Biomedical subjects

M J Besson

Publications and source records attributed to M J Besson.

At least 37 records · Page 2Linked to original sources

PubMed1996

Distribution of preproenkephalin, preprotachykinin A, and preprodynorphin mRNAs in the rat nucleus accumbens: effect of repeated administration of nicotine.

The effects of a repeated treatment with nicotine on the expression of mRNAs encoding preproenkephalin (PPE), preprotachykinin-A (PPT-A), and preprodynorphin (PPDYN) were examined by in situ hybridization histochemistry in various subregions of the nucleus accumbens (Acb). In saline-treated rats, optical density measurements on autoradiographic films showed marked anteroposterior decreasing gradients for PPE and PPT-A mRNAs in the rostral pole and the core, in the cone, and in the ventral shell of the Acb, whereas a lower anteroposterior gradient was observed for PPDYN mRNA signals. The intensity of the three mRNA signals also varied according to Acb subregion. However, analysis of percentages of prepropeptide mRNA-containing neurons as compared to total neurons showed, in the rostral pole, the core, and the cone, a similar percentage of PPE mRNA (around 45%)- and PPT-A mRNA (around 40%)-expressing neurons. The ventral shell can be distinguished from the other subregions by a lower percentage of PPE mRNA (35.8%)- and PPT-A mRNA (30.6%)-expressing neurons. The percentage of PPDYN mRNA-containing neurons, by contrast, was similar (around 37%) in the core, the cone, and the ventral shell. Repeated nicotine administration increases the PPE mRNA level in the rostral pole and the anterior third of the core without any change in PPT-A and PPDYN mRNA levels in the various Acb subregions examined. The PPE mRNA increase does not support an effect mediated through an interaction of nicotine with DA neurons. The effect could be linked to a nicotine activation of other afferents to the anterior Acb and/or to a direct nicotine stimulation of PPE mRNA neurons.

Animals↗

PubMed1995

Chronic blockade of muscarinic cholinergic receptors by systemic trihexyphenidyl (Artane) administration modulates but does not mediate the dopaminergic regulation of striatal prepropeptide messenger RNA expression.

A striatal dopaminergic denervation leads to changes in the expression of messenger RNA encoding prepropeptides contained in striatal efferent neurons. Such a dopaminergic lesion also abolishes a functional equilibrium between dopaminergic and cholinergic transmissions, generally believed to operate within the neostriatum, which constitutes the theoretical basis for the clinical use of antimuscarinic drugs in extrapyramidal diseases. It is possible, therefore, that changes in prepropeptide messenger RNA expression are mediated by an alteration in cholinergic transmission. To test this hypothesis, we have examined in rats whether trihexyphenidyl, an antimuscarinic drug of wide clinical use, can counteract the changes in preproenkephalin, preprotachykinin and preprodynorphin messenger RNA expression produced by a unilateral 6-hydroxydopamine lesion of substantia nigra dopaminergic neurons. Two weeks after the lesion, trihexyphenidyl was continuously administered through an osmotic minipump (5 mg/day for 15 days) to half of the lesioned and sham-operated rats, the other half receiving the vehicle. Using quantitative in situ hybridization histochemistry, messenger RNAs were analysed at two rostrocaudal levels (anterior and central) of the neostriatum. In parallel, M1 muscarinic receptors were measured by autoradiography of [3H]pirenzepine binding sites. In sham-operated rats, trihexyphenidyl administration produced a significant increase (17-27%) in M1 binding sites. In addition, preproenkephalin messenger RNA levels were decreased (-38%) in the central part, while preprodynorphin messenger RNA levels were significantly increased (+22%) at both striatal levels. In 6-hydroxydopamine-lesioned rats, the expected changes in messenger RNAs were observed when ipsi- versus contralateral side values were compared, but changes were not always detected when comparison was established between values from the dopamine-denervated neostriatum and those from sham-operated rats. The trihexyphenidyl administration in 6-hydroxydopamine-lesioned animals was unable to reproduce the up-regulation of M1 receptors, even in the intact neostriatum. This antimuscarinic treatment further increased preproenkephalin messenger RNA levels in the denervated anterior neostriatum, amplifying the ipsi- versus contralateral difference. It also potentiated the imbalance in preprotachykinin messenger RNA expression, mainly as a result of an increase of preprotachykinin messenger RNA levels in the intact neostriatum. In contrast, trihexyphenidyl treatment by increasing preprodynorphin messenger RNA in both neostriata abolished the ipsi- versus contralateral difference observed in lesioned rats. In conclusion, with the exception of preprodynorphin messenger RNA, trihexyphenidyl treatment was unable to counteract the imbalance in prepropeptide messenger RNA expression produced by a unilateral striatal dopaminergic denervation and even amplified this effect. These results question the neostriatum as the site of action of antimuscarinic drugs in producing their therapeutic effect in extrapyramidal syndromes.

