Biochemical and behavioural consequences of interactions between dopaminergic and noradrenergic systems in rat prefrontal cortex

Neurochem. Int. Vol. 20, Suppl., pp. 225S-230S, 1992

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BIOCHEMICAL AND BEHAVIOURAL CONSEQUENCES OF INTERACTIONS BETWEEN DOPAMINERGIC AND NORADRENERGIC SYSTEMS IN RAT PREFRONTAL CORTEX J. P. TASSIN,F. TROVERO,D. HERVI~,G. BLANCand J. GLOWINSKI Chaire de Nouropharmacologie,INSERM U114, Coll~gede France, 11, Place Marcelin Berthelot, 75005 Paris Cedes 05, France The rat prefrontal cortex receives a dopaminergic (DA) innervation that arises mainly from cell bodies in the rostro-medial part of the ventral tegraental area (VTA) (Fuxe et al., 1974). This cortical DA innervation is particulary dense in the deeper layers of the cortex (Berger et al., 1974; Bj6rklund and Lindvall, 1978). In 1984, H6kfelt and his colleagues have shown that some DA cell bodies located in the VTA contain, in addition to DA, an other neurotransmitter, neurotensin (NT) (H6kfelt et ai., 1984). It is assumed that these cell bodies correspond mostly to mesocortical DA neurons since an injection of 6-OHDA into the VTA induced a dramatic decrease of NT levels in the prefrontal cortex. Moreover, immuno-histochemical studies have indicated an extensive co-localisation of DA and NT fibers innervating the prefrontal and rhinal cortices in the rat (Studler et al., 1988). In these cortical areas are also located DA receptors coupled to adenylate cyclase (DI receptors) (Von Hungen and Roberts, 1973; Bockaert et al., 1977). The topographical distribution of these D~ receptors in the anterior cerebral cortex matches closely that of DA terminals and lesion studies have indicated that these receptors are located postsynaptically on cortical cells (Tassin et al., 1978a, 1982a). Within the cortical projection field of the mixed DA/NT fibers, localization of DA (D~) receptors and NT binding sites are strikingly similar (Savasta et al., 1986; Tassin et al.,1988). On the other hand, noradrenergic (NA) fibers, which originate in the locus coeruleus, are distributed more extensively in the cortical superficial layers although they also are present in the DA/NT projection field (Swanson and Hartman, 1975; Morrison et al., 1981). Several cells, distributed in this cortical DA area and sensitive to microiontophoretic application of DA, are also sensitive to NA (Bunney and Aghajanlan, 1976), suggesting that DA/NA interactions may occur in this anterior part of the cerebral cortex. Many reports have provided evidences for inter-

actions between NA and DA transmission in the central nervous system (Antelman and Caggiula, 1977; Cools et al., 1978; Tassin et al., 1978b; Van Kammen and Antelman, 1984). These interactions, which can be demonstrated by biochemical analysis, seem to have consequences on pharmacological and behavioural grounds. For example, Arnsten and Goldman-Rakic (1985) have been able to ameliorate the cognitive deficits induced by loss of cortical DA innervation by treating with clonidine, an alpha-2 adrenergic agonist. Sirnilary, it has been shown that alpha-1 and alpha-2 adrenoreceptors antagonist influence behaviours induced by DA agonists (Dickinson et al., 1988). In this brief review, we will try to summarize some of our contributions to a better knowledge of the different levels of interactions which occur between NA and DA transmission. First, we will show that ascending NA neurons can modulate the activity and development of mesocortical DA neurons. Secondly, we will describe experiments indicating that both monoaminergic systems act on the same neuronal network in the prefrontal cortex. Indeed, mesocortical DA/NT neurons modulate the sensitivity of ~adrenergic receptors in the prefrontal cortex. Similary, the presence of an intact NA innervation is necessary to obtain denervation hypersensivity of prefrontal DA (DI) receptors. Furthermore, it seems that it is the absence of NA innervation which allows the development of denervation supersensivity of NT binding sites located in the prefrontal cortex. Finally, experiments showing the behavioural consequences of such receptor heteroregulations will be presented. COLLATERAL SPROUTING AND REDUCED ACTIVITY OF THE MESOCORTICAL DA NEURONS FOLLOWING THE DESTRUCTION OF ASCENDING NA FIBERS

