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Inhibitory effects of mesocortical dopaminergic neurons on their target cells: electrophysiological and pharmacological characterization
Neurochem. Int. Vol. 20, Suppl., pp. 251S-254S,1992 Printed in Great Britain
0197-0186/92$5.00+0.00 PergamonPresspie
INHIBITORY EFFECTS OF MESOCORTICAL DOPAMINERGIC N E U R O N S ON THEIR TARGET CELLS: ELECTROPHYSIOLOGICAL A N D PHARMACOLOGICAL CHARACTERIZATION J. MANTZ, R. GoDeotrr, S. PmoT, J. GLOWlNSKIand A. M.
THIERRY
Inserm U 114, CoU~gede France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France
The medial prefrontal cortex (PFC) was defined by Rose and Woolsey (1948) as the neocortical area receiving projections from the mediodorsal thalamic nucleus (MD). It also receives both dopaminergic (DA) afferents originating from the ventral tegrnental area (VTA) and a noradrenergic (NA) innervation from the the locus eoeruleus (LC). The DA innervation of the PFC is partieulary dense in layers V and VI with only light input to the superficial layers (Bergers et al., 1976; Desearries et al., 1987). In contrast, NA fibers are distributed in all layers of the neocortex with a predilection for layer I (Audet et al., 1988). Microiontophoretic studies indicate that both DA and NA have an inhibitory effect on the spontaneous firing rate of PFC cells (Bunney and Aghajanian, 1976). More recently, using extracellular recordings in ketamine anesthetized rats, we have shown that the DA and NA ascending systems exert an inhibitory influence upon the activity of PFC neurons (Ferron et al., 1984; Mantz et a l . , 1988). However, major differences in the influences of DA and NA fibers were observed in these studies. Indeed, activation of the mesocortical DA system induced a phasic inhibition of the spontaneous firing rate of PFC neurons and blocked the excitatory responses evoked by MD stimulation or a peripheral noxious stimulus. In contrast, activation of the NA system produced a long lasting inhibition of the basal firing of PFC neurons without blocking the evoked responses, thus resulting in enhancement of the signal to noise ratio. However, since NA fibers are known to run dorsally to the VTA, it could be speculated that VTA stimulation results in coactivation of both NA and DA systems. We will first show that the inhibitory effect induced by VTA stimulation on PFC cells involves the activation of DA but not NA fibers. Moreover, we will discuss the pharmacological characteristics of the DA receptor subtype by which the inhibitory effect of the DA mesocortical system is mediated.
INHIBITORY EFFECT OF VTA STIMULATION ON PFC CELLS: EVIDENCE FOR THE INVOLVEMENT OF DOPAMINERGIC BUT NOT NORADRENERGIC FIBERS
Stimulation of the VTA at 1 Hz induces an inhibition of most cells located in layers II to IV of the PFC (Ferron et al., 1984; Peterson et al., 1987). Several lines of evidence suggest that this inhibitory effect is mediated by the activation of DA and not NA afferents. Indeed, the inhibitory effect is markedly decreased following destruction of catecholamine projections by 6-OHDA or catecholamines depletion by u-methylparatyrosine, but still occurs after selective destruction of ascending NA fibers (Figure 1). On the other hand, using a direct pharmacological approach, it had been shown that the inhibitory effect of DA applied iontophoretically in the P F C is not affected by the NA antagonists prazosin (czl), idazoxan (a2) or sotalol (~) (Burmey and Sesack, 1987). Moreover, using a similar pharmacological approach, we have also shown that iontophoretic application of the adrenergic antagonists prazosin (ctl), yohimbine (a2) or propanolol (fl) fails to reverse the inhibitory effect of DA application as well as of VTA-induced inhibition on PFC cells. In contrast, these effects are blocked by neuroleptics (Godbout et al., in preparation). These results strongly suggest that the inhibitory effect of VTA stimulation on PFC cells is not mediated by an adrenergic but rather by a DA receptor. INHIBITORY EFFECT OF VTA STIMULATION ON PFC CELLS : CHARACTERIZATION OF THE DOPAMINERGIC RECEPTOR SUBTYPE IMPLICATED
