Mesocortical DopamineNeurotensin Neurons Possible Opposite Role of Noradrenergic Pathways on Heteroregulations of Dopamine (D1) and Neurotensin Postsynaptic Receptors in the Rat Prefrontal Cortex J. P. TASSIN,a F. TROVERO, D. HERVE, G. BLANC, AND J. GLOWINSKI INSERM U.114 Collkge de France 75005 Paris, France
The rat prefrontal cortex receives a dopaminergic (DA) innervation that arises mainly from cell bodies located in the rostromedial part of the ventral tegmental area (VTA).' This cortical DA innervation is particularly dense in the deeper layers of the cortex.2.3 In 1984, Hokfelt and his colleagues have shown that some DA cell bodies located in the VTA contain, in addition to DA, another neurotransmitter, neurotensin (NT).4 It has been proposed that these cell bodies correspond mostly to mesocortical DA neurons because an injection of 6-OHDA into the VTA induced a dramatic decrease of NT levels in the prefrontal cortex.5 Also located in these cortical areas are DA receptors coupled to adenylate cyclase (DI receptor^).^.^ The topographical distribution of these DI receptors in the anterior cerebral cortex closely matches that of DA terminals, and lesion studies have indicated that these receptors are located postsynaptically on cortical cells.*-9Moreover, within the cortical projection field of the mixed DA-NT fibers, localizations of DA (DI) receptors and NT-binding sites are strikingly similar. I O J ~ On the other hand, noradrenergic (NA) fibers, which originate in the locus ceruleus, are distributed more extensively in the cortical superficial layers, although they also are present in the DA-NT projection field.I*J Several cells, distributed in this cortical DA area and sensitive to microiontophoretic application of DA, are also sensitive to NA,l4 suggesting that DA/NA interactions may occur in this anterior part of the cerebral cortex. In this presentation, we will first describe evidence of colocalization of DA and NT in the DA neurons that innervate the rat prefrontal cortex. Second, an analysis of the role of NA neurons on the regulation of the cortical DA D I receptors postsynaptic to these mixed DA-NT mesocortical neurons Will be presented. We will ina
Address for correspondence: INSERM U.114, College de France, 11, Place Marcelin Berthelot,
75005 Paris, France. 205
206
ANNALS NEW YORK ACADEMY OF SCIENCES
dicate that the permissive role of NA fibers on the development of the denervation supersensitivity of cortical DI receptors seems related to the stimulation by NA of a specific type of al-adrenergic receptor. Many reports have indeed provided evidence for interactions between NA and DA transmissions in the central nervous system. 15-'* These interactions, which have been demonstrated by biochemical analysis, seem to have pharmacological and behavioral consequences. Accordingly, it will be shown that the stimulation by NA of this a,-adrenergic receptor may be responsible for the expression of behavioral deficits induced by destruction of the DA-VTA neurons, particularly the mixed mesocortical DA-NT neurons. Finally, a putative role of NA neurons on the respective modifications of the densities of cortical DI receptors and NT binding sites following either electrolytic or chemical (6-OHDA) destruction of the mixed DA-NT mesocortical neurons will be proposed.
EXTENSIVE COLOCALIZATION OF NEUROTENSIN WITH DOPAMINE IN RAT MESOCORTICAL DA NEURONS Following the demonstration by Hokfelt et al. in 19844 of the presence of NT in some neurons of the VTA, we injected 6-OHDA into the VTA and measured the levels of DA and NT in microdiscs of tissues taken from different DA forebrain areas. Results indicated that, although DA contents in the nucleus accumbens and the anterior striatum were decreased by 95 and 78%, respectively, no significant change in NT levels could be obtained in these structures two to three weeks after the lesions. In the prefrontal cortex, however, NT and DA levels were both affected in similar proportions (respectively, 69 and 82% for NT and DA).5 Because 6-OHDA injections into the VTA affect not only DA neurons but also NA ascending fibers,9 this result was verified on animals injected with 6-OHDA into the lateral part of the pedunculus cerebellaris superior in order to specifically destroy NA neurons. Three weeks after these injections, NA levels into the prefrontal cortex were lesioned by 99%, but neither cortical DA nor NT contents were decreased.5 These results were in good agreement with those of Seroogy et al. who had indicated that some presumed DA neurons containing both NT and cholecystokinin were projecting to the prefrontal cortex.19 Our biochemical data did not provide any information, however, on the proportion of DA fibers innervating the prefrontal cortex and containing NT. To answer this question, attempts were