Striking modifications of the properties of the mesocortical DA neurons projecting to the ante-

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romedial cerebral cortex of the rat were seen alter the degeneration of the ascending NA pathways. Indeed, the cortical DA levels were increased by up to + 70%, 3 to 6 months following the bilateral 6-OHDA lesions of DA neurons. The increased density of the cortical [3H]DA high affinity uptake activity in good correlation with the individual modifications of the DA levels (Tassin et al., 1978b). Finally, the histochemical analysis made with a tecnique which has previously been clearly shown to distinguish NA from DA nerve terminals in control rats, confirmed the presence of a denser network of DA nerve terminals in some cortical areas following the degeneration of NA neurons. The sprouting process concerned both the thin (pregenual) and thick (supragenual) fibers originating respectively from the VTA and the SN (Fallon and Moore, 1978; Tassin et al., 1978b). Interestingly, this increased cortical DA innervation was accompanied by marked decreases (.-50%) of the dihydroxyphenylacetic acid (DOPAC)/DA ratios in prefrontal cortices of animals devoid of NA nerve terminals. These decreases in cortical DA utilization were constant for all the lesioned animals and were therefore not dependent on changes of cortical DA levels. Indeed, animals with almost no increase of cortical DA levels still exhibited 50% decreases of their cortical D O P A C / D A ratios (Tassin et al., 1978b). It seems plausible that the collateral sprouting of the cortical DA fibers was due to the physical disappereance of the cortical NA nerve terminals. The decrease of cortical DA utilization, however, could be induced by N A / D A interactions either at the levels of the nerve terminals (prefrontal cortex) or DA cell bodies (VTA), since our 6-OHDA lesions destroyed both the dorsal and the ventral NA pathways. To test this hypothesis, 6-OHDA lesions were made in the vicinity of the NA pathway connecting the locus coeruleus to the VTA and corresponding to the dorsal part of the decussatio of the pedunculus cerebellaris superior (P.C.S.) in the medial region of the tegmental radiatio (Herv6 et al., 1982). These lesions, which decreased NA levels by 64% in the VTA, only slightly affected NA levels in the prefrontal cortex (-19%). They induced, however, a 38% decrease of the DOPAC/DA ratio in the prefrontal cortex. No change in DA utilization was observed in the nucleus accumbens of these lesioned animals suggesting that this N A / D A interaction in the VTA is specific for the mesocortical DA neurons. They indicate, moreover, that interactions between NA ascending fibers and mesocortical DA neurons occur not only in the prefrontal cortex but also in the VTA (Herv6 et al., 1982).

INVOLVEMENT OF M E S O C O R T I C A L DA NEURONS IN THE REGULATION OF fl-ADRENERGIC RECEPTOR SENSITIVITY IN RAT PREFRONTAL CORTEX

The contribution of DA afferents to the regulation of /3-adrenergic receptor sensitivity (isoproterenolstimulated adenylate cyclase activity) in thc rat prefrontal cortex was investigated by comparing the effects of lesions affecting either both DA and NA neurons or NA fibers alone. Bilateral 6-OHDA lesions made in the VTA destroyed ascending DA and to a variable extent ascending NA fibers innervating the prefrontal cortex (Tassin et al., 1982b). As previously described (Sporn et al., 1976), when the NA innervation was complete, a marked increase in the isoproterenol-stimulated adenylate cyclase activity ( + 78%) was found. However, when 6-OHDA injections into the VTA led to a partial destruction of cortical NA afferents (10-40% of control values), a hyposensitivity of the isoproterenol-induced adenylate cyclase activity (-30%) was observedl This effect contrasted with the fl-adrenergic receptor hypersensitivity seen in rats which had received bilateral 6-OHDA lesions laterally into the P.C,S. and presenting partial but selective (no change in cortical DA levels) NA denervations. The hyposensitivity of fladrenergic receptors obtained in rats with partial lesions of cortical DA innervation, therefore suggests that the mesocortical DA neurons may regulate ,Badrenergic receptors density when the activity of ascending NA neurons is partially decreased (Herv6 et al., 1990). INFLUENCE O F THE CORTICAL NA INNERVATION ON THE REGULATION O F D 1 R E C E P T O R S AND NT BINDING SITES IN THE P R E F R O N T A L CORTEX