Although the D J D 2 receptor classification is widely accepted, intensive studies over the last years using pharmacological, biochemical and behavioural approaches have provided results that are in some
251S
Dopa m~nc 9t)
252S
CONTROL
100
(zMPT
6-OHDA 6-OHDA (NA+ DA) ( N A )
.1o
50
E
tD
2 ID tO
2 II
If
Fig. 1. Effect of ~MTP or 6-OHDA pretreatment on the inhibitory responses induced by VTA stimulation on the spontaneous activity of prefrontal cortical cells. 2-MPT: rats treated with a-methylparatyrosine (200 mg/kg) 18 and 2 h before the recording session. 6-OHDA (DA + NA): rats in which DA and NA ascending bundles were lesioned by 6OHDA microinjections. 6-OHDA (NA): rats in which NA ascending bundle only was lesioned by 6-OHDA microinjection into a brain site which left intact DA ascending system (from Ferron et aL, 1984). cases difficult to reconcile with the existence of only two DA receptor subtypes (see for review: Andersen et al., 1990). Classically, D t receptors act through stimulation of adenylate cyclase, whereas D 2receptors are either inhibitory or not coupled to this enzyme. Several lines of evidence also suggest that D I receptors could stimulate the hydrolysis of phosphoinositides, whilst D2 receptors might open K + or modulate Ca ++ channels and phospholipase C activity. Interestingly, pharmacological and radioligand binding studies have shown that both D~ and D2 receptors are present in the PFC although the number of D, receptors exceeds that of D 2receptors (Bockaert et al., 1977; Marchais et al., 1980). In a first attempt to characterize the DA receptor mediating the effect of VTA-stimulation in the PFC, the ability of several neuroleptics to block this inhibitory effect was analyzed (Thierry et al., 1986). The intraperitoneal injection of fluphenazine, spiroperidol or sulpiride reversed the inhibitory response elicited by VTA stimulation (Figure 2A). All these compounds are potent D 2 antagonists. In contrast, levomepromazine and pipotiazine palmitate ester were not effective. These drugs are known to act primarily on D, receptors and non DA receptors such as ~adrenoreceptors. A surprising result was obtained with the butyrophenone haloperidol (a DI and D 2 receptor blocking agent ) which failed to reverse VTA inhibitory effect in the PFC when delivered systemically (i.p. or i.v.). In contrast, the inhibitory responses induced in the Nucleus Accumbens by VTA stimu-
lation were blocked following i.p. administration o| either sulpiride or haloperidol. More recently, Sesack and Bunney (1989) analyzed the effect of selective D~ and D 2 antagonist applied iontophoretically on DAinduced inhibition. Sulpiride, a selective D_~ receptor antagonist, was found more effective than SCH 23390, a selective D, antagonist, in blocking the DA mediating response, confirming that the effect of DA is mediated by D2 rather than a D, receptor. However, only a small number of DA sensitive neurons were inhibited by the selective D2 agonist quinpirole. In order to further characterize the receptor subtype implicated in the cortical inhibitory responses, we analyzed the ability of selective D~ and D 2antagonists applied microiontophoretically to reverse VTAinduced inhibition (Goudbout et al., in preparation). The inhibitory effect was not affected by the selective D~ antagonist SCH 23390, but was reversed by (+ ,-) sulpiride in most PFC neurons tested (Figure 2B). This effect was stereospecific since the ( + )-sulpiride isomer was no effective. In addition, the inhibitory response to VTA stimulation was also reversed by two other benzamide derivatives, RIV 2093 and LUR 2366, that are known to be selective ligands of Dt/D 4 receptor subtypes (Martres et al., 1984; Sokoloffet al., 1984). These results strongly support that the inhibitory influence of the mesocortical DA system on PFC neurons is exerted via D2 receptors. Interestingly, haloperidol applied iontophoretically was also not able to antagonize the inhibitory effect of the local DA application or VTA stimulation on PFC neurons. Thus, it can be suggested that in the PFC, the DA receptor which mediates the inhibitory responses to VTA stimulation or DA local application displays most of the pharmacological characteristics of a D2 subtype, but this receptor may not be identical to D~ sites in other brain areas. CONCLUSIONS