made to visualize NT and tyrosine hydroxylase, the first enzyme of DA synthesis, by immunohistochemistry using cortical tissue sections of rats previously deprived of their ascending NA fibers. We first observed that varicose fibers stained with NT- and tyrosine hydroxylasespecific antisera displayed a similar distribution in the anterior cerebral cortex (FIG. 1). Successive stainings of the same section were then performed according to the elutionrestaining procedure of Tramu et a1.20 Cortical beaded fibers were stained first for NT and then, following decolorization and antibody elution, for tyrosine hydroxylase. In these conditions, all fibers stained for tyrosine hydroxylase, which are located in deep layers of the anteromedial cortex and in the rhinal fissure as well, exhibited NT immunoreactivity. Therefore, our combined immunohistochemical and biochemical data strongly suggest that most, if not all, mesencephalic DA neurons that innervate the prefrontal cortex in the rat contain NT. These results have been recently confirmed by two teams.21.22In addition, Von Euler et al.2' found some DA nerve terminals labeled by an antiserum against NT
TASSIN el al. : MESOCORTICAL DA/NT NEURONS
207
FIGURE 1. Comparison of the topographical distributions of DA nerve terminals, NT nerve terminals, and D I and NT binding sites in the rat anterior cerebral cortex. (a) Distribution of DA nerve terminals as drawn by Lindvall er al.46 (b) Distribution of NT nerve terminals as obtained by Tramu in the course of the study with Studler er aL5 (c) Distribution of [3H]SCH 23390 (2 nM) binding sites in presence of unlabeled spiroperidol (10 nM) in order to avoid labeling of 5-HT2 binding sites. (d) Distribution of 125I-labeled NT (0.1 nM) binding sites. Background differences in c and d are due to the different specific activities of the two ligands used (70 and 2,000 Ci/rnmole, respectively, for r3H]SCH 23390 and 125I-labeled NT).
in the cingulate, piriform, and entorhinal cortices and in the cortical and deep nuclei of the amygdaloid cortex. They could not demonstrate any colocalization in the caudateputamen, nucleus accumbens, and tuberculum olfactorium. Febvret et al. 22 have, however, determined that DA projections to the superficial layers of the anterior cingulate, motor, retrosplenial, and visual cortices were not colocalized with NT, while mixed DA-NT fibers could be demonstrated in layer VI of whole cerebral cortex and in layers 1-111 of the medial and entorhinal cortex. Moreover, these latter authors found only
208
ANNALS NEW YORK ACADEMY OF SCIENCES
a 40% colocalization between NT and tyrosine hydroxylase in the DA nerve terminals of the rat prefrontal cortex.22 Two reasons at least may explain quantitative discrepancies between their results and our data: First, the antisera raised against tyrosine hydroxylase or NT may be more or less sensitive from one laboratory to another and second, most importantly, there may be strain differences. Indeed, while Febvret et al.22 used Wistar rats, our data5 and those of Von Euler ef al.21 were obtained with Sprague-Dawley rats. In fact, species differences seem even more important. Gaspar et al. have recently reported that they could not find any colocalization between tyrosine hydroxylase and NT in prefrontal cortex of human brain.23 Even in zones where tyrosine hydroxylase and NT innervations were abundant, such as the anterior cingulate cortex or area 32, double-labeling procedures disclosed no colocalized fibers. Nevertheless, the colocalization of DA and NT in the rat mesocortical neurons prompted us to study their cortical postsynaptic receptors. Concerning the DA receptors, biochemical studies performed on microdiscs of cortical tissue indicated that DI receptors, besides their higher density than D2 receptors, presented a topographical distribution closer to the localization of DA nerve terminals than that of D2 binding sites.8.24.25 This was later confirmed by in uitro autoradiography performed in presence of 2 nM [3H]SCH 23390, a specific antagonist of DI receptors, and 10 nM spiroperidol, in order to avoid any labeling of 5-HT2 binding sites10.26(FIG.1). In the following experiments, we will therefore focus on DI receptors. The topographical distribution of the cortical NT binding sites was obtained by autoradiography of 0.1 nM iodine-125-labeled NT2627 and indicated interesting similarities with the distribution of DI receptors and DA-NT nerve terminals (FIG. 1). As will be shown below, destruction of mixed mesocortical DA-NT neurons did not induce any decrease in labeling of either [3H]SCH 23390 or l2Wabeled NT binding sites, suggesting that these sites were not localized on afferent DA-NT nerve terminals. Further experiments were then designed in order to study regulation of these postsynaptic receptors.