(a) Effects o f N A innervation on cortical DI receptors

As mentioned previously, lesions experiments of mesocortical DA neurons have indicated that cortical D~ receptors were post-synaptic to the cortical DA afferents. Indeed, 6-OHDA injections into the VTA did not produce any change in the activity of the prefronto-cortical D~ linked adenylate cyclase even though DA cortical levels were reduced by more than 98%. 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 post-synaptic receptors (Tassin et al., 1982a). However, when the VTA lesions were performed electrolitically, the DA-sensitive adenylate cyelase activity, measured on tissue homogenates, and the density of D~ receptors, obtained by

Dopamine 90 quantitative autoradiography, presented increases of + 48% and + 24%, respectively (Trovero et al., 1991 a). Since electrolytic V I A lesions spare the cortical NA innervation whereas 6-OHDA V I A lesions destroy ascending NA fibers that pass near the location of the DA cells (Tassin et al., 1982a), the destruction of the cortical NA innervation could be responsible for the lack of development of denervation supersensitivity of cortical D~ 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 D~ receptors (extimated on electrolytically lesioned rats) (Tassin et ai., 1982b). This permissive role of ascending NA fibers originating in the locus coeruleus in the appearance of denervation supersensitivity of cortical D, receptors was also supported by experiments conducted on rats with simultaneous bilateral electrolytic lesions of the VTA and bilateral 6-OHDA lesions of the dorsal NA bundle (made near the P.C.S.). Indeed, no significant change in DA-sensitive adenylate cyclase activity was found in the prefrontal cortex of rats with both types of lesions (Tassin et al., 1986). Lesions of NA neurons alone were without effect on the enzyme activity.

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regulation process since electrolytic and chemical lesions of the VTA produce differential effects on their density. The existence of such a hetero-regulation has been confirmed by treating animals with a long acting neuroleptic, the palmitate of pipotiazine. Five weeks following the blockade of DA transmission, the density of cortical NT binding sites was increased by + 54% (Herv~ et al., 1986). This is probably due to the fact that, as it will be discussed below, palmitate of pipotiazine blocks not only DA transmission but also alpha-I adrenergic receptors. Interestingly, cortical D~ receptors and NT binding sites seem to be regulated in opposite directions: hypersensitivity of Dt cortical receptors develops when there is no change in cortical NT binding sites (electrolytic VTA lesions) and increased density of cortical NT binding sites appears when there is no change in cortical D~ receptors (6-OHDA lesion). Although it has yet to be demonstrated, it is very likely that NA fibers, as shown for cortical Dt receptors, regulate cortical NT binding sites; however, in this case, it is the absence of NA innervation which would be necessary for the denervation supersensitivity of cortical NT binding sites to develop.

(b) Possible effects o f N A innervation on cortical N T binding sites

BEHAVIORAL CONSEQUENCES OF DA/NA INTERACTIONS

In 1984, Palacios and Kuhar showed that most of the NT binding sites localized by autoradiography with [3HINT in the mesencephalon were located on DA cells (Palacios and Kuhar, 1981). Moreover, following a 6-OHDA injection into the VTA-SN complex they obtained an important decrease of 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 mesocortical DA nerve terminals was so strikingly similar to that of cortical NT binding sites (Tassin et al., 1988). Other findings, however, suggested that these cortical NT binding sites were postsynaptic to the mixed NT/DA mesocortical neurons since an electrolytic lesion of the VTA did not modify the autoradiographic density of [t25I]NTin the prefrontal and rhinal cortices (Trovero et al., 1991a). Moreover, when, in collaboration with Drs Kitabgi and Rost~ne, the ascending DA neurons were destroyed by a 6-OHDA lesion in the VTA, an increased density of these cortical NT binding sites (+35%) was obtained (Herv~ et ai., 1986). These results indicate not only that most of the cortical NT binding sites are postsynaptic but also that they are subjected, like D~ receptors, to a hetero-