Animals↗

PubMed1994

Role of dopamine in the plasticity of glutamic acid decarboxylase messenger RNA in the rat frontal cortex and the nucleus accumbens.

The modulatory role of dopamine (DA) on the expression of mRNA encoding the large isoform of glutamic acid decarboxylase (GAD67), the biosynthesis enzyme of gamma aminobutyric acid (GABA), was examined in GABA neurons of two structures innervated by DA neurons originating from the ventral tegmental area (VTA): the medial frontal cortex (MFC) and the nucleus accumbens (NAcc). A bilateral electrolytic lesion of VTA was performed in rats to produce a DA denervation of both the MFC and NAcc. The efficacy of VTA lesions was verified by measurement of locomotor activity and by immunohistochemical detection of tyrosine hydroxylase in the mesencephalon. GAD67 mRNA was detected by in situ hybridization histochemistry using a 35S-labelled cDNA probe. Densitometric analysis of GAD67 mRNA hybridization signals revealed in VTA-lesioned rats a significant decrease (-24%) in GAD67 mRNA levels in the prelimbic area of the MFC and no significant effect in the anterior cingulate area or the frontoparietal cortex. Single cell analyses by computer-assisted grain counting showed that the decrease in GAD67 mRNA levels in prelimbic MFC was due to a change in GAD67 mRNA expression in a subpopulation of GABA interneurons located in the deep cortical layers (V-VI). By contrast, in the NAcc of VTA-lesioned rats, GAD67 mRNA levels were significantly increased in the anterior part and in the core but were unchanged in the shell part. These results suggest that in two target structures of VTA DA neurons, GAD67 mRNA expression is, in normal conditions, under a tonic stimulatory and a tonic inhibitory DA control in the MFC and the NAcc respectively. A schematic diagram is proposed for functional interactions between these structures.

Animals↗

PubMed1994

Stimulation by nicotine of the spontaneous release of [3H]gamma-aminobutyric acid in the substantia nigra and in the globus pallidus of the rat.

The effect of (-)-nicotine on the spontaneous release of [3H]gamma-aminobutyric acid ([3H]GABA) was studied in vitro in rat substantia nigra (SN) and globus pallidus (GP) slices. In both structures, nicotine (10(-4) M) elicited a transient increase of [3H]GABA release lasting no more than 2.5 min. At the peak of the effect, a 18.5% and 25% increase of [3H]GABA was observed in GP and SN slices, respectively. At lower concentration (10(-5) M), nicotine produced a small but significant transient increase (+8%) in GP slices whereas this concentration was ineffective in SN slices. Pempidine (10(-5) M) totally antagonized the 10(-4) M nicotine-induced effect in SN and GP. The increase of [3H]GABA release elicited by 10(-4) M nicotine was abolished when Ca2+ concentration in the superfusion medium was lowered from 2.4 to 0.4 mM. To investigate a possible dopaminergic (DA) link in the response, we examined the sensitivity of the nicotine-induced effect to DA D1 (SCH23390) and D2 (sulpiride) receptor antagonists. In SN, SCH23390 (10(-6) M) abolished the 10(-4) M nicotine-induced effect. In GP, sulpiride (10(-5) M) failed to modify the response. Moreover, SCH23390 partially reversed the nicotine-induced effect (-37%) in GP. Taken together these results indicate that nicotine differentially modulate the [3H]GABA release in SN and GP. In SN, the nicotine-induced [3H]GABA release appears to be mediated by DA neurons. In GP, only a part of the nicotinic response involved a DA link. A possible direct stimulation of nicotinic receptors localized on striato-pallidal terminals is discussed.

