Blockade of Prefronto-cortical α1-Adrenergic Receptors Prevents Locomotor Hyperactivity Induced by Subcortical D-Amphetamine Injection

European Journal of Neuroscience, Vol. 6 , pp. 293-298

@ 1994 European Neuroscience Association

Blockade of Prefronto-cortical a1-Adrenergic Receptors Prevents Locomotor Hyperactivity Induced by Subcortical D-Amphetamine Injection G. Blanc, F. Trovero, P. Vezina, D. Herve, A.-M. Godeheu, J. Glowinski and J.-P. Tassin Chaire de Neuropharmacologie, INSERM U.114, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France Key words; prefrontal cortex, nucleus accumbens, noradrenaline, dopamine, prazosin, scopolamine, rat

Abstract The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et a/., fur. J. Neurosci., 3, 1001 - 1007, 1991). Moreover, an a1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et a/., Neuroscience, 47, 69-76, 1992). Attempts were thus made to see whether blockade of a1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens Damphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mglkg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmokide) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamineevoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount ( > 4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16- 160 pmol), recovery occurred within 3 days. It is suggested that the blockade of cortical d-adrenergic receptors facilitates locally dopaminergic D1 transmission. This latter effect may counteract the increased locomotor activity induced by the application of D-amphetamine into the nucleus accumbens.

Introduction Systemic injections of low doses of D-amphetamine have been shown to affect numerous behaviours in rodents. Animals increase their spontaneous locomotor activity (Creese and Iversen, 1975), exhibit altered patterns of exploration mainbridge, 1970; Robbins and Iversen, 1973) and show a tendency to stimulus perseveration (Kokkinidis and Anisman, 1976). These D-amphetamine injections also induce consistent unidirectional body turning (Jerussi and Glick, 1974) and increases in startle amplitude in response to a buzzer (Davis et a / . , 1975). Although D-amphetamine is known to increase both dopamine (Besson et a/., 1971; Gauchy et al., 1974; Zetterstrom et al., 1986) and noradrenaline (Carr and Moore, 1970) synaptic concentrations, it is generally admitted that the D-amphetamine-induced behavioural modifications are mainly due to an increase in dopamine release. This was suggested by three lines of evidence. The first deals with the relative potencies of the amphetamine isomers, since the D-isomer was found to be more potent than the L-isomer in releasing dopamine and in modifying behaviour (Thornburg and Moore, 1973). The second piece of evidence is based on the finding that most of the effects induced by Correspondence to: G. Blanc, as above Received 22 April 1993, revised 26 July 1993, accepted I 1 October I993

D-amphetamine were reproduced by the dopamine receptor stimulant apomorphine and antagonized by the dopamine receptor blocker haloperidol (Davis and Aghajanian, 1976; Roberts et al., 1975; Kelly et al., 1975; Joyce et al., 1983; Ogren et al., 1983). Finally, it has been established that some of the effects of D-amphetamine can be suppressed by the local administration of 6-hydroxydopamine into areas richly innervated by dopaminergic neurons. In particular, dopamine depletion in the nucleus accumbens attenuated the increased spontaneous motor activity observed with low doses of D-amphetamine (Kelly and Iversen, 1976; Koob et al., 1978). The role of noradrenergic neurons in the behavioural effects of D-amphetamineshould not, however, be overlooked. For example, both the circling behaviour and the increase in startle arousal induced by D-amphetamine were antagonized by pretreatment with FLA-63, an inhibitor of dopamine-0-hydroxylase (Kokkinidis and Anisman, 1978, 1979). More recently, a functional synergism between noradrenaline and dopamine neurons has been further substantiatedby the demonstration that the apomorphine-enhanced startle was blocked by prazosin, an