Several lines of evidence suggest that VTA-induced inhibition in the PFC is mediated by a DA receptor rather than an adrenergic recognition site, since a and /3 adrenergic antagonists fail to block these inhibitory responses (which are reversed by DA antagonists). Moreover the inhibitory influence of the mesocortical DA system very likely mediated by a DA receptor of the D 2 subtype. The lack of effect of haloperidol suggest that the pharmacological characteristics of the D2 receptor which mediated the electrophysiological inhibitory effect of DA in the PFC may not be identical to the D2 sites in other brain regions. Additional experiments are required to determine the exact
Dopamine 90 CONTROL
253S CONTROL
tOme
FIECOVERY
15mn
50ms
Fig. 2. A: Effect of VTA stimulation on a prefrontal cortical neuron before and various times after i.p. administration of sulpiride (100 mg/kg). The inhibitory response was markedly reduced at l0 rain. and at no longer apparent 15 min. after the drug injection (from Thierry et al., 1986). B: Effect of the microiontophoretic application of ( - )sulpiride on the inhibitory response elicited by VTA stimulation on a PFC neuron. From top to bottom : basal inhibitory response to VTA stimulation; blockade of this response by microiontophoretically application of ( - )sulpiride in the PFC; recovery following discontinuation of sulpiride application. identity and pharmacological characteristics of the D2 subtype and the intracellular mechanism of DAinduced inhibition in the PFC. A better understanding of the functional implication of this particular 0 2 receptor might be of importance, since D A neurotransmission in the P F C is basically involved in the prominent role played by this cortical area in the control of locomotor activity, regulation of emotional states and cognitive processes. REFERENCES
Andersen, P.H., Gingrich, J.A., Bates, M.D., Dearry, A., Falardeau, P., Senogles, S.E. and Caron, M.G. (1990). Dopamine receptors subtypes: beyond the DJD2 classification. Trends in Neuroscience, 11,231-236. Audet, M.A., Doucet, G., Oleskevich, S. and Descarries, L. (1988). Quantified regional and laminar distribution of the noradrenaline innervation in the anterior half of the adult rat cerebral cortex. J. Comp. Neur. 274, 307-318. Berger, B., Thierry, A.M., Tassin, J.P. and Moyne, M.A. (1976). Dopaminergic innervation of the rat prefrontal
cortex: a fluorescence histochemical study. Brain Res., 106, 215--222. Bockaert, J., Tassin, 3.P. Thierry, A.M., Glowinski, J. and Pr~mont, J.(1977). Characteristics of ~adrenergic sensitive adenylate cyclase in the frontal cortex of the rat: Comparative effects of neuroleptics on frontal cortex and striatal dopamine sensitive adenylate cyclase. Brain Res., 122, 71-86. Bunney, B.S. and Aghajanian, G.K. 0976). Dopamine and norephinephrine innervated cells in the rat prefrontal cortex: Pharmacological differentiation using microjontophoretic tecniques. Life Sci., 19, 1783-1792. Bunney, B.S. and Sesack, S.R. (1987). Electrophysiological identification and pharmacological characterization of dopamine sensitive neurons in the rat prefrontal cortex. In: Neurophysiology of dopaminergic systems. (eds L.A. Chiodo and A.S. Freeman). Lakeshore Publishing Company, Grosse Point. Descarries, L., Lernay, B., Doucet, G., and Berger, B. (1987). Regional and laminar density of the dopamine innervationin the adult rat cerebral cortex. Neuroscience, 21,807-824. Ferron, A., Thierry, A.M., Le Douarin, C. and Glowinski, J. (1984). Inhibitory influence of the mesocortical
254S
Dopamine 90