INFLUENCE OF THE CORTICAL NORADRENERGIC INNERVATION ON THE REGULATION OF D1 RECEPTORS IN THE PREFRONTAL CORTEX Effects of Noradrenergic Innervation on Cortical DI Receptors The destruction of mixed mesocortical DA-NT neurons were first obtained by bilateral 6-OHDA injections into the VTA. These lesions did not produce any change in the activity of the prefronto-cortical Ddinked adenylate cyclase nor in the density in ['HISCH 23390 binding sites in the prefrontal cortex, even though DA cortical levels were reduced by more than 90%.9*Z6Besides the postsynaptic localization of cortical DI receptors, these results indicated further that, in the central nervous system, even the total destruction of a homogeneous population of afferent presynaptic fibers does not necessarily produce denervation hypersensitivity of the corresponding postsynaptic r e ~ e p t o r s . ~ However, . ~ ~ ~ ~ 9 when the VTA lesions were performed electrolytically, the DA-sensitive adenylate cyclase activity, measured on tissue homogenates,
TASSIN et al.: MESOCORTICAL DA/NT NEURONS
209
and the density of DI receptors, obtained by quantitative autoradiography, presented increases of +38% and +20%,respectively.26.mThe significant differences observed between the increases of the cortical DA-sensitive adenylate cyclase activity and of the density of cortical DI binding sites following the electrolytic lesion of the VTA may be related to the fact that variations of adenylate cyclase activity indicate not only changes in the density of receptors but also modifications in coupling between receptor and transducing subunits. It is therefore possible that electrolytic lesions of the VTA in the prefrontal cortex induce a higher content, or an increased availability, of a transducing factor such as the protein G as. Since electrolytic VTA lesions spare the cortical NA innervation whereas 6-OHDA VTA lesions destroy ascending NA fibers that pass near the location of the DA cells,Q the destruction of the cortical NA innervation could be responsible for the lack of development of denervation supersensitivity of cortical DI receptors in animals lesioned in the VTA with 6-OHDA. A good correlation was found between the extent of damage to NA fibers and the reduction of the expected supersensitivity of cortical DI receptors (estimated on electrolytically lesioned rats).” This permissive role of ascending NA fibers originating in the locus ceruleus in the appearance of denervation supersensitivity of cortical DI receptors was also supported by experiments conducted on rats with simultaneous bilateral electrolytic lesions of the VTA and bilateral lesions of the dorsal NA bundle obtained by injections of 6-OHDA laterally to the pedunculus cerebellaris superior. Indeed, no significant change in DA-sensitive adenylate cyclase activity was found in the prefrontal cortex of rats with both types of 1esions.m Lesions of NA neurons alone were without effect on the enzyme activity.
Behavioral Consequences of Noradrenergic-Dopaminergic Znteractions Bilateral electrolytic lesions of the VTA in the rat induce behavioral deficits such as locomotor hyperactivity and the disappearance of spontaneous alternation (“VTA syndrome”).3* Correlation studies have indicated that the amplitude of locomotor hyperactivity is proportional to the extent of destruction of the DA fibers innervating the prefrontal cortex and, more interestingly, to the development of a DI receptor supersensitivity in this area.31.33 Since destruction of the ascending NA pathways downregulates cortical D1 receptor denervation supersensitivity induced by the electrolytic lesion of the VTA, it was tempting to investigate whether chemical (6-OHDA) lesions of the cortical NA innervation could affect the locomotor hyperactivity induced by the electrolytic lesion of the VTA. In experiments conducted in collaboration with Drs. Taghzouti, Simon, and Le Mod, animals were either lesioned by bilateral electrocoagulations of the VTA, by bilateral injections of 6-OHDA made laterally into the pedunculus cerebellaris superior (in order to destroy ascending NA fibers), or simultaneously by both types of lesions. These experiments revealed that the NA neurons play a permissive role in the expression of the behavioral deficits induced by the electrocoagulation of the VTA. Indeed, while animals lesioned only in the VTA exhibited, as expected, increased nocturnal locomotor activity (+56%) and reduced spontaneous alternation behavior (59% instead of 76%, respectively, for the lesioned and sham-operated animals), no significant changes in locomotor activity or in spontaneous alternations were seen in rats with simultaneous bilateral electrolytic lesion of the VTA and bilateral 6-OHDA
2 10
ANNALS NEW YORK ACADEMY OF SCIENCES