294 Cortical ar 1-adrenergic subcortical DA interactions arl-adrenergic antagonist (Davis et al., 1985). Such a critical role of arl-adrenergic receptors was also observed in some other dopamineregulated functions, since the locomotor activity induced by dopamine agonists could be blocked by prazosin (Snoddy and Tessel, 1985; Dickinson et al., 1988). All these results suggest that the stimulation by noradrenaline of al-adrenergic receptors is necessary for some behavioural expression linked to subcortical dopamine stimulation. However, in previous studies, we have shown in the rat that the permanent locomotor hyperactivity induced by the bilateral destruction of ascending dopamine neurons is prevented by either the simultaneous destruction of ascending noradrenergic innervation or the acute injection of a low dose of prazosin (Taghzouti et al., 1988; Trovero et al., 1992a). Since we had some evidence that locomotor activity was under the inhibitory influence of mesocortical dopamine neurons (Tassin et a l . , 1978; Vezina et al., 1991), we have proposed that prazosin can restore, in dopamine-lesioned animals, some of the cortical dopaminergic functions (Trovero et al., 1992a). Therefore, the aim of the present study was to define the nature and localization in the brain of the relationships which could exist between the noradrenergic and dopaminergic neuronal systems. We have first verified in our experimental conditions that systemic injection of a low dose of prazosin can block the locomotor hyperactivity induced by a systemic injection of D-amphetamine, whereas this effect of prazosin is not observed when scopolamine, a centrally acting muscarinic antagonist (Joyce and Koob, 1981), is injected instead of D-amphetamine. Then, to test our hypothesis, the consequences of bilateral prefronto-cortical injections of ar 1-adrenergic receptor antagonists on the locomotor hyperactivity induced by bilateral local injections of D-amphetamine into the nucleus accumbens were examined. Results indicate the presence of a cortical noradrenergic control on a dopamine-regulated subcortical function.

Material and methods All animals used were male Sprague-Dawley rats (Iffa-Credo, Lyon; 250-300 g on arrival) maintained on a 12 h light/l2 h dark cycle at constant temperature (22"C), with food and water continuously available.

Surgery Animals were housed individually. Three weeks after their arrival, rats were anaesthetized with ketamine (150 mg/kg; Imalgene, Iffa-MCrieux, Lyon, France) and stereotaxically implanted with chronic bilateral guide cannulae (22 gauge stainless steel tubing) aimed at both the nucleus accumbens (A/P + 3 mm from bregma, L f 1.5 mm from the midline and DN -7.8 nun from skull) and the medial prefrontal cortex (mPFC) (A/P +4.3 mm from bregma, L ~ t 0 . 5mm from the midline and D/V -5.4 mm from the skull) and positioned 1 mm above the final injection site. The incisor bar was placed 3.5 mm above the interaural line. Following surgery, gauge stainless steel obturators were inserted in the guide cannulae and the animals were returned to their home cages for a minimum 20 day recovery period. The cannulae placed into the nucleus accumbens allowed the injection of D-amphetamine and those in the mPFC the injection of either D-amphetamine or of each a I-adrenergic antagonist tested, i.e. prazosin or WB-4101.At the end of the behavioural experiments, animals were perfused transcardially with saline and a 10% formalin solution under deep anaesthesia. Histological verification of cannula tip placement was subsequently made on 80 pm cresyl-violetstained coronal sections. Behavioural testing Two banks of four circular corridors were used to measure locomotor activity. Each corridor was 14 cm wide and 70 cm long. Four photocells, positioned 3 cm above the floor and spaced evenly along the length of

