continuous infusion of nicotine increases the disappearance of choline acetyltransferase immunoreactivity in the cholinergic cell bodies of the medial septal nucleus following a partial unilateral transection of the fimbria fornix.

Previous studies have demonstrated that chronic continuous nicotine treatment via minipumps partially protects against mechanically induced degeneration of the nigrostriatal dopamine neurons in the male Sprague-Dawley rat. In the present study we investigated how a 4-week continuous infusion with (-)-nicotine via minipumps implanted subcutaneously in the male Sprague-Dawley rat (0.125 mg/kg-1 h-1) influences the anterograde and retrograde changes occurring in the septohippocampal cholinergic neurons following a unilateral transection of the fimbria fornix.

Galanin-(1-15), but not galanin-(1-29), modulates 5-HT1A receptors in the dorsal hippocampus of the rat brain: possible existence of galanin receptor subtypes.

The aim of the present study was to evaluate whether galanin-(1-29) and galanin-(1-15) can modulate the 5-hydroxytryptamine1A (5-HT1A) receptors using [3H]8-OH-2-(di-n-propylamino)-tetralin ([3H]8-OH-DPAT) as a radioligand. Membrane preparations of the dorsal hippocampus, an area having the recently described [125I]galanin-(1-15) fragment binding sites, but having very few porcine [125I]galanin-(1-29) binding sites, were used. Galanin-(1-15) produced a concentration-dependent increase in the Kd value of [3H]8-OH-DPAT with a maximum effect of approximately 65% at 3 nM of galanin-(1-15), whereas galanin-(1-29) had no effect.

Neuromedin N is a potent modulator of dopamine D2 receptor agonist binding in rat neostriatal membranes.

In the concentration range of 1-10 nM, neuromedin N produced a significant concentration-related increase in the Kd values of [3H]L-(-)-N-propylnorapomorphine binding sites in rat neostriatal membranes with a peak action at 10 nM (36% increase versus the control group mean value). The Bmax values were not affected by neuromedin N. Neurotensin at 10 nM induced an increase in the Kd values, which was not affected by a threshold concentration of neuromedin N (0.

The C-terminal neurotensin-(8-13) fragment potently modulates rat neostriatal dopamine D2 receptors.

The effects of neurotensin fragments and of neurotensin itself on the characteristics of neostriatal dopamine D2 agonist binding were studied in competition experiments with dopamine using the D2 antagonist, [3H]raclopride. The biologically active neurotensin-(8-13) fragment, but not the inactive neurotensin-(1-7) fragment, caused a concentration-related increase in the KH and KL values of dopamine with a maximal increase by 110 and 97%, respectively, at 1 nM, while neurotensin-(1-13) only induced such changes at 10 nM. In view of the higher potency and the increased ability of neurotensin-(8-13) versus neurotensin (1-13) to reduce the affinities of the high- and low-affinity states of the neostriatal D2 receptors, the C-terminal neurotensin fragments may be among the endogenous ligands of the neostriatal neurotensin receptors.

The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway.

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p.

Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.

Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c.

Acute and subchronic corticosterone treatment differentially modulates subcortical limbic and neostriatal nicotinic cholinergic receptors.

The effects of acute and subchronic corticosterone treatment were analyzed on the competition by (-)nicotine ((-)nicotine hydrogen(+)-tartrate) on N-[3H]methylcarbamyl choline iodide ([ 3H]MCC) binding sites in membranes from the subcortical limbic forebrain and the neostriatum. Acute treatment with corticosterone (5 mg/kg, i.p.

Changes in pituitary-adrenal activity affect the binding properties of striatal dopamine D-2 receptors but not their modulation by neurotensin and cholecystokinin-8.

The effects of adrenalectomy were investigated on the binding properties of [ (3)H] N- propylnorapomorphine ([(3)H]NPA) binding sites in membrane preparations from the rat neostriatum. Adrenalectomy (1 week) was found to increase the K(D) value of [(3)H]NPA binding sites by 30 +/- 3%, without affecting the B(max) values. These effects were fully counteracted by replacement treatment with corticosterone (5 mg/kg, twice daily, 1 week, last injection given 2 h before killing).