Animals↗

PubMed1994

Muscarinic receptor stimulation increases the spontaneous [3H]GABA release in the rat substantia nigra through muscarinic receptors localized on striatonigral terminals.

The effect of muscarinic agonists on the spontaneous release of [3H]GABA was investigated in vitro on rat substantia nigra slices. Acetylcholine (5 x 10(-5) M) in the presence of eserine (5 x 10(-5) M) induced a 12.3% increase of the spontaneous release of [3H]GABA. Similarly, carbachol (5 x 10(-4) M) enhanced by 9% the release of [3H]GABA. This effect was Ca(2+)-dependent, it was abolished in the presence of 0.4 mM Ca2+ and enhanced from 9 to 17% when Ca(2+)-concentration of the superfusion medium was increased from 1.3 to 2.4 mM. The carbachol effect was mediated by muscarinic receptors since it was abolished by atropine (2 x 10(-6) M). The pharmacologically M2 muscarinic receptor subtypes seems to be involved as the carbachol-induced effect was abolished by AF-DX384MS (10(-6) M), an M2 antagonist and was only partially reversed by pirenzepine (10(-5) and 10(-4) M), an M1 antagonist which at these doses also block the M2 receptors. The absence of effect of SCH23390 (10(-6) M) a D1 antagonist as well as the lack of effect of CNQX (10(-5) M) and dizocilpine maleate (10(-6) M), two glutamate antagonists, on the carbachol-induced effect indicated that neither dopamine (through D1 receptors) nor glutamate (through ionotropic receptors) were involved in the response. In addition, the persistence of the carbachol-induced effect in the presence of tetrodotoxin (2 x 10(-7) M) suggests a direct muscarinic-mediated modulation of [3H]GABA. The localization of muscarinic receptors on striatonigral fibres was confirmed by autoradiographic studies showing a decrease of [3H]pirenzepine binding in the substantia nigra after a unilateral striatal lesion induced by kainic acid injection. This latter result provides evidence of the presence of M1 receptors on striatonigral terminals as the concentration of [3H]pirenzepine used (10 nM) is M1-selective. These results indicate a cholinergic modulation of GABA release in the rat substantia nigra mediated by muscarinic receptors localized on striatonigral terminals. The involvement of the m4 muscarinic receptor subtype that have a M1/M2 pharmacology is discussed.

Acetylcholine↗

PubMed1993

The rat nucleus accumbens: two levels of complexity in the distribution of glutamic acid decarboxylase (67 kDa) and preproenkephalin messenger RNA.

The distribution of messenger RNAs (mRNAs) encoding the 67 kDa isoform of glutamic acid decarboxylase (GAD67), a rate-limiting enzyme in the biosynthesis of gamma-aminobutyric acid, and preproenkephalin (PPE), the precursor of enkephalin, was analysed in the rat nucleus accumbens (NAS) taking in account its compartmentation in 'core' (NAS(core)) and 'shell' (NASshell). While GAD67 mRNA levels were more abundant (+48%) in NASshell than in NAS(core), hybridization signals for PPE mRNA were mainly found in NAScore. At a cellular level, hybridization signals for GAD67 mRNA were present in 75% and 80% of neurons NASshell and NAS(core), respectively. The level of GAD67 mRNA found higher in the NASshell corresponds in fact to a greater density of neurons in NASshell than in the NAS(core). The hybridization signals for PPE mRNA were observed in very few neurons of NASshell and in around half of the neurons in NAS(core). Besides this medio to lateral difference, GAD67 and PPE mRNAs were distributed in NAS(core) according to a rostro-caudal gradient, the content of both mRNAs being higher in the rostral part than the caudal part of this area.

Animals↗

PubMed1993

GABA interneurons in the rat medial frontal cortex: characterization by quantitative in situ hybridization of the glutamic acid decarboxylase (GAD67) mRNA.