each corridor, estimated locomotion. Photocell beam interruptions were recorded by a computer and the data were analysed using Imetronic software (Bordeaux, France). Animals receiving intraperitoneal injections Seven days after their arrival, rats were habituated to the circular corridor during three night sessions (17.00- 10.00h) and injected intrapentoneally with 1 ml saline. On the day of the test, animals were again habituated to the corridor for 30 min. Four animals received 0.06 mglkg of prazosin (i.p.) in 1 ml and four others received 1 ml solvent, and their activity was recorded for 60 min. Then, all of them received 0.75 mg/kg of D-amphetamine (i.p.) or 0.8 mglkg of scopolamine (i.p.) in I ml saline and the locomotor activity was again recorded for 60 min. An identical experiment was performed the following day with two groups of four other rats which received saline instead of D-amphetamine or scopolamine. Experiments were replicated in order to obtain at least eight rats in each group. Animals with implanted cannulae Prior to testing, all animals were given an intracerebral injection of saline in each of their four cannulae located in the mPFC and nucleus accumbens and were habituated to the corridors for 1 h. Two days later, following a 20 min habituation to the corridors, D-amphetamine (4.0 nmol/side in 0.5 pl) was injected bilaterally into the nucleus accumbens and locomotor activity was recorded for a further 30 min. In order to select animals having their four cannulae properly located, the following two criteria were used. First, only animals which exhibited locomotor hyperactivity superior to +70% following the bilateral injections of D-amphetamine into the nucleus accumbens were retained. This ensured good localization of the cannulae into the nucleus accumbens. Second, among these preselected animals, the localization of the cannulae into the mPFC was tested by verifying that the locomotor hyperactivity induced by the bilateral injections of D-amphetamine into the nucleus accumbens was reduced by at least 30% following the bilateral injections of D-amphetamine (4.0 nmol/side in 0.5 pl) into the mPFC (Vezina et al., 1991). Of 80 operated animals, 48 (60%) were kept for further experiments. Animals were then left in their home cages for at least 7 days and either prazosin (0.016- 160 pmol/side in 0.5 pl) or WB-4101 (0.16- 160 pmol/side in 0.5 pl) was injected bilaterally into the mPFC 20 min before the bilateral injections of saline or D-amphetamine into the nucleus accumbens. Locomotor activity was recorded for a further 30 min. From the next day on, animals were regularly reinjected, on the days indicated in the figures, bilaterally with D-amphetamine into the nucleus accumbens until they recovered their initial locomotor hyperactivity (Figs 3 and 4). Drugs The drugs tested were D-amphetamine sulphate, prazosin hydrochloride (Sigma), WB-4 101 (RBI) and scopolamine bromhydrate (Laboratoires Meram, France). All drugs were dissolved in saline except prazosin at higher concentrations than 160 pmol/pl, which was dissolved in water. Solution pH ranged from 6.5 to 7.0 after adjustment with NaOH. Drugs were injected either into the periphery (i.p.) or locally into the nucleus accumbens and the mPFC. Simultaneous bilateral intracranial microinjectionsinto these sites were performed in unrestrained rats. These injections were made in a volume of 0.5 pllside over 45 s with gauge stainless steel injector cannulae inserted to 1 mm below the guide cannulae. These were connected via polyethylene tubing to 1 p1 Hamilton syringes and were replaced by obturators 60 s after injection. Statistical analysis Differences between treatments were evaluated using one-factor analysis of variance for repeated measures. Individual comparisons between

Cortical a1 -adrenergic subcortical DA interactions 295 treatments were evaluated with Fisher's PLSD and the Scheffe F-test. The level for significance was set at P < 0.05.

I

Results

Prazosin

W B 4101

Ii -

600 -

T

Effect of the peripheral injection of prazosin on locomotor hyperactivity induced by o-amphetamine or scopolamine The intraperitoneal injection of a low dose of prazosin (0.06 mg/kg) partly antagonized the locomotor hyperactivity induced by an intraperitoneal injection of D-amphetamine (0.75 mg/kg) made 60 min later. In two experiments, performed at a 7 day interval on the same animals, the mean locomotor activities were increased by 878 and 997% respectively in the presence of D-amphetamine alone and by 302 and 350%with D-amphetamine and prazosin, when compared to locomotor activities of saline-injected animals (Fig. I). It can be noted that, at this low concentration, prazosin had no effect on spontaneous locomotor activity, except for the first 10 min after its injection. Similar experiments were performed on animals whose locomotor hyperactivity was induced by an intraperitoneal injection of scopolamine (0.8 mg/kg). In these conditions, pretreatment with prazosin did not modify the scopolamine-induced locomotor hyperactivity [753 f 196 and 859 f 278 counts/60 min for the saline and prazosin-injectedanimals respectively, corresponding to +736 and +854% compared to control locomotor activities (eight animals per group)].

