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Accelerated Resensitization of the D 1 Dopamine Receptor-Mediated The Journal of Neuroscience, October 1994, 74(10): 6260-6266 Accelerated Resensitization of the D 1 Dopamine Receptor-mediated Response in Cultured Cortical and Striatal Neurons from the Rat: Respective Role of CY1 -Adrenergic and /U-methybaspartate Receptors Fabrice Trovero, Philippe Marin, Jean-PO1 Tassin, JoQl Premont, and Jacques Glowinski INSERM U 114, Chaire de Neuropharmacologie, College de France, 75231 Paris Cedex, France As previously shown in vivo, noradrenergic and glutama- cortex. In the rat, bilateral electrolytic lesions of the mesence- tergic neurons can regulate the denervation supersensitivity phalic ventral tegmental area induce a complex and permanent of Dl dopaminergic (DA) receptors in the rat prefrontal cor- behavioral syndrome characterized by a locomotor hyperactiv- tex and striatum respectively. Therefore, the effects of meth- ity and the incapacity of the animal to focalize its attention (Le oxamine (an al-adrenergic agonist) and glutamate on the Moal et al., 1969). Some of the behavioral deficits observed in resensitization of Dl DA receptors were investigated in cul- the lesioned animals, particularly the locomotor hyperactivity, tured cortical and striatal neurons from the embryonic rat. have been attributed for a large part to the selective destruction In the presence of sulpiride and propranolol, DA stimulated of the cortical dopaminergic (DA) innervation (Tassin et al., the Dl DA receptor-mediated conversion of 3H-adenine into 1978). This locomotor hyperactivity was markedly reduced in 3H-cAMP in both intact cortical and striatal cells and these rats with 6-hydroxydopamine (6-OHDA) lesions,which destroy responses were markedly desensitized in cells preexposed not only the ascendingDA neurons but also the ascendingnor- for 15 min to DA (50 AM). The complete recovery of the Dl adrenergicfibers passingnear the ventral tegmental area (Tassin DA response was more rapid in striatal (15 min) than in et al., 1982). (Y1 -Adrenergic receptors sensitive to the (Y1 antag- cortical (80 min) neurons. Methoxamine accelerated the re- onist prazosin seemto play a prominent role in the permissive sensitization of the Dl response in cortical but not in striatal effect of cortical noradrenalineon the appearanceof behavioral neurons. The effect of the al -adrenergic agonist in cortical deficits in rats with ventral tegmental area electrolytic lesions. neurons was blocked by prazosin and chlorethylclonidine. Indeed, in these lesioned animals, the peripheral injection of In contrast, glutamate accelerated the resensitization of the prazosin immediately suppressed locomotor hyperactivity Dl response in striatal but not in cortical neurons and the (Trovero et al., 1992a). The effect of prazosin appears to be effect observed in striatal neurons was totally blocked by mediated at the cortical level since high affinity binding sites 2-amino-5-phosphonovaleric acid, an NMDA receptor antag- for prazosin were found in the prefrontal cortex, and the cortical onist. Protein kinase C was shown to be involved in the al - application of prazosin abolished the increased locomotor ac- adrenergic-induced resensitization of the cortical Dl re- tivity evoked by amphetamine application into the nucleus ac- sponse but not in the glutamate-evoked resensitiration of cumbens (Blanc et al., 1993). In addition, the denervation su- the striatal Dl response. Finally, for comparison, similar ex- persensitivity of cortical DA-sensitive adenylate cyclaseobserved periments were performed on 8-adrenergic receptors using in rats with electrolytic lesionsof the ventral tegmental area was isoproterenol (1 PM) as an agonist. Methoxamine did not prevented by the concomitant destruction of the cortical nor- modify the resensitization of the B-adrenergic response in adrenergicinnervation (Tassin et al., 1982, 1986). Similarly, the cortical neurons, but glutamate accelerated the resensiti- denervation supersensitivity of the cortical DA-sensitive ad- zation of this response in striatal neurons. enylate cyclase was not seen in rats with bilateral [Key words: cortical neurons, striatal neurons, D 1 DA re- 6-hydroxydopamine (6-OHDA) lesionsof the ventral tegmental ceptors, heterologous resensitization, a 1 -adrenergic recep- area (Tassin et al., 1982). tors, NMDA receptors] Together, thesebehavioral and biochemical observations led us in the present study to determine whether the stimulation of Several years ago, we provided behavioral and biochemical ev- 011-adrenergic receptors could regulate the sensitivity of the D 1 idence for an interaction between the mesocorticoprefrontal do- DA-induced formation of CAMP (Dl response)in intact cortical paminergic (DA) neurons and the noradrenergic neurons orig- neurons from rat embryos in primary culture. For this purpose, inating from the locus coeruleus and innervating the cerebral we first investigated the effect of an (~1agonist, methoxamine, on the recovery of the D 1 responsefollowing a short-term DA- induced desensitization. For comparison, similar experiments Received Jan. 13, 1994; revised Apr. 14, 1994; accepted