In situ hybridization of mRNA encoding one isoform of glutamic acid decarboxylase (GAD67) was performed in the rat medial frontal cortex (MFC) to characterize GABA interneurons. Qualitatively, the labelling obtained with a [35S]cDNA probe was in register with neurons and was never associated with glial cells. No obvious differences in the density of labelled cells were observed between the different areas of the MFC examined (infralimbic, prelimbic, anterior cingulate and precentral medial) and between the various cortical layers. Grain counting was performed on single cells in the various layers of the prelimbic and the anterior cingulate area, two main areas of the MFC. According to their grain density, neurons were arbitrarily classified as low, high and very high GAD67 mRNA content. The neurons with the high GAD67 mRNA content corresponded to around 50% of the labelled cells in all the layers and in both areas. In the prelimbic area, the neuronal population with a low GAD67 mRNA content varied from 50% in layers I and II-III to 40% in layers V-VI whereas the very high GAD67 mRNA content neurons corresponded to around 5% of the labelled neurons in all layers. In the anterior cingulate area the neuronal population showing low GAD67 mRNA content varied from 35% in layers I and II-III to 20% in layers V-VI. In this area, neurons with a very high GAD67 mRNA content were more numerous than in the prelimbic area: they varied from 15% in layers I and II-III to 30% in layers V-VI. Parallel to the presence of very highly labelled cells, GAD enzymatic activity measured both in the presence and in the absence of pyridoxal 5'-phosphate was higher in the anterior cingulate area than in the prelimbic area. The heterogeneity of GAD67 mRNA content at the cellular level might underlie the existence of subpopulations of GABA interneurons in the MFC and suggests a higher GABAergic inhibitory control in the anterior cingulate area than in the prelimbic area.

Animals↗

PubMed1993

Ontogenic distribution of muscarinic receptors and acetylcholinesterase in the rabbit hippocampus.

Ontogenic development of muscarinic receptors was examined in the hippocampus of rabbits (from P2 to P60) using radioautographic method. Muscarinic sites were labelled with (3H)-quinuclinidyl-benzilate and pharmacologically defined M1 and M2 receptor subtypes with (3H)-pirenzepine and (3H)-oxotremorine, respectively. The distribution of binding sites was compared to acetylcholinesterase (AChE) staining in adjacent hippocampal sections. The two cholinergic components are progressively set up in the hippocampus during the first three postnatal weeks. The AChE staining was very low in all hippocampal fields in P2 rabbits. At P8 and after, the AChE staining was more pronounced in CA3 and CA4 than in CA1 and CA2. On the contrary, the M1 muscarinic binding sites were more abundant in CA1 and CA2 hippocampal fields than in CA3 and CA4 at all ages studied. M2 muscarinic binding sites were only distinguishable at P45 and have a relatively homogeneous distribution. This study shows a differential developmental evolution in the distribution of AChE and muscarinic M1 receptors, and no obvious correspondence between these two cholinergic markers was observed.

Acetylcholinesterase↗

PubMed1993

Haloperidol increases PPE mRNA levels in the caudal part of the nucleus accumbens in the rat.

Dopamine exerts a tonic inhibitory control in the regulation of mRNA encoding preproenkephalin (PPE), the precursor of enkephalin, in the dorsal part of the rat striatum. Less is known about the role of this amine in the regulation of PPE mRNA in the ventral part of the striatum which corresponds to the nucleus accumbens. In this study, the effects of an interruption of dopamine transmission by haloperidol (a dopaminergic receptor antagonist) were examined in the rat nucleus accumbens. The levels of PPE mRNA were analysed by in situ hybridization histochemistry by taking into account the complexity of the nucleus accumbens, i.e. by differentiating the rostro-caudal extension of the structure. It was found that PPE mRNA content was increased significantly only in the caudal part of the nucleus, indicating rostro-caudal differences in the haloperidol effects. The differential reactivity of PPE mRNA to dopaminergic receptor blockade and to a lesion of dopaminergic neurones along the rostrocaudal axis of the ventral striatum is discussed.

Animals↗

PubMed1992

Distribution of [3H]clonidine binding sites in the brain of the convulsive mutant quaking mouse: a radioautographic analysis.

The radioautographic analysis of [3H]clonidine binding was performed on brain slices from the convulsive mutant mice quaking and their controls of the same strain. In the quaking mice significant increases were observed mostly in the brainstem and the cerebellum, but also in a few regions of the forebrain, such as the lateral and medial thalamic nuclei, the medial geniculate nucleus, the amygdala and the hypothalamus. Other regions, such as the cerebral cortex and the hippocampus, which are classically involved in various models of epilepsy, but not in the quaking mice, did not show any modification of [3H]clonidine binding. A high degree of correlation was found between the structures with an increased density of alpha 2-adrenoceptor binding sites and the distribution of regions from which seizures can be elicited by intracerebral electrical stimulation in head-restrained quaking mice. This comparison emphasizes the role of noradrenaline acting at the level of alpha 2-adrenoceptors in the epileptic syndrome of the quaking mutants.