lesions of the dorsal NA bundle when compared to sham-operated rats.34 Chemical lesions of the NA fibers alone had no effect either on the locomotor activity or on spontaneous alternation. Therefore, the simultaneous destruction of NA neurons and of VTA DA-NT neurons markedly reduced the deficits observed in rats with electrolytic VTA lesions. This functional recovery indicates that dysfunctions induced by a given lesion can be abolished by another type of lesion and provides new insights into the antagonistic properties of ascending NA and DA neurons. It is proposed that a functional hierarchy exists between these systems since no significant modification of locomotor activity or spontaneous alternation was observed in rats with NA lesions alone. These results may explain why many deficits of the VTA syndrome are more pronounced in rats with electrolytic lesions than in animals with 6-OHDA lesions.32.33~35 Recently, we have tried to determine the type of NA receptor (a or p) that is implicated in these DA-NA cortical interactions. This was done in behavioral experiments in which animals rendered hyperactive by electrolytic lesions of the VTA were treated with low doses (0.5 mg/kg i.p.) of prazosin, one hour before recording of nocturnal locomotor activity. This treatment, which had no effect on sham-operated animals, completely abolished the locomotor hyperactivity seen in lesioned animals up to 24 hours following the injection. This interaction seems specific to al-adrenergic receptors occupied by prazosin, since the same experiment performed with WB 4101, another a 1-adrenergic antagonist that binds to a l A - and ale-adrenergic receptors36 did not modify the locomotor hyperactivity of lesioned animals. Indeed, autoradiographic experiments, using tritiated prazosin and WB 4101 as ligands, have demonstrated two different patterns in the cortical binding sites of these ligands.37
POSSIBLE EFFECTS OF NORADRENERGIC INNERVATION ON THE REGULATION OF THE DENSITY OF CORTICAL NEUROTENSIN BINDING SITES In 1981, Palacios and Kuhar showed that most of the NT binding sites localized by autoradiography with [3H]NT in the mesencephalon were located on DA ~ e l l s . 3 ~ Moreover, following a 6-OHDA injection into the VTA-SN complex, they obtained an important decrease in the density of NT binding sites in the striatum. These data suggested that DA cell bodies and axons bore high densities of NT binding sites and could explain why the topographical distribution of mixed mesocortical DA/NT nerve terminals was so strikingly similar to that of cortical NT binding sites. However, when, in collaboration with Drs. Kitabgi and Rosthe, the ascending mesocortical DA/NT neurons were destroyed by a 6-OHDA lesion in the VTA, an increased density of these cortical NT binding sites (+35%) was obtained.” These results indicated not only that most of the cortical NT binding sites are postsynaptic but also that they are not subjected to the same heteroregulation process as DI receptors. Indeed, in further autoradiographic experiments performed on cortical slices of animals lesioned by injection of 6-OHDA into the VTA, it was shown that the same rats that presented an important increase (+40%) of the density of their cortical NT binding sites had their cortical Dl receptors unchanged.*6 It is, however, interesting to note that this increased density of NT binding sites in the prefrontal cortex was not observed in the rhinal cortex. This distinct heteroregulation of DI and NT cortical binding sites was confirmed
TASSIN et al.: MESOCORTICAL DAlNT NEURONS
211
on animals electrolytically lesioned in the VTA. Five weeks after the lesions, quantitative analysis of autoradiograms obtained from nine hyperactive animals revealed a slight but significant increase in [3H]SCH 23390 binding sites in the prefrontal (8 anteroposterior slices analyzed) and rhinal(3 anteroposterior slices analyzed) cortices (mean increases +20%and +25%, p < 0.01, respectively, for the prefrontal and rhinal cortices when compared with corresponding control values). On the contrary, in both cortical regions of the same animals, 1Z9-labeledNT binding sites were not affected by the lesion.26 Interestingly, cortical DI receptors and NT binding sites seem to be regulated in opposite directions: Hypersensitivity of DI cortical receptors develops when there is no change in cortical NT binding sites (electrolytic VTA lesion) and increased density of cortical NT binding sites appears when there is no change in cortical DI receptors (6-OHDA VTA lesion) (FIG. 2). Although it has yet to be demonstrated, it is very likely that NA fibers, as shown for cortical D, receptors, regulate cortical NT
PREFRONTAL CORTEX
HF-VTA LESION
6 OHDA VTA LESION
FIGURE 2. Schematization of the effects of electrolytic or chemical (6-OHDA) lesions of the VTA on D I receptors and NT binding sites in the rat prefrontal cortex. Following the electrolytic lesion of the VTA (HF-VTA, lefr), mixed DA/NT mesocortical neurons are destroyed and NA ascending pathways are spared. The 6-OHDA lesion of the VTA (righr) destroys both mixed mesocortical DA/NT neurons and NA ascending pathways. For reason of simplification, D I receptors (DI-R),NT binding sites (NT-R) and NA receptors (NA-R) have been drawn on the same target cell, although it has not yet been demonstrated. As discussed in the text, the NA receptor implicated in the heteroregulation of cortical DI receptors is likely to be of the at-adrenergic subtype.