dopaminergic system on spontaneous activity or excitatory responses induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex. Brain Res., 302, 257-265. Mantz, J., Milla, C., Glowinski, J. and Thierry, A.M. (1988). Differential effects of ascending neurons containing dopamine and noradrenaline in the control of spontaneous activity and of evoked responses in the rat prefrontal cortex. Neuroscience, 27, 517-526. Marchais, D., Tassin, J.P. and Bockaert, J. (1980). Dopaminergic component of [3H]spiroperidol binding in the rat anterior cerebral cortex. Brain Res., 183,235--240. Martres, M.P., Sokoloff, P., Delandre, M., Schwartz, J.C.. Protais, P. and Costentin, J. (1984). Selection of dopamine antagonists discriminating various behavioural responses and radioligand binding sites. NaunynSchmiedeberg's Arch. Pharmacol., 325, 102-115. Rose. J.E. and Woolsey, C.N. (1948). The orbitofrontal
cortex and its connections with the mediodorsal nucleus in rabbit, sheep and cat. Res. Publ. Assoc; Nerw Ment. Dis., 27, 210-232. Sesack, S.R. and Bunney, B.S: (1989). Pharmacological characterization of the receptor mediating electrophysiological responses to dopamine in the rat medial prefrontal cortex: a microiontophoretic study. J. Pharmacol. Exp. Ther., 248, 1323-1333. Sokoloff, P., Martres, M.P., Delandre, M., Redouane, K. and Schwartz, J.C. (1984). [3H]domperidone binding sites differ in rat striatum and pituitary. NaunynSchmiedeberg's Arch~ Pharrnacol., 327, 221-227. Thierry, A.M., Le Douarin, C., Penit, J., Ferron, A. and Glowinski, J. (1986).Variation in the ability of neuroleptics to block the inhibitory influence of dopaminergic neurons on the activity of cells in the rat prefrontal cortex. Brain Res. Bull., 16, 155-160
0197-0186/92$5.00+0.00 PergamonPresspie
INHIBITORY EFFECTS OF MESOCORTICAL DOPAMINERGIC N E U R O N S ON THEIR TARGET CELLS: ELECTROPHYSIOLOGICAL A N D PHARMACOLOGICAL CHARACTERIZATION J. MANTZ, R. GoDeotrr, S. PmoT, J. GLOWlNSKIand A. M.
THIERRY
Inserm U 114, CoU~gede France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France
The medial prefrontal cortex (PFC) was defined by Rose and Woolsey (1948) as the neocortical area receiving projections from the mediodorsal thalamic nucleus (MD). It also receives both dopaminergic (DA) afferents originating from the ventral tegrnental area (VTA) and a noradrenergic (NA) innervation from the the locus eoeruleus (LC). The DA innervation of the PFC is partieulary dense in layers V and VI with only light input to the superficial layers (Bergers et al., 1976; Desearries et al., 1987). In contrast, NA fibers are distributed in all layers of the neocortex with a predilection for layer I (Audet et al., 1988). Microiontophoretic studies indicate that both DA and NA have an inhibitory effect on the spontaneous firing rate of PFC cells (Bunney and Aghajanian, 1976). More recently, using extracellular recordings in ketamine anesthetized rats, we have shown that the DA and NA ascending systems exert an inhibitory influence upon the activity of PFC neurons (Ferron et al., 1984; Mantz et a l . , 1988). However, major differences in the influences of DA and NA fibers were observed in these studies. Indeed, activation of the mesocortical DA system induced a phasic inhibition of the spontaneous firing rate of PFC neurons and blocked the excitatory responses evoked by MD stimulation or a peripheral noxious stimulus. In contrast, activation of the NA system produced a long lasting inhibition of the basal firing of PFC neurons without blocking the evoked responses, thus resulting in enhancement of the signal to noise ratio. However, since NA fibers are known to run dorsally to the VTA, it could be speculated that VTA stimulation results in coactivation of both NA and DA systems. We will first show that the inhibitory effect induced by VTA stimulation on PFC cells involves the activation of DA but not NA fibers. Moreover, we will discuss the pharmacological characteristics of the DA receptor subtype by which the inhibitory effect of the DA mesocortical system is mediated.