Effects of intra-mPFC injection of prazosin or WB-4101 on the locomotor hyperactivity induced by intra-nucleus accumbens injection of o-amphetamine As shown in Figure 2, animals which had their cannulae correctly located

in the nucleus accumbens exhibited a large increase in locomotor activity following bilateral injection of 4.0 nmol of D-amphetamine into the nucleus accumbens ( - 100%). Their locomotor activity returned to

0 -

FIG.2. Effects of intra-mPFC injection of prazosin or WB-4101 on the locomotor hyperactivity induced by intra-nucleus accumbens (N. Acc.) injection of Damphetamine. Rats received simultaneous microinjections of either prazosin or WJ-4101 (0.16 pmollside) or saline into the d F C and of D-amphetamine (4.0 nmohide) or saline into the nucleus accumbens. The locomotor activity of animals receiving saline in the mPFC and D-amphetamine into the nucleus accumbens was significantly increased compared to that of rats receiving only saline injectiom (*P < 0.05). Rats receiving simultaneous injections of prazosin or WB-4101 and D-amphetamine showed significantly lower activity than animals injected with D-amphetamine only (0,P < 0.05). The results are means SEM of counts per 30 min for eight animals in each group.

*

+

I c0--

Prazosin (pmoles) (80)

Saline + Amphetamine Prazosin + Amphetamine

Q I

loollli/11 0

loo[

50

tI

L

0

9

0 1 2 4

0 1 2

0 1

0 1 2 416

(day8 after intra mPFC prazosin injection)

0

s.1 PPC + imph

N. Ace.

=

praz PFC + unph N. Acs.

~

mi

FIG. 1. Effects of peripheral treatment with prazosin and o-amphetamine on locomotor activity. Four groups of rats received prazosin (0.06 mg/kg i.p.) or d i e and, 60 min later, D-amphetamine (0.75 mgkg i.p.) or saliie. In the salinepretreated rats, the D-amphetamine injection resulted in a significant increase in locomotor activity (*P< 0.05). Pretreatment with prazosin significantly reduced (AP < 0.05) the locomotor hyperactivity induced by o-amphetamine. Except for the first 10 min following the injection, prazosin pretreatment did not modify spontaneous locomotor activity. The results are the mean ( *SEM of counts per 10 min for at least 16 animals in two experiments.

F1G.3. Time-course of recovery in locomotor hyperactivity induced by Damphetamine injection into the nucleus accumbens (N. Acc.) after the injection

of prazosin into the mPFC. The animals first received D-amphetamine in the nucleus accumbens (light columns). Two days later, prazosin (0.16, 13, 80,160 pmollside) and D-amphetamine (4.0 nmollside) were injected into the mPFC and the nucleus accumbens respectively (day 0, dark columns). Finally, the rats received 0-amphetamine in the nucleus accumbens until the loo'%stimulating locomotor effect was found (light columns). *Sigmiicantly diflerent from the group of animals injected with 0-amphetamine into the nucleus accumbens (P < 0.05). Data are shown as mean counts per 30 min SEM of an experiment with eight rats in each group.

296 Cortical

1-adrenergic subcortical DA interactions

(11

control levels when either prazosin (0.16 pmollside) or WB-4101 (0.16 pmol/side) was injected bilaterally into the mPFC before the injection of D-amphetamine into the nucleus accumbens This effect was also observed when higher doses (13, 80 and 160 pmollside and 80 and 160 pmol/side for prazosin and WE-4101 respectively (Figs 3 and 4)) of either antagonist were injected. When animals received only the bilateral injections of either prazosin or WB-4101 in the mPFC (0.16 pmol/side) and saline in the nucleus accumbens, the mean locomotor activity was not different from control values [280 f 22,254 f 34 and 285 f 29 counts/30 min respectively for the animals injected with prazosin, WB-4101 and saline in the mPFC (see also Table 1; eight animals per group)]. Table 1 shows, in addition, that a dose of 0.016 pmol/side of prazosin injected in the mPFC did not have any effect on D-amphetamine-inducedlocomotor hyperactivity. Finally, when animals were injected with 0.05 pmol/side of prazosin in the mPFC and 4.0 nmol/side of D-amphetamine in the nucleus accumbens, they exhibited locomotor activities in the ranges of either

h

W B 4lOl(pmoles)

4

(0.16)

a 5%

the nucleus accumbens saline- or amphetamine-injected group, thus resulting in a mean locomotor activity intermediate between the two groups' values (Table 1).