Animals↗

PubMed1992

Expression of GAD mRNA in GABA interneurons of the rat medial frontal cortex.

The distribution of glutamic acid decarboxylase (GAD) mRNA containing cells was studied in the rat medial frontal cortex (MFC). The neurons labelled by the 35S-labelled cDNA probe were distributed uniformly throughout all the layers and represented 16% of the total neuronal population. It was possible to distinguish two cell populations expressing high and low levels of GAD mRNA corresponding to 63% and 27% of labelled cells, respectively. Concerning the laminar distribution of these two populations of GAD mRNA containing neurons, no marked difference was observed between the various areas of the MFC.

Animals↗

PubMed1991

The quaking mouse: an epileptic mutant with alterations affecting the modulatory mechanisms of the NMDA receptor complex.

The binding of [3H]glutamate and of [3H]1-(1-(2-thienyl)cyclohexyl)piperidine [( 3H]TCP) has been examined in the genetically epileptic mutant mouse, quaking. The density of [3H]glutamate binding sites did not differ between the quaking mice and their controls of the same strain. In the absence of exogenous glutamate or glycine, the density of [3H]TCP binding sites was also similar in the two strains. In both the mutants and their controls, exogenously added glutamate, glycine and glutamate plus glycine dose-dependently increased the binding of [3H]TCP. In the 3 conditions, the modulation of [3H]TCP binding was significantly more efficient in the quaking mice than in the controls. Furthermore, in the presence of glutamate (10(-5) M), the increase of the affinity of the ligand for the ion channel binding site was higher in the mutants than in the controls. These results suggest that the modulatory mechanisms of the N-methyl-D-aspartate/ionophore receptor complex might be altered in these mutants. These alterations might be related to the previously observed anticonvulsant properties of NMDA receptor antagonists in the quaking mouse model of inherited epilepsy.

Animals↗

PubMed1991

In vivo release of newly synthesized [3H]GABA in the substantia nigra of the rat: relative contribution of GABA striato-pallido-nigral afferents and nigral GABA neurons.

The release of [3H]gamma-aminobutyric acid ([3H]GABA) continuously formed from [3H]glutamine has been measured with a push-pull cannula implanted in the substantia nigra of the rat anesthetized with ketamine. Consistent with the high density of GABA terminals coming from both the striato-pallido-nigral afferents, and from GABA nigrofugal neurons, our results showed that a large amount of [3H]GABA was spontaneously released in the reticulata, about 4 times higher than in the compacta. In the absence of calcium the spontaneous [3H]GABA release was reduced (-30%), as well as the K(+)-induced release of [3H]GABA (-66%). Bicuculline (10(-4) M) did not affect the K(+)-evoked release of [3H]GABA, suggesting that autoreceptors on GABA afferent fibers are distinct from the GABAA subtype. Partial lesions of striato- and pallido-nigral GABA neurons with kainic acid (1.2 micrograms) decrease by 40% the glutamic acid decarboxylase (GAD) activity in the ipsilateral SN without decreasing the spontaneous release of [3H]GABA; even following extensive lesions with kainic acid (2.5 micrograms), GAD activity (-72%) and spontaneous [3H]GABA release (-83%) were not completely abolished. These results suggest that a non-negligible contribution of GABA nigral neurons accounts for the spontaneous GABA release measured in the substantia nigra. This is further supported by the decrease (-20%), and the increase (+40%) of [3H]GABA release produced by the local application of glycine (10(-6) M), and bicuculline (10(-4) M), which respectively, inhibits and activates the nigral neuron activity. The contribution of nigral GABA neurons to the amount of [3H]GABA release from the substantia nigra, is likely linked to their high spontaneous firing rate.

Anesthesia↗

PubMed1991

Comparative development of D1-dopamine and mu opiate receptors in normal and in 6-hydroxydopamine-lesioned neonatal rat striatum: dopaminergic fibers regulate mu but not D1 receptor distribution.

