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0270-6474/83/0306-1270$02.00/O The Jourhal of NeuroscienceCopyright 0 Society for Neuroscience Vol. 3, No. 6, pp. 1 270-1278Pr in ted i n U .S .A . June 1983

ELECTROPHYSIOLOGICAL INVESTIGATIONS ON THE EFFECT OFREPEATED ZIMELIDINE ADMINISTRATION ON SEROTONERGICNEUROTRANSMISSION IN THE RAT1PIERRE BLIER AN D CLAUDE DE MONTIGNY2Centre de Recherche en Sciences Neurologiques, Faculte de Mkdecine, Uniuersite de Mont&al, Case postale 6128, SuccursaleA, Mont&al, Quebec, Canada H3C 3J7

Received August 18, 1982; Revised December 15, 1982; Accepted January 28, 1983

AbstractZimelidine, a selective serotonergic (5HT) reuptake blocker, is a clini cally effective antidepressant.

However, its rapid action on reuptake is in apparent discrepancy with its delayed c linica l efficacy,and data on the effect of its chron ic administration on 5-HT neurotransmission have never beenprovided.In the first series of experiments, the response of CA3 hippocampus pyramida l neurons to theelectrical stimulation of the ventromedial ascending 5-HT pathway was assessed from peristimulustime histograms, and the respons iveness of the same cel ls to iontophoretic applica tions of 5-HT andy-aminobutyric acid (GABA) was measured using the I.TbO method. The suppression of firing ofpyramidal neurons induced by the stimulation was significantly greater in zimelidine-treated rats(5 mg/kg, i.p., q.d. for 14 days) than in controls, but the I. T50 for 5-HT and GAB A was not modifiedby the zimelidine treatment.In a