INHIBITORY EFFECT OF VTA STIMULATION ON PFC CELLS: EVIDENCE FOR THE INVOLVEMENT OF DOPAMINERGIC BUT NOT NORADRENERGIC FIBERS
Stimulation of the VTA at 1 Hz induces an inhibition of most cells located in layers II to IV of the PFC (Ferron et al., 1984; Peterson et al., 1987). Several lines of evidence suggest that this inhibitory effect is mediated by the activation of DA and not NA afferents. Indeed, the inhibitory effect is markedly decreased following destruction of catecholamine projections by 6-OHDA or catecholamines depletion by u-methylparatyrosine, but still occurs after selective destruction of ascending NA fibers (Figure 1). On the other hand, using a direct pharmacological approach, it had been shown that the inhibitory effect of DA applied iontophoretically in the P F C is not affected by the NA antagonists prazosin (czl), idazoxan (a2) or sotalol (~) (Burmey and Sesack, 1987). Moreover, using a similar pharmacological approach, we have also shown that iontophoretic application of the adrenergic antagonists prazosin (ctl), yohimbine (a2) or propanolol (fl) fails to reverse the inhibitory effect of DA application as well as of VTA-induced inhibition on PFC cells. In contrast, these effects are blocked by neuroleptics (Godbout et al., in preparation). These results strongly suggest that the inhibitory effect of VTA stimulation on PFC cells is not mediated by an adrenergic but rather by a DA receptor. INHIBITORY EFFECT OF VTA STIMULATION ON PFC CELLS : CHARACTERIZATION OF THE DOPAMINERGIC RECEPTOR SUBTYPE IMPLICATED
Although the D J D 2 receptor classification is widely accepted, intensive studies over the last years using pharmacological, biochemical and behavioural approaches have provided results that are in some
251S
Dopa m~nc 9t)
252S
CONTROL
100
(zMPT
6-OHDA 6-OHDA (NA+ DA) ( N A )
.1o
50
E
tD
2 ID tO
2 II
If
Fig. 1. Effect of ~MTP or 6-OHDA pretreatment on the inhibitory responses induced by VTA stimulation on the spontaneous activity of prefrontal cortical cells. 2-MPT: rats treated with a-methylparatyrosine (200 mg/kg) 18 and 2 h before the recording session. 6-OHDA (DA + NA): rats in which DA and NA ascending bundles were lesioned by 6OHDA microinjections. 6-OHDA (NA): rats in which NA ascending bundle only was lesioned by 6-OHDA microinjection into a brain site which left intact DA ascending system (from Ferron et aL, 1984). cases difficult to reconcile with the existence of only two DA receptor subtypes (see for review: Andersen et al., 1990). Classically, D t receptors act through stimulation of adenylate cyclase, whereas D 2receptors are either inhibitory or not coupled to this enzyme. Several lines of evidence also suggest that D I receptors could stimulate the hydrolysis of phosphoinositides, whilst D2 receptors might open K + or modulate Ca ++ channels and phospholipase C activity. Interestingly, pharmacological and radioligand binding studies have shown that both D~ and D2 receptors are present in the PFC although the number of D, receptors exceeds that of D 2receptors (Bockaert et al., 1977; Marchais et al., 1980). In a first attempt to characterize the DA receptor mediating the effect of VTA-stimulation in the PFC, the ability of several neuroleptics to block this inhibitory effect was analyzed (Thierry et al., 1986). The intraperitoneal injection of fluphenazine, spiroperidol or sulpiride reversed the inhibitory response elicited by VTA stimulation (Figure 2A). All these compounds are potent D 2 antagonists. In contrast, levomepromazine and pipotiazine palmitate ester were not effective. These drugs are known to act primarily on D, receptors and non DA receptors such as ~adrenoreceptors. A surprising result was obtained with the butyrophenone haloperidol (a DI and D 2 receptor blocking agent ) which failed to reverse VTA inhibitory effect in the PFC when delivered systemically (i.p. or i.v.). In contrast, the inhibitory responses induced in the Nucleus Accumbens by VTA stimu-
