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. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections.

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. Rat galanin produced the same pattern of response but was less potent and effective. These results indicate the existence of a galanin receptor subtype in the ventral limbic cortex mainly recognizing N-terminal galanin fragments and capable of more strongly modulating 5-HT1A receptors than cloned galanin receptors.

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. This indicates that the binding of the ligand to the receptor determines its potency, but has no direct correlation with its intrinsic activity.

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. Analysis of the neostriatum and SN ipsilateral to the lesion revealed that toluene (80 ppm, but not 40 ppm) counteracted the 6-OH DA-induced reductions of DA tissue levels both within the SN and the neostriatum. Also the lesion-induced reduction of immunoreactivity for tyrosine hydroxylase (TH IR) in the neostriatum was partly counteracted by the toluene exposure (80 ppm). In conclusion, a subchronic exposure to low doses of toluene (80 ppm) leads to signs of reduced dysfunction of the nigrostriatal dopaminergic system after the neurotoxic treatment.

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+/-0.8 nM and this did not depend on the presence of dopamine. The displacement of [35S]GTPgammaS binding by GDP could be characterized with an inhibition constant (K(i)) = 78+/-15 microM in the presence of 10 microM of butaclamol, while the presence of 100 microM of dopamine decreased it to a K(i) = 0.13+/-0.02 mM. Dopamine increased the association rate of [35S]GTPgammaS binding in the presence of GDP in a dose-dependent manner with an EC50 = 1.45+/-0.48 microM. Other dopamine receptor agonists studied displayed a potency to stimulate the [35S]GTPgammaS binding in the order R(-)-10,11dihydroxy-N-n-propylnorapomorphine (NPA) > pergolide > or = apomorphine > dopamine approximately quinpirole > R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) > S(+)(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]be nzopyrano[4,3-b]-1,4-oxazin-9-ol hydrocholoride (PD 128,907). The dopamine-induced stimulation of [35S]GTPgammaS binding was inhibited by different dopamine receptor antagonists in the potency order: (+)butaclamol > haloperidol approximately clorpromazine > or = raclopride > (-)-sulpride > remoxipride > 5,6-dimethoxy-2-(dipropylamine)indan (U 991944A) > R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine (SCH-23390). Comparison of the obtained data with the dissociation constants of these ligands to different subtypes of dopamine receptors gave a good correlation only with constants for the D2 subtype, supporting the idea that this subtype is most likely responsible for the dopaminergic activation of [35S]GTPgammaS binding in rat striatal membranes.

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. In view of the present findings, galanin antagonists may represent a new type of anti-depressant drug, based on the 5-HT hypothesis of depression, by enhancing 5-HT release and postjunctional 5-HT1A-mediated transmission. Moreover, following intracerebroventricular injection galanin was found to be internalized in a population of hippocampal nerve cells mainly representing GABA, somatostatin, and/or NPY-immunoreactive nerve cells. The relevance of these findings is discussed in relation to the concept of volume transmission.

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. By contrast, activation of the constitutively expressed adenosine A2B receptors with 5'-N-ethyl-carboxamidoadenosine (NECA) did not modify dopamine D2 receptor binding. In A2A-D2 cells CGS 21680 failed to induce or induced only a small increase in adenosine-3',5'-cyclic-monophosphate (cAMP) accumulation. In D2 cells NECA- or forskolin-induced adenylyl cyclase activation was not associated with any change in dopamine D2 receptor binding. These results indicate that adenylyl cyclase activation is not involved in the adenosine A2A receptor-mediated modulation of the binding characteristics of the dopamine D2 (long-form) receptor.

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. The present results therefore provide evidence, by use of a NPY Y1 receptor antagonist, for the existence of a NPY Y1/alpha 2 receptor interaction in the nucleus tractus solitarii.

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. Toluene at 80 and 1000 ppm significantly enhanced the depletion of striatal DOPAC levels induced by the lesion and produced at 80 and 300 ppm a trend for intensifying the 6-OH DA-induced depletion of striatal DA stores. The alterations induced after the combined challenge to the dopaminergic nigrostriatal system may reflect endangering actions of toluene.

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. 1 nM of CCK-8 caused a significant 38% increase in the KD value of the D2 agonist [3H]NPA binding sites in the L-hD2l/CCK cell membranes. This change was blocked by the CCKB receptor antagonist PD 134308 (50 nM). Furthermore, 1 nM of CCK-8 increased the KD value of the D2 antagonist [3H]raclopride binding sites by 34% (P < 0.05) in the L-hD2l/CCK cell membranes. Control cells (L-hD2l cells) expressing D2L receptors showed no specific [3H]CCK-8S binding sites and no modulation by CCK-8 of the D2L receptors. These findings indicate a modulation of the D2L receptor affinity by activation of the CCKB receptor also when they are coexpressed in a fibroblast cell line. One possible explanation of these data may include a receptor-receptor interaction between the CCKB and D2L receptors.