The postnatal development of D1 dopaminergic receptors (D1 receptors) was investigated in the rat striatum in relation to distribution of mu opiate receptor patches and islandic tyrosine hydroxylase (TH)-immunoreactive fibers. The possible influence of dopaminergic (DA) fibers originating from the substantia nigra on the postnatal distribution of striatal D1 and mu receptors was also examined by producing an early 6-hydroxydopamine (6-OHDA) lesion of DA fibers. D1 and mu receptors were labeled with selective ligands: [3H]SCH 23390 and [3H]DAGO, respectively. During the first postnatal week, control rats showed patches of dense D1 binding sites in the entire rostro-caudal extension of the striatum. The localization of D1 receptor patches corresponded to striosomes identified by TH-immunoreactive islands. The striatal distribution of mu receptors was relatively homogeneous at postnatal day 0 (P0) but was clearly patchy at P3-P4. During the second postnatal week the striosomal pattern of D1 binding sites disappeared along a dorso-ventral gradient whereas mu binding sites remained distributed in patches. Densitometric measurements showed that there was a parallel increase of D1 binding sites in both striosomes and the surrounding matrix from P0 to P4. The disappearance of D1 receptor patches observed in the dorsal striatum at P9 was due to a faster increase of D1 binding sites in the matrix than in striosomes between P4 and P9 whereas a significant difference was still observed between these two compartments in the ventral striatum of P9 rats. During the third postnatal week, the density of D1 binding sites still increased but became progressively uniform in the whole striatum. The intrastriatal injection of 6-OHDA in 2-day-old rats produced a local disappearance of TH-immunoreactive fibers in the striatum and a distal degeneration of TH-immunoreactive cell bodies in the substantia nigra. However an early lesion of striatal DA fibers did not modify the pattern of development or the density of D1 binding sites during the postnatal period examined (1 and 3 weeks after the lesion). The distribution of mu receptors was unchanged 1 week after the lesion but showed a clear disorganization 3 weeks after the lesion. We discuss the differential influence of DA fibers on the distribution of D1 and mu receptors in the rat striatum and the possible role of DA in the regulation of the expression of mu receptors.

Animals↗

PubMed1991

Opposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortex slices.

The spontaneous and the electrically evoked release of [3H]GABA were studied in vitro on slices of rat medial prefrontal cortex. The slices were preincubated with [3H]GABA and then superfused with a Krebs' solution. The superfusion with a Ca(2+)-free medium progressively increased the spontaneous [3H]GABA release and strongly decreased the electrically evoked release of [3H]GABA (-65%). The effects of three dopaminergic D2 receptor agonists (RU24926, lisuride and LY171555) were studied on both the spontaneous and the electrically evoked [3H]GABA release. The spontaneous release of [3H]GABA was increased by exposure to each of these three D2 agonists. RU24926 produced a dose-dependent increase from 10(-9) to 3 x 10(-8) M and the maximal effect was totally abolished by the dopaminergic D2 receptor antagonist sulpiride (10(-5) M). With lisuride a progressive increase of [3H]GABA release was observed and a plateau value was reached with concentrations between 10(-7) and 10(-6) M. These effects were totally reversed by 10(-5) M sulpiride. The dose-response relation for LY171555 was bell-shaped, with a maximal effect being obtained with 10(-9) M) LY171555. This effect decreased with a higher concentration (10(-8) M) and finally was no longer observed for 10(-7) M LY171555. The maximal increase induced by LY171555 was totally abolished by 10(-5) M sulpiride. In contrast, the electrically evoked release of [3H]GABA was inhibited by these three D2 agonists. The IC50 value of the inhibition was 4.1 x 10(-8) M for RU24926 and 2 x 10(-7) M for lisuride. Sulpiride (10(-5) M) totally abolished the effect of 10(-7) M RU24926. In the concentration range of lisuride examined, a 50% reduction of the lisuride inhibition was obtained in the presence of sulpiride (10(-5) M). The dose-response curve obtained with LY171555 had a U-shape, with a maximal inhibition reached with 10(-8) M, whereas no effect was observed with 10(-6) M. The inhibition induced by 10(-8) M LY171555 was completely antagonized by 10(-5) M sulpiride. The D2 agonist-induced inhibition of the electrically evoked release of [3H]GABA was mimicked by dopamine endogenously released by 10(-5) M amphetamine. This effect was reversed by 10(-5) M sulpiride. Our data provide further evidence for a dopaminergic control of GABA interneurons in the prefrontal cortex. This regulation implies the activation of D2 dopaminergic receptors. The possible mechanisms underlying the opposite effects of D2 agonists on the spontaneous and the electrically evoked release of [3H]GABA are discussed.