212
ANNALS NEW YORK ACADEMY OF SCIENCES
binding sites; however, in this case, it is the absence of NA innervation that would be necessary for the denervation supersensitivity of cortical NT binding sites to develop. As previously demonstrated, it seems that it is the stimulation by NA of an aladrenergic receptor specifically sensitive to prazosin that is necessary for the development of a denervation supersensitivity of cortical DI receptors (see above). We do not yet have evidence of this being the case for the regulation of cortical NT binding sites. However, parallel experiments have shown that the density of prefronto-cortical NT binding sites is increased by 64%in rats treated with palmitate of p i p ~ t i a z i n e , ~ ~ without change in the affinity of 125I-labeled NT for NT binding sites. It is interesting to note that this long-term neuroleptic, in addition to its blocking effect on DA receptors, antagonizes NA transmission through al-adrenergic receptors, as has been demonstrated for other phenothiazine deri~atives.3~ It must, however, be emphasized that increases of NT binding sites following a treatment by palmitate of pipotiazine occur not only in other structures innervated by mixed DA/NT neurons, such as the entorhinal cortex (+30%),but also in areas innervated by DA neurons that do not synthesize NT. This is the case for the nucleus accumbens and the central part of the striatum where increases in NT binding sites density were, respectively, +34%and +25%.” Interestingly, palmitate of pipotiazine did not induce any significant modification of NT binding site density in the lateral part of the striatum.
CONCLUDING REMARKS Although colocalization of DA and NT in some DA neurons does not turn out to be a universal characteristic across species, the extensive colocalization between DA and NT in Sprague-Dawley’s mesocortical neurons and the codistribution of DADI and NT receptors in the terminal field of these neurons may represent an interesting paradigm to study cotransmission in the central nervous system. The data presented here confirm previous finding~2**~9 that modifications of the density of postsynaptic receptors following denervation of afferent fibers is linked to the type and/or specificity of the lesions made and to heteroregulation of the receptors. Indeed, they could be related to the concomitant destruction or dysregulation of other neuronal pathways. More precisely, the destruction of the mixed mesocortical DA/NT neurons does not induce simultaneously, on the same animals, denervation supersensitivity of both DI and NT cortical receptors. Depending on the type of VTA lesion used, electrolytic or chemical (6-OHDA), it is one or the other receptor that becomes hypersensitive while the other is not modified. The permissive role of NA neurons on the development of supersensitivity of cortical DI receptors seems well established even if the precise mechanism through which NA neurons modify cortical DI receptors’ sensitivity is still not known. Some recent data indicate, however, that the occupation by prazosin of a]-adrenergic receptors blocks the hypersensitivity of cortical DA-sensitive adenylate cyclase activity obtained by an in vivo N-ethoxy-ethyl-dihydro-quinoline(EEDQ) treatment.40 These results are in good agreement with behavioral experiments that suggest that the blockade by prazosin of the locomotor hyperactivity obtained by the electrolytic lesion of the VTA
TASSIN et al.: MESOCORTICAL DAlNT NEURONS
213
is due to an increased efficacy of the cortical DI transmission induced by prazosin.37v41.42 Indeed, if prazosin is able to improve the efficacy of the cortical DI transmission, it may also make the hypersensitization of the cortical DI receptors unnecessary. Obviously, the demonstration of the role of NA neurons on the regulation of cortical NT binding sites needs further experimentation. The existence of a heteroregulation of cortical NT binding sites seems, however, demonstrated since two different modes of destruction of the mixed mesocortical DA/NT neurons do not have the same consequences on the sensitivity of these postsynaptic receptors. In fact, data obtained following a treatment with a long-term neuroleptic, palmitate of pipotiazine, may give some interesting information. First, results obtained in DA subcortical structures, such as the nucleus accumbens and the striatum which do not exhibit fibers containing both DA and NT, indicate that increases of NT binding sites are not necessarily related to the presence of a DA-NT colocalization. Moreover, the NT binding sites modified by the neuroleptic treatment are probably postsynaptic to the DA neurons since no increase of NT binding sites density can be observed in the region containing the highest density of NT binding sites located on afferent DA fibers, that is, the lateral striatum.27 The higher sensitivity to the neuroleptic treatment of NT binding sites postsynaptic to DA neurons excludes the possibility that the modifications observed are due to a prolonged decreased release of NT induced by n e u r o l e p t i ~ s . ~On 3 ~the ~ contrary, these differences of reactivity between the two types of NT binding sites, pre- and postsynaptic to DA neurons, rather suggest that DA is controlling either the synthesis or the degradation of the NT binding sites postsynaptic to DA neurons. Finally, since almost all the neurons of the nucleus accumbens or of the striatum possess either DI or D2 receptors,45 it is very likely that NT binding sites modified by the neuroleptic treatment are located on cells bearing DA receptors; the increased density of NT binding sites would then be related to intracellular mechanisms, such as changes in second messenger levels and subsequent modification of phosphorylations following the blockade of the DA receptors. Nothing indicates that DA control of NT binding site density is different in subcortical DA structures from areas where an extensive colocalization of DA and NT has been demonstrated. Moreover, the striking codistribution of DI receptors and NT binding sites strongly suggests that, as in subcortical structures, both types of receptors are located on the same cells. This is why DI receptors and NT binding sites have been schematized on FIGURE2 on the same cell, although it has not yet been demonstrated. If we assume that the permissive role of NA pathways on the development of cortical DI supersensitivity is due to an antagonistic effect of NA neurons on the cortical DI transmission, it may be similarly proposed that NA neurons facilitate cortical NT transmission. The blockade of a I-adrenergic receptors by palmitate of pipotiazine would then decrease cortical NT transmission and induce the development of a denervation supersensitivity of these latter receptors. Finally, the analysis of long-term heteroregulation of receptors in abnormal situations such as lesions provides new insights not only on interactions between different pathways of a complex neuronal network, but also between two neurotransmissions conveyed by the same neurons. Such interactions may intervene in physiological states. This approach seems, therefore, of heuristic value for determining the respective roles of identified neuronal pathways in cerebral functions.