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. injection (1 mg/kg) of (-)-nicotine resulted in a reduction of the KD value of the D2 antagonist [3H]raclopride binding sites in rat neostriatal membrane preparations at 12 h without any significant change in the Bmax value. This action of (-)-nicotine was counteracted by pretreatment 15 min earlier with the nicotine antagonist mecamylamine (1 mg/kg, i.p.). However, the KD and the Bmax values of the D2 agonist [3H]NPA binding sites in the rat neostriatal membrane preparations were not significantly affected 0.5-48 h after a single i.p. injection with 1 mg/kg of (-)-nicotine. No significant change in neostriatal D2 receptor mRNA levels was observed at any time interval after the (-)-nicotine injection. No significant change was observed in tyrosine hydroxylase (TH) immunoreactivity in either the substantia nigra or the neostriatum, nor in nigral TH mRNA levels during the time interval studied (4-24 h posttreatment). Furthermore, addition of low (10 nM) or high (1 microM) concentrations of (-)-nicotine in vitro to rat neostriatal membranes did not alter the characteristics of [3H]raclopride or [3H]NPA binding. These results indicate that a single (-)-nicotine injection can produce a selective and delayed increase in the affinity of D2 receptors for the antagonist, but not for the agonist without modifying the levels of D2 receptor mRNA, probably via the activation of central nicotinic receptors.

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. The A1-D1 receptor-receptor interaction might represent an important additional mechanism of action responsible for the motor depressant effects of adenosine agonists and for the motor stimulant effects of adenosine antagonists, like the methylxanthines caffeine and theophylline.

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. Choline acetyltransferase and acetylcholinesterase immunocytochemistry was performed in combination with computer-assisted morphometry and microdensitometry. Measurements of choline acetyltransferase enzyme activity was performed in the dorsal hippocampus. The chronic nicotine infusion significantly increased the disappearance of the choline acetyltransferase immunoreactive nerve cell area within the medial septal nucleus of the lesioned side. However, the disappearance of the acetylcholinesterase immunoreactive nerve terminals within the dentate gyrus (molecular layer) and of choline acetyltransferase enzyme activity within the dorsal hippocampus was not found to be influenced by the chronic nicotine infusion. Thus, chronic infusion of (-)-nicotine does not appear to exert any protective activity on mechanically injured septohippocampal cholinergic neurons but may instead increase their dysfunction. In comparison with the dopaminergic neurons it may therefore be that the continuous chronic nicotine exposure does not lead to sufficient desensitization of the nicotinic cholinoceptors of the cholinergic neurons to reduce the chronic influx of sodium and calcium ions via the nicotinic ion channels and thus intraneuronal calcium levels and energy demands.(ABSTRACT TRUNCATED AT 250 WORDS)

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. This increase of the Kd value of [3H]8-OH-DPAT could be completely counteracted by the putative galanin antagonist M35 (1 nM). The Bmax values of [3H]8-OH-DPAT were not affected in any experiment. In conclusion, the present results give further evidence for the existence of a galanin receptor subtype mainly recognizing N-terminal galanin fragments, also having the ability to reduce the affinity of 5-HT1A receptors.

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 (0.1 nM). In view of the higher potency of neuromedin N versus neurotensin to modulate neostriatal D2 receptors in contrast to the higher potency of neurotensin versus neuromedin N to bind to the cloned neurotensin receptors, it seems possible that the neuromedin N activated neostriatal neurotensin receptors controlling the D2 receptors represent a distinct subtype of neurotensin receptors.

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. in doses of 10-100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10-100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemistransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.

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. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)

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., 2 h) increased the IC50 values of (-)nicotine by 230% in the subcortical limbic areas but not in the neostriatum. Subchronic corticosterone treatment (5 mg/kg, twice a day, 7 days) increased the IC50 values of (-)nicotine by 50% and slightly decreased the specific binding of [3H]MCC (5 nM) in the subcortical limbic area. In the neostriatum, subchronic treatment with corticosterone instead decreased by 50% the IC50 values of (-)nicotine and slightly increased the specific binding of [3H]MCC. The results indicate that corticosterone treatment selectively reduces the affinity of nicotinic cholinergic receptors within the subcortical limbic forebrain.