Latency of the recovery of intra-nucleus accumbens D-amphetamine-inducedlocomotor hyperactivity following intra-mPFC injections of either prazosin or WB4101 The latency of the recovery of the intra-nucleus accumbens D-amphetamine-induced locomotor hyperactivity following the intracortical injections of different doses of each a 1 antagonist was then tested. On the day following the mPFC injections of the lowest active dose of prazosin (0.16 pmol), animals presented hyperreactivity to intranucleus accumbens D-amphetamine (Fig. 3). This hyperreactivity to D-amphetamine was not observed on the day after the injections of the same dose of WB-4101 (0.16 pmol) (Fig. 4). However, following these bilateral injections of WB-4101 the animals were completely insensitive to infusions of D-amphetamine the next day. When higher doses of prazosin (13 - 160 pmol) were used, prolonged hyporeactivity to D-amphetamine was observed and recovery to normal reactivity, which was dose-dependent, lasted from 2 to 16 days (Fig. 4). Finally, whatever the dose of WB-4101 (0.16 -160 pmol), animals recovered normal reactivity to bilateral injections of D-amphetamine into the nucleus accumbens in 3 days (Fig. 4).

,

Discussion

1-7 0

1

3

0

1

3

(days after intra mPPC WB 4101 injection)

[3 ad PPC + lmph N. ACC.

=

WB 4101 PPC + amph N. Ace.

Flc.4. Time-course of recovery in locomotor hyperactivity induced by Damphetamine (amph) injection in the nucleus accumbens (N. Acc.) after the injection of WB-4101 into the mPFC. The animals first received D-amphetamine in the nucleus accumbens (light columns). Two days later WB-4101 (0.16, 80, 160 pmol/side)was injected into the mPFC and D-amphetamine (4.0 nmohide) into the nucleus accumbens (day 0, dark columns). Finally, the rats received Damphetamine in the nucleus accumbens until the 100% stimulating locomotor effect was found (light columns). *Significantly different from the Damphetamine-nucleus accumbens group (P < 0.05). Data are mean counts per 30 min (+SEM) of an experiment with eight rats in each group.

In this study we have first confirmed and extended the results of Snoddy and Tessel (1985) and those of Dickinson et al. (1988), indicating that the locomotor hyperactivity induced by a systemic injection of D-amphetamine is partly blocked by pretreatment with prazosin. In our study, however, locomotor activities were measured in a circular corridor, and Snoddy and Tessel (1985) obtained their data on mice. In addition, Dickinson et al. (1988) injected D-amphetamine and prazosin at doses which were respectively 2.5 and 16 times higher than those used in the present investigation. The fact that prazosin was active at doses as low as 0.06 mglkg in our experiments suggests that this compound has a high affinity for the receptors responsible for the observed effects. Moreover, since the locomotor hyperactivity induced by scopolamine, a muscarinic antagonist, was not modified by prazosin pretreatment, it indicates that the effects of prazosin on amphetamineinduced locomotor hyperactivity are specifically due to interactions with catecholaminergic systems and not to unspecific sedative effects. Attempts were then made to localize the sites through which prazosin was exerting its action. We have previously shown by autoradiography the presence of a high density of high-affinity [3H]prazosinbinding sites

TABLE1. Effects on locomotor activity of amphetamine injected into the nucleus accumbens together with different doses of prazosin injected into the mPFC.