ANNALS NEW YORK ACADEMY OF SCIENCES
214
REFERENCES 1, FUXE,K., T. H~KFELT, 0. JOHANSSON. G. JONSSON, P. LIDBRINK & A. LJUNGDAHL. 1974. The
2. 3. 4. 5. 6. 7.
8. 9.
10. 11. 12. 13. 14.
origin of DA nerve terminals in limbic and frontal cortex. Evidence for mesocortical neurons. Brain Res. 82: 349-355. BERGER,B., J. P. TASSIN,G. BLANC,M. A. MOYNE& A. M. THIERRY.1974. Histochemical confirmation for dopaminergic innervation of the rat cerebral cortex after destruction of NA ascending pathways. Brain Res. 81: 332-337. BJ~RKLUND, A. & 0. LINDVALL. 1978. The meso-telencephalic dopamine neuron system: A review of its anatomy. In Limbic Mechanisms. K. E. Livingstone & 0. Hornykiewicz, Eds. Plenum Press. New York. HOKFELT,T., B. J. EVERITT,E. THEODORSON-NORHEIM& M. GOLDSTEIN.1984. Occurrence of neurotensin-like immunoreactivity in subpopulation of hypothalamic, mesencephalic and medullary catecholamine neurones. J. Comp. Neurol. 22: 543-559. STUDLER, J. M., P.KITABGI, G. TRAMU,D. H E R V J.~ ,GLOWINSKI & J. P. TASSIN.1988. Extensive co-localization of neurotensin with dopamine in rat mesocortico-frontal DA neurons. Neuropeptides 11: 95-100. VON HUNGEN,K. & S. ROBERTS.1973. Adenylate cyclase receptors for adrenergic neurotransmitters in rat cerebral cortex. Eur. J. Biochem. 36: 391-401. BOCKABRT, J., J. P.TASSIN,A. M. THIERRY, J. GLOWINSKI & J. P ~ M O N T1977. . Characteristics of DA and P-adrenergic sensitive adenylate cyclases in the frontal cerebral cortex of the rat. Comparative effects of neuroleptics on frontal cortex and striatal DA-sensitive adenylate cyclases. Brain Res. 122: 71-86. TASSIN,J. P., J. BOCKAERT, G. BLANC,L. STINUS,A. M. THIERRY, S. LAVIELLE, J. P ~ M O N T & J. GLOWINSKI.1978. Topographical distribution of DA innervation and DA receptors of the anterior cerebral cortex of the rat. Brain Res. 154: 241-251. TASSIN,J. P., H. SIMON,D. HERVE,G. BLANC,M. LE MOAL,J. GLOWINSKI & J. BOCKAERT. 1982. Nondopaminergic fibers may regulate DA-sensitive adenylate cyclase in the prefrontal cortex and the nucleus accumbens. Nature 295: 696-698. SAVASTA, M., A. DUBOIS& B. SCATTON. 1986. Autoradiographic localization of D1 DA receptors in the rat brain with )H-SCH 23390. Brain Res. 259: 291-301. TASSIN,J. P., P. KITABGI,G. TRAMU, J. M. STUDLER,D. HERVE,F. TROVERO & J. GLOWINSKI. 1988. Rat mesocortical DA neurons are mixed NT/DA neurons: Immunohistochemical and biochemical evidence. Ann. N. Y. Acad. Sci. 537: 531-533. SWANSON, L. W. & B. K. HARTMAN. 1975. The central adrenergic system. An immunotluorescence study of the location of cell bodies and their efferent connections in the rat utilizing DA-P-hydroxylase as a marker. J. Comp. Neurol. 163: 467-506. MORRISON, J. H., M. E. MOLUVER,R. GRZANNA & J. T. COYLE.1981. The intra-cortical trajectory of the coeruleo-cortical projection in the rat: A tangentially organized cortical afferent. Neuroscience 6: 139-158. BUNNEY, B. S. & G. K. ACHAJANIAN. 1976. DA and NA innervated cells in the rat prefrontal cortex. Pharmacological differentiation using microiontophoretic techniques. Life Sci. 19:
1783-1792. 15. ANTELMAN, S. M. & A. R. CAGGIULA. 1977. Norepinephrine-dopamine interactions and behavior. Science 195: 646-653. A. R., P. A. M. VANDONGEN,H. J. JANSSEN & A . A. P. H. MEGENS.1978. Functional 16. COOLS,