lation were blocked following i.p. administration o| either sulpiride or haloperidol. More recently, Sesack and Bunney (1989) analyzed the effect of selective D~ and D 2 antagonist applied iontophoretically on DAinduced inhibition. Sulpiride, a selective D_~ receptor antagonist, was found more effective than SCH 23390, a selective D, antagonist, in blocking the DA mediating response, confirming that the effect of DA is mediated by D2 rather than a D, receptor. However, only a small number of DA sensitive neurons were inhibited by the selective D2 agonist quinpirole. In order to further characterize the receptor subtype implicated in the cortical inhibitory responses, we analyzed the ability of selective D~ and D 2antagonists applied microiontophoretically to reverse VTAinduced inhibition (Goudbout et al., in preparation). The inhibitory effect was not affected by the selective D~ antagonist SCH 23390, but was reversed by (+ ,-) sulpiride in most PFC neurons tested (Figure 2B). This effect was stereospecific since the ( + )-sulpiride isomer was no effective. In addition, the inhibitory response to VTA stimulation was also reversed by two other benzamide derivatives, RIV 2093 and LUR 2366, that are known to be selective ligands of Dt/D 4 receptor subtypes (Martres et al., 1984; Sokoloffet al., 1984). These results strongly support that the inhibitory influence of the mesocortical DA system on PFC neurons is exerted via D2 receptors. Interestingly, haloperidol applied iontophoretically was also not able to antagonize the inhibitory effect of the local DA application or VTA stimulation on PFC neurons. Thus, it can be suggested that in the PFC, the DA receptor which mediates the inhibitory responses to VTA stimulation or DA local application displays most of the pharmacological characteristics of a D2 subtype, but this receptor may not be identical to D~ sites in other brain areas. CONCLUSIONS
Several lines of evidence suggest that VTA-induced inhibition in the PFC is mediated by a DA receptor rather than an adrenergic recognition site, since a and /3 adrenergic antagonists fail to block these inhibitory responses (which are reversed by DA antagonists). Moreover the inhibitory influence of the mesocortical DA system very likely mediated by a DA receptor of the D 2 subtype. The lack of effect of haloperidol suggest that the pharmacological characteristics of the D2 receptor which mediated the electrophysiological inhibitory effect of DA in the PFC may not be identical to the D2 sites in other brain regions. Additional experiments are required to determine the exact
Dopamine 90 CONTROL
253S CONTROL
tOme
FIECOVERY
15mn
50ms
Fig. 2. A: Effect of VTA stimulation on a prefrontal cortical neuron before and various times after i.p. administration of sulpiride (100 mg/kg). The inhibitory response was markedly reduced at l0 rain. and at no longer apparent 15 min. after the drug injection (from Thierry et al., 1986). B: Effect of the microiontophoretic application of ( - )sulpiride on the inhibitory response elicited by VTA stimulation on a PFC neuron. From top to bottom : basal inhibitory response to VTA stimulation; blockade of this response by microiontophoretically application of ( - )sulpiride in the PFC; recovery following discontinuation of sulpiride application. identity and pharmacological characteristics of the D2 subtype and the intracellular mechanism of DAinduced inhibition in the PFC. A better understanding of the functional implication of this particular 0 2 receptor might be of importance, since D A neurotransmission in the P F C is basically involved in the prominent role played by this cortical area in the control of locomotor activity, regulation of emotional states and cognitive processes. REFERENCES