Amphetamine↗

PubMed1991

Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex.

In order to examine a possible interaction between D1 and D2 receptors in the dopaminergic control of the electrically-evoked release of [3H]GABA in the rat prefrontal cortex, the effects of D1 and D2 dopamine agonists were studied in vitro on cortical slices. The D1 agonist SKF38393 (10(-5) M) inhibited the electrically-evoked release of [3H]GABA. This effect was totally reversed by both the D1 antagonist SCH23390 (10(-7) M) and the D2 antagonist sulpiride (10(-5) M). We previously observed that maximal D2-mediated inhibition of the electrically-evoked release of [3H]GABA was obtained with 10(-7) M RU24926 and 10(-8) M LY171555. Here we showed that the inhibition produced by these two D2 agonists is also abolished by 10(-7) M SCH23390. In dopamine-depleted slices from reserpine-treated animals, it was not possible to detect an effect of either RU24926 (10(-7) M) or SKF38393 (10(-5) M), suggesting a permissive role of endogenous dopamine in the effect of either D2 or D1 agonist. Finally, SKF38393 used at a subliminar concentration (10(-6) M) was able to potentiate the effect of a liminar concentration of RU24926 (1.5 x 10(-8) M). Taken together these results strongly suggest that in the rat prefrontal cortex a D1-D2 receptor synergism is involved in the dopaminergic control of the electrically-evoked release of [3H]GABA.

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

PubMed1991

Parallel decrease of glutamic acid decarboxylase and preproenkephalin mRNA in the rat striatum following chronic treatment with a dopaminergic D1 antagonist and D2 agonist.

The levels of mRNA encoding glutamic acid decarboxylase (GAD) and preproenkephalin (PPE) were measured by Northern blot analysis, in the dorsal and the ventral part of the striatum, following long-term treatments with drugs acting selectively on D1 or D2 dopaminergic receptors. Chronic injection of the selective D1 antagonist SCH 23390 elicited a significant decrease in level of both GAD and PPE mRNA (-30%) in the dorsal striatum, whereas no significant change was observed in the ventral striatum. Chronic administration of both SCH 23390 and RU 24926, a D2 agonist, decreased the GAD and PPE mRNA levels in the dorsal (-38 and -57%, respectively) as well as in the ventral (-70 and -60%, respectively) striatum. In the ventral striatum the marked reduction of GAD mRNA levels was paralleled by a significant decrease of Vmax values of GAD enzymatic activity (-41%). These results suggest that the decrease in content of both GAD and PPE mRNA, promoted by the chronic blockade of D1 receptors, is mainly due to the action of dopamine acting on unaffected D2 receptors. Indeed, this decrease is further amplified when the D2 agonist and the D1 antagonist are administered together. Our results substantiate further the molecular mechanisms by which dopamine acts on different populations of GABAergic and enkephalinergic neurons in the two striatal regions examined.

Animals↗

PubMed1990

Anticonvulsant effects of antagonists of the N-methyl-D-aspartate receptor complex in a genetic model of epilepsy: the quaking mouse.

Tonic-clonic convulsions of mutant quaking mice were antagonized by the intracerebroventricular injection of N-methyl-D-aspartate receptor antagonists. The competitive antagonists, CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)-2-piperidine carboxylic acid), exerted a partial anticonvulsant action, with ED50S of 0.115 and 0.076 nmol, respectively. The non-competitive antagonists, TCP (1-(1-(2-thienyl)cyclohexyl)piperidine) and MK-801 [+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine), provided full protection, with ED50s of 4.49 and 2.67 nmol, respectively. The competitive antagonists elicited a marked ataxia whereas the non-competitive antagonists did not have side-effects. These results might reflect the involvement of glutamatergic neurotransmission in the convulsions of the quaking mutants.

Animals↗