Apr. 21, 1994. were performed on cultured striatal neurons. Following this, the This work was supported by grants from Institut National de la Sante et de la Recherche MCdicale (INSERM) and RhBne Poulenc Rarer. We thank Robert effects of glutamate on the rate of resensitization of the cortical Williams for critical reading of the manuscript. and striatal Dl responseswere also analyzed since the cerebral Correspondence should be addressed to Fabrice Trovero, INSERM U 114, Chaire de Neuropharmacologie, Coll&e de France, 11 Place Marcelin Berthelot, cortex is rich in glutamatergic neurons and the corticostriatal 7523 1 Paris Cedex, France. glutamatergic innervation has been shown to contribute to the Copyright 0 1994 Society for Neuroscience 0270-6474/94/146280-09$05.00/O regulation of the denervation supersensitivity of striatal D 1 DA The Journal of Neuroscience, October 1994, f4(10) 6281 more than 95% of the cells were immunocytochemically defined as cortical neurons neurons according to El Etr et al. (1989). ‘H-CAMP assay 1000 r Cells cultured in 24 well culture dishes were incubated for 2 hr with 2-‘H-adenine (27 Ci/mmol, Amersham, 2 j&i per well containing 0.5 ; ; ml of culture medium). Desensitization procedure. DA (50 PM) was added to the culture me- dium 15 min before the end of 3H-adenine incorporation, in the presence of both propranolol(1 NM) and sulpiride (50 PM) to prevent &adrenergic and D2 DA receptor stimulation. Resensitization procedure. After removal of the desensitization me- dium, neurons were washed once with 0.5 ml of Krebs’ phosphate buffer (in mM: NaCl, 120; NaH,PO,, 15.6; KCI, 4.8; MgSO,, 1.2; CaCl,, 1.2; **glucose, 33.3; pH 7.4), and then incubated for the indicated time in 0.5 ml of the same medium containing appropriate agonists and/or antag- onists. 3H-cAMP measurement. After removal of the resensitization medi- um, cells were incubated for 5 min in 0.5 ml of Krebs’ phosphate buffer containing DA (50 PM), sulpiride (5 PM), propranolol (1 PM), and the nonselective inhibitor of phosphodiesterases, 3-isobutyl- 1 -methylxan- thine (IBMX: 1 mtvt). The incubation was stonned bv reolacina the medium with 0.5 mi of ice-cold trichloroacetic acid (I?%).- Cells-were 0 then scraped and 100 ~1 of medium containing 1% SDS, 50 mM Tris- HCI, 3 mM ATP, 3 mM CAMP, pH 7.4, was added to the samples. After Dopamine + + I centrifugation (10 min at 12000 x g), the labeled ATP and CAMP Sulpiride + + present in 0.5 ml of supematant were separated according to the pro- +cedure described by Salomon et al. (1974). Radioactivity was estimated Propranolol + in 10 ml of Aquasol- (New England Nuclear-Du Pont) with a beta +scintillation counter. Results, calculated as percentage of conversion of Yohimbine +)H-ATP into 3H-cAMP by (‘H-CAMP x lOO)/CH-ATP + ‘H-CAMP), SCH 23390 were expressed as a percentage of the basal values obtained without agonists. Figure 1. Pharmacological characterization of the dopamine-induced production of CAMP in cortical neurons. Cortical neurons from+ rat Inositol phospholipid turnover assay embryos were cultured for 6 din serum-free medium and then incubated for 2 hr with 3H-adenine. DA (50 PM) and antagonists (sulpiride, 5 PM; Neurons were incubated for 24 hr in culture medium supplemented propranolol, 1 PM; yohimbine, 1 PM; SCH 23390, 0.2 PM) were then with 1 &/well of myo-3H-inositol. Cells were then preincubated for added to the medium in the presence of IBMX (1 mM) and incubated 10 min in Krebs’ phosphate buffer supplemented with LiCl (10 mM). for 5 min. The 3H-cAMP that accumulated in cells was then estimated. Methoxamine (100 PM) or glutamate (100 PM) was then added for 20 Neither sulpiride nor propranolol nor yohimbine significantly modified min. The incubation was stopped by adding successively 200 pl of 0.1% the response obtained with DA alone. Results are the mean ? SEM of Triton X-100/0.1 M NaOH, 200 ~1 of 0.1% Triton X-100/0.1 M HCl, values obtained from triplicate in a typical experiment. *, significantly and 500 ~1 ofwater. Cells were then scraped, and )H-inositol phosphates different (p < 0.05, Student’s t test) from basal values; **, significantly were extracted and estimated according to the procedure of El Etr et different (p < 0.05, Student’s t test) from the DA-evoked response. Four al., (1989). other experiments performed with different cultures provided similar results. Results Desensitization of the DI DA-induced formation of CAMP in cortical neurons by preexposureto DA receptors (Hervt et al., 1989). Finally, in order to demonstrate As illustrated in Figure 1, a 5 min exposure to DA stimulated further the specificity of the effects observed with methoxamine and glutamate, parallel experiments were made on the resen- the formation of 3H-cAMP in cortical neurons prelabeled with 3H-adenine(EC,, = 1.5 * 0.2 PM, mean + SEM calculated from sitization of the /3-adrenergic-inducedformation of CAMP @- three independent experiments, n = 3). Most of the responseto adrenergic response),following isoproterenol-induced desensi- DA (50 PM) was blocked by the Dl antagonist SCH 23390 (0.2 tization of p-adrenergic receptors in cortical and striatal neu- rons.
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