Bilateral electrolytic lesions of the VTA in the rat induce deficits such as locomotor hyperactivity and the disappearance of spontaneous alternation ("VTA syndrome") (Le Moal et ai., 1976). 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 D~ receptor supersensitivity in this area (Tassin et al., 1978c, 1982a). Since destruction of the ascending NA pathways down-regulates cortical D~ receptor denervation supersensivity 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 Moal, animals were either lesioned by bilateral electrocoagulations of the VTA, by bilateral injections of 6-OHDA made laterally into the P.C.S. (site of 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 behavioural deficits induced by the electrocoagulation of the VTA. Indeed, while animals lesioned only in the VTA exhibited, as

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expected, increases nocturnal locomotor activity (+ 56%) and reduced spontaneous alternation behaviour (59% instead of 76% for the 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 lesion of the dorsal NA bundle when compared to sham-operated rats (Taghzouti et al., 1988). 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 neurons markedly reduced the deficits observed in rats with electrolytic VTA lesions. This functional recovery indicates that deficits induced by a given lesion can be abolished by another type of lesion and provides new insights into the agonistic 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 syndrom are more pronounced in rats with electrolytic lesions than in animals with 6-OHDA lesions (Le Moal et al., 1976; Galey et al., 1977; Tassin et al., 1978c). Since the modulation of D~ receptors and NT binding sites by ascending NA neurons seems to occur in the prefrontal cortex, this structure could be an important site of interaction between NA fibers and the target cells of the mixed mesocortical NT/DA neurons involved in expression of the behavioural deficits examined. It cannot be excluded, however, that this type of interactions also occurs in other structures innervated by the VTA DA cells such as the different subcortical structures. Similar opposite effects of NA and DA ascending systems projecting into the prefrontal cortex have, however, been demonstrated on the anxiolytic-like effect of a prefrontal DA lesion (Ravard et al., 1990), Recently, we have tried to determine the type of NA receptor (~ or 13) which is implicated in these DA/NA cortical interactions. This was done in behavioural 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 1-adrenergic receptors occupied by prazosin since

the same experiment performed with the WB 4101, another 1 adrenergic antagonist which binds to 7 I A and a 1B adrenergic receptors (Morrow and Creese, 1986) 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 (Trovero et aL, 1991b). CONCLUDING REMARKS

Different evidences of interactions between NA and DA ascending systems have been presented. Except for one case, in which NA fibers control the activity of DA/NT mesocortical neurons at VTA level, we have focussed our attention on Na/DA interactions occurring in the prefrontal cortex. Three main conclusions can be drawn: First, the collateral sprouting of cortical DA nerve terminals induced by the disappearance of N A axons suggest that DA fibers are in physical competition with NA axons in structures where both types of innervation occour. Second, NA and DA neurons can respectively modulate DA and NA receptor sensitivies. These hctero-regulations have been demonstrated for DA (DO and NA ( ~ receptors but may occur for other NA or DA receptor subtypes. Neurotensin binding sites, postsynaptic to mesocortical mixed DA/NT neurons, are also hetero-regulated. Finally, the regulation by NA neurons of the cortical DA (D~) receptors may explain why different DA behavioural deficits (locomotor hyperactivity, disappereance of spontaneous alternation and diminished reactions to anxiogenic situations) are counterbalanced by superimposed NA lesions. Additional experiments have indicated that NA neurons may act on cells bearing DA receptors via the stimulation by NA of a specific type of alpha ladrenergic receptor blocked by prazosin. Our data provide evidences that NA and DA neurons have agonistic properties on the behavioural outputs they modulate. A functional hierarchy between these two systems seems to exist since no behavioural modification is observed when NA neurons are lesioned alone. It should be mentioned, however, that Arnsten and Goldman-Rakic (1985) have proposed that NA and DA transmission act in synergy. Indeed, these authors have shown that cognitive deficits due to a cortical loss of DA can be compensated for by treating animals with clonidine, an alpha 2-adrenergic receptor agonist. Both our

Dopamine 90 conclusions could be reconcilied if it is assumed that, in their experimental conditions, the stimulation by clonidine o f presynaptic alpha 2-adrenergic receptors has induced a decrease in N A release. In any case, the putative roles o f N A and D A neurons in the pathogeny of various mental diseases compel to take into consideration interactions between these two neuromodulatory systems. REFERENCES

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