Cortex, prazosin (pmollside)

Saline

Saline

0.016

0.05

0.16

4.0

4.0

4.0

saline

4.0

584 *45 205 %"

576 f 55 202 %

372 34

280*22 98%d

269*51 95 %e

0.16 ~~

Nucleus accumbens, saline amphetamine (nmol/side) Locomotor activity (counts/30 min)

285 + 29 100%

*

*

131%'

Locomotor activities are expressed in counts/30 min SEM and X of salinehaline-injected animals. aSignificantlydifferent (P < 0.05) from corresponding control values. bSignificantlydifferent (P < 0.05) from corresponding control values and not significantly different from a . =Not significantly different from either group (controls, a and b), dNot significantly different from corresponding control values and significantly different (P < 0.05) from a , CNotsignificantly different from (eight animals per group).

Cortical a 1-adrenergic subcortical DA interactions 297 in layer 111 of the anterior cortex but not in the nucleus accumbens (Trovero er af., 1992a). Therefore, the prefrontal cortex seemed to be an appropriate cortical site in which to look for the inhibitory effect of prazosin on the D-amphetamine-evoked locomotor activity. Such an involvement of the prefrontal cortex was also predicted by several observations indicating that locomotor activity is also dependent on dopaminergic transmission in the prefrontal cortex (Tassin et af., 1978; Vezina et al., 1991). Our study shows that the blockade of cortical Q 1-adrenergic receptors by either prazosin or WB-4101, two a 1-adrenergic antagonists, is sufficient to disrupt the locomotor hyperactivity induced by bilateral injections of D-amphetamine into the nucleus accumbens. This is in agreement with recent observations of Lategan et al. (1990), who demonstrated using microdialysis that the increased release of dopamine in the nucleus accumbens evoked by a local injection of D-amphetamine can be reduced (by 37%) following the destruction of ascending noradrenergic pathways. However, it seems unlikely that this partial effect on dopamine release is the only factor responsible for the complete blockade of the D-amphetamine-evoked locomotor hyperactivity induced by bilateral injections in the prefrontal cortex of a low dose of either prazosin or WB-4101. Previous studies have indicated that descending cortico-nucleus accumbens glutamatergic pathways can prevent the development of dopaminergic denervation hypersensitivity of D1 receptors in the nucleus accumbens (Reibaud et al., 1984). Such a control by cortical efferent glutamatergic neurons has also been demonstrated on D1 receptors located in the antero-median part of the striatum (Hervt et al., 1989). These experiments have indicated that the destruction of the corticosubcortical neurons or the presence of an intact mesocortical dopaminergic innervation appears to be necessary to obtain subcortical D 1 receptor hypersensitivity following dopamine denervation of subcortical dopaminergic structures. It is our view that the hypersensitivity of Dl receptors in a particular structure reflects, whatever its origin, loss of the ability of the cells bearing the D1 receptors to process correctly the dopamine signal they may receive. In other words, when they are not under the control of mesocortical dopaminergic neurons, glutamatergic cortico-subcortical cells may compensate for a subcortical dopamine deficit. On the other hand, increased or excessive cortical dopaminergic control may induce a functional subcortical dopamine deficit. We have obtained some indications that the blockade of cortical a 1-adrenergic receptors would facilitate cortical D 1 transmission (Tassin et al., 1986; Trovero et al., 1992a). Supporting this view, prazosin pretreatment suppresses the D 1 receptor supersensitivity resulting from a cortical deficient dopaminergic transmission (Trovero et al., 1992b). Therefore, since cortical and subcortical D1 transmissions have opposite effects on the behavioural outputs they modulate (Vezina et al., 1991), the increase in cortical D1 transmission induced by the blockade of a 1-adrenergic receptors would decrease the subcortical D1 function. Such a mechanism may explain why a systemic injection of prazosin reverses the locomotor hyperactivity induced by an electrolytic lesion of the ventral tegmental area (Trovero et al., 1992a). It may also explain why an intracortical injection of prazosin or WB-4101 blocks the locomotor hyperactivity obtained by an intra-nucleus accumbens amphetamine injection. Surprisingly, WB-4101 had no effect in our previous experiments on locomotor hyperactivity induced by the electrolytic lesion of the ventral tegmental area when it was injected systemically (Trovero et af., 1992a), whereas, in the present in siru experiments, the effect of WB-4101 is similar to that of prazosin. These differences are not due to distinct pharmacokinetic properties since it has been verified previously that wB-4101 can pass through the blood-brain barrier. However, this latter compound has a better affinity for some cortical binding sites which