Andersen, P.H., Gingrich, J.A., Bates, M.D., Dearry, A., Falardeau, P., Senogles, S.E. and Caron, M.G. (1990). Dopamine receptors subtypes: beyond the DJD2 classification. Trends in Neuroscience, 11,231-236. Audet, M.A., Doucet, G., Oleskevich, S. and Descarries, L. (1988). Quantified regional and laminar distribution of the noradrenaline innervation in the anterior half of the adult rat cerebral cortex. J. Comp. Neur. 274, 307-318. Berger, B., Thierry, A.M., Tassin, J.P. and Moyne, M.A. (1976). Dopaminergic innervation of the rat prefrontal
cortex: a fluorescence histochemical study. Brain Res., 106, 215--222. Bockaert, J., Tassin, 3.P. Thierry, A.M., Glowinski, J. and Pr~mont, J.(1977). Characteristics of ~adrenergic sensitive adenylate cyclase in the frontal cortex of the rat: Comparative effects of neuroleptics on frontal cortex and striatal dopamine sensitive adenylate cyclase. Brain Res., 122, 71-86. Bunney, B.S. and Aghajanian, G.K. 0976). Dopamine and norephinephrine innervated cells in the rat prefrontal cortex: Pharmacological differentiation using microjontophoretic tecniques. Life Sci., 19, 1783-1792. Bunney, B.S. and Sesack, S.R. (1987). Electrophysiological identification and pharmacological characterization of dopamine sensitive neurons in the rat prefrontal cortex. In: Neurophysiology of dopaminergic systems. (eds L.A. Chiodo and A.S. Freeman). Lakeshore Publishing Company, Grosse Point. Descarries, L., Lernay, B., Doucet, G., and Berger, B. (1987). Regional and laminar density of the dopamine innervationin the adult rat cerebral cortex. Neuroscience, 21,807-824. Ferron, A., Thierry, A.M., Le Douarin, C. and Glowinski, J. (1984). Inhibitory influence of the mesocortical
254S
Dopamine 90
dopaminergic system on spontaneous activity or excitatory responses induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex. Brain Res., 302, 257-265. Mantz, J., Milla, C., Glowinski, J. and Thierry, A.M. (1988). Differential effects of ascending neurons containing dopamine and noradrenaline in the control of spontaneous activity and of evoked responses in the rat prefrontal cortex. Neuroscience, 27, 517-526. Marchais, D., Tassin, J.P. and Bockaert, J. (1980). Dopaminergic component of [3H]spiroperidol binding in the rat anterior cerebral cortex. Brain Res., 183,235--240. Martres, M.P., Sokoloff, P., Delandre, M., Schwartz, J.C.. Protais, P. and Costentin, J. (1984). Selection of dopamine antagonists discriminating various behavioural responses and radioligand binding sites. NaunynSchmiedeberg's Arch. Pharmacol., 325, 102-115. Rose. J.E. and Woolsey, C.N. (1948). The orbitofrontal
cortex and its connections with the mediodorsal nucleus in rabbit, sheep and cat. Res. Publ. Assoc; Nerw Ment. Dis., 27, 210-232. Sesack, S.R. and Bunney, B.S: (1989). Pharmacological characterization of the receptor mediating electrophysiological responses to dopamine in the rat medial prefrontal cortex: a microiontophoretic study. J. Pharmacol. Exp. Ther., 248, 1323-1333. Sokoloff, P., Martres, M.P., Delandre, M., Redouane, K. and Schwartz, J.C. (1984). [3H]domperidone binding sites differ in rat striatum and pituitary. NaunynSchmiedeberg's Arch~ Pharrnacol., 327, 221-227. Thierry, A.M., Le Douarin, C., Penit, J., Ferron, A. and Glowinski, J. (1986).Variation in the ability of neuroleptics to block the inhibitory influence of dopaminergic neurons on the activity of cells in the rat prefrontal cortex. Brain Res. Bull., 16, 155-160