antagonism between DA and NA within the caudate nucleus of cats: A phenomenon of rhythmically changing susceptibility. Psychopharmacology 59: 231-242. 17. TASSIN,J. P., S. LAVIELLE, D. H E R V ~G., BLANC,A. M. THIERRY, C. ALVAREZ,B. BERGER & J. GLOWINSKI. 1978. Collateral sprouting and reduced activity of the rat mesocortical dopaminergic neurons after selective destruction of the ascending noradrenergic bundles. Neuroscience 4: 1569-1582. 18. VANKAMMEN, D. P. & S. ANTELMAN. 1984. Impaired noradrenergic transmission in Schimphrenia? Life Sci. 34: 1403-1413. 19. SEROOGY, K. B., A. MEHTA& J. H. FALLON.1987. Neurotensin and cholecystokinin coexistence within neurons of the ventral mesencephalon: Projections to forebrain. Exp. Brain Res. 68: 277-289.
TASSIN et al. : MESOCORTICAL DA/NT NEURONS
215
20. TRAMU, G., A. PILLEZ& J. LEONARDELLI. 1978. An efficient method of antibody elution for the successive or simultaneous localization of two antigens by immunocytochemistry. J. Histochem. Cytochem. 26: 322-324. 21. VONEULER,G., B. MEISTER,T. HOKFELT,P. ENEROTH & K. FUXE.1990. Intraventricular injection of neurotensin reduces dopamine D2 agonist binding in rat forebrain and intermediate lobe of the pituitary gland. Relationship to serum hormone levels and nerve terminals existence. Brain Res. 531 253-262. 22. FEBVRET,A., B. BERGER,P. GASPAR & C. VERNEY.1991. Further indication that distinct dopaminergic subsets project to the rat cerebral cortex: Lack of colocalization with neurotensin in the superficial dopaminergic fields of the anterior cingulate, motor, retrosplenial and visual cortices. Brain Res. 547 37-52. 23. GASPAR,P.,B. BERGER& A. FEBVRET.1990. Neurotensin innervation of the human cerebral cortex: Lack of colocalization with catecholamines. Brain Res. 530: 181-195. D., J. P.TASSIN& J. BOCKAERT. 1980. Doparninergic component of 3H-spiroperidol 24. MARCHAIS, binding in the rat anterior cortex. Brain Res. 183: 235-240. 25. BOYSON,S. J., P. MCGONIGLE & P. B. MOLINOFF.1986. Quantitative autoradiographic localization of the D1 and D2 subtypes ofdopamine receptors in rat brain. J. Neurosci. 6:3177-3188. 26. TROVERO, F., D. HERVB,G. BLANC,J. GLOWINSKI & J. P. TASSIN.1991. Different regulations of dopamine D I receptors and neurotensinergic binding sites in the rat prefrontal cortex. Neurosci. Lett. U7:198-202. 27. HERVB,D., J. P. TASSIN,J. M. STUDLER, C. DANA,P. KITABGI,J. P. VINCENT,J. GLOWINSKI & W. ROSTENE.1986. Dopaminergic control of 1251-labeledneurotensin binding site density in corticolimbic structures of the rat brain. Proc. Natl. Acad. Sci. USA 83: 6203-6207. 28. REIBAUD, M., G. BLANC,J. M. STUDLER, J. GLOWINSKI & J. P. TASSIN.1984. Non-DA prefrontocortical efferents modulate D1 receptors in the nucleus accumbens. Brain Res. 305: 43-50. 29. HERVB,D., F. TROVERO, G. BLANC,A. M. THIERRY, J. GLOWINSKI & J. P. TASSIN.1989. Nondopaminergic prefronto-cortical efferent fibers modulate D1 receptor denervation supersensitivity in specific regions of the rat striatum. J. Neurosci. 9: 3699-3708. 30. TASSIN,J. P., J. M. STUDLER, D. HERVB,G. BLANC& J. GLOWINSKI. 1986. Contribution of noradrenergic neurons to the regulation of dopaminergic (DI) receptor denervation supersensitivity in rat prefrontal cortex. J. Neurochem. 