are different from those labelled by prazosin (Trovero et al., 1992a). It is therefore possible that the in situ effect of WB-4101 is due to its low activity at the prazosin binding site. This is confirmed by experiments showing that the reversibility of amphetamine-induced locomotor hyperactivity appears quicker following high doses of WB-4101 than following prazosin. The consequence for biochemical events (synthesis of second messenger, phosphorylation etc.) induced by WB-4101 is probably not as profound as that obtained following prazosin injection. Although the hyperreactivity to amphetamine observed on the day following the 0.16 pmol injection of prazosin but not after the injection of the same dose of WB-4101 is not easy to explain, it may be proposed that these different reactivities are due to a lack of specificity of WB-4101. It could be argued that the effects of intracortical injections of al-antagonists induce trauma, which may explain the effects observed on locomotor activity. We have, however, injected into the mPFC other compounds, such as sulpiride, spiroperidol, a-flupenthixol and SCH-23390, which either do not affect or increase locomotor activities induced by intra-nucleus accumbens amphetamine injections (Vezina et al., 1991). Moreover, it should be noted that delayed effects of intramPFC SCH-23390 have recently been observed (Vezina et a l . , 1993). Indeed, an acute cortical injection of SCH-23390 induces immediate hyperreactivity to D-amphetamine injection in the nucleus accumbens and, 2 days later, hyporeactivity to an identical subcortical injection. Altogether these data suggest that the blockade of prefrontocortical a 1-adrenergic or D 1 receptors modifies the processing of stimuli in such a way that it disturbs the subcortical dopaminergic function for a period longer than the time required for the elimination of the antagonist. This effect may be related to the role of noradrenergic and dopaminergic neurons in the preservation of the stability of neural networks, and is reminiscent of the delay necessary to obtain therapeutic improvement with antidepressants. In conclusion, we have shown that the blockade of a prefrontocortical al-adrenergic receptor, either by prazosin or WB-4101, prevents the locomotor hyperactivity induced by amphetamine injected in the nucleus accumbens. We suggest that this effect is due to facilitation of the cortical D1 transmission which, through changes in the pattern of activity of glutamatergic cortico-subcortical cells, will desensitize nucleus accumbens dopaminergic function. It cannot be excluded, however, that prazosin and WB-4101 also act on cortical efferent cells by a process which is independent of their action on dopaminergic transmission.

Acknowledgements The authors wish to thank Mrs Patricia Babouram for her technical assistance and Dr Marie-Mile Krebs for skilful statistical analysis. This work was supported by grants from INSERM and Phillip Moms Europe.

Abbreviation mPFC

medial prefrontal cortex

References Bainbridge, J. G . (1970) The inhibitory effect of amphetamine on exploration in mice. Psychophannacology, 18, 314-319. Besson, M. J., Cheramy, A., Feltz, P. and Glowinski, J. (1971) Dopamine: spontaneous and drug-induced release from the caudate nucleus in the cat. Brain Res., 32, 407-424. Can, L. A. and Moore, K. E. (1970) Effects of amphetamine on contents of norepinephrine and its metabolites in the effluent of perfused cerebral ventricles of the cat. Biochem. Phannacol., 19, 2361 -2374. Creese, I. and Iversen, D. (1975). The pharmacological and anatomical substrates of the amphetamine response in the rat. Brain Res., 83, 419-436. Davis, M. and Aghajanian, G . K. (1976) Effects of apomorphine and haloperidol on the acoustic startle response in the rats. fsychophmcoology, 47, 217.

298 Cortical

01

1-adrenergic subcortical DA interactions

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