46: 243-248. & J. BOCKAERT. 1982. Modulations of the sensitivity 31. TASSIN,J. P., H. SIMON,J. GLOWINSKI of DA receptors in the prefrontal cortex and the nucleus accumbens: Relationship with locomotor activity. In Brain Peptides and Hormones. R. Collu, J. R. Ducharme, A. Barbeau & G. Tobis, Eds.: 17-30. Raven Press. New York. 32. LE MOAL,M., L. STINUS& D. GALEY.1976. Radio-frequency lesions of the ventral mesencephalic tegmentum: Neurological and behavioural considerations. Exp. Neurol. 50: 521-535. 33. TASSIN,J. P., L. STINUS,H. SIMON,G. BLANC,A. M. THIERRY, M. LE MOAL,B. CARDO& J. GLOWINSKI. 1978. Relationship between the locomotor hyperactivity induced by A10 lesions and the destruction of fronto-cortical DA innervation in the rat. Brain Res. 141 267-281. 34. TAGHZOUTI, K . , H. SIMON,D. HERVE,G. BLANC,J. M. STUDLER, J. GLOWINSKI, M. LE MOAL & J. P. TASSIN.1988. Behavioural deficits induced by an electrolytic lesion of the rat ventral mesencephalic tegmentum are corrected by a superimposed lesion of the dorsal noradrenergic system. Brain Res. 440: 172-176. 35. GALEY,D., H. SIMON& M. LE MOAL.1977. Behavioural effects of lesions of the DA A10 area of the rat. Brain Res. U4: 83-97. 36. MORROW, A. L. & I. CREESE.1976. Characterization of alpha I-adrenergic receptor subtypes in rat brain: A reevaluation of W W B 4101 and 3H-prazosin binding. Mol. Pharmacol. 29: 321-330. 37. TROVERO, F., G. BLANC,D. HERVE,P. VEZINA,J. GLOWINSKI & J. P. TASSIN.1992. Contribution of an al-adrenergic receptor subtype to the expression of the ”ventral tegmental area syndrom.” Neuroscience 47 69-76. J. M. & M. J. KUHAR.1981. Neurotensin receptors are located on DA-containingneurons 38. PALACIOS, in rat midbrain. Nature 294: 587-589. 39. SEEMAN, P. 1980. Brain dopamine receptors. Pharmacol. Rev. 32: 229-313. F., D. HERVB,G. BLANC,J. GLOWINSKI & J. P. TASSIN.1992. In vivo partial inac40. TROVERO,
216
41. 42. 43.
44. 45.
46.
ANNALS NEW YORK ACADEMY OF SCIENCES tivation of dopamine DI receptors induces hypersensitivity of cortical dopamine-sensitiveadenylate cyclase: Permissive role of a!-adrenergic receptors. J. Neumchem. 59: 331-337. VI~ZINA,P., G. BLANC,J. GLOWINSKI & J. P. TASSIN.1991. Opposed behavioural outputs of increased dopamine transmission in prefrontocortical and subcortical areas: A role for the cortical DI dopamine receptor. Eur. J. Neurosci. 3: 1001-1007. J. P. 1992. NElDA interactions in prefrontal cortex and possible implications of neuroTASSIN, modulators in Schizophrenia. J. Neur. Trans. In press. GOVINI,S., J. S. HONG,H. Y.T. YANG& E. COSTA.1980. Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. J. Pharmacol. Exp. Ther. 225: 337-345. GOEDERT, M., S. D. IVERSEN & P.C. EMSON.1985. The effects of chronic neuroleptic treatment on neurotensin-like immunoreactivityin the rat central nervous system. Brain Res. 335: 334-336. L. C. MAHAN,Z. SUSEL,T. N. CHASE,F. J. MONSMA & GERFEN, C. R., .T. M. ENGBER, D. R. SIBLEY. 1990. D1 and D2 receptor-regulatedgene expression of striatonigral and striatopallidal neurons. Science 250: 1429-1432. LINDVALL, O., A. BJ~RKLUND & I. DIVAC.1978. Organization of catecholamine neurons projecting to the frontal cortex in the rat. Brain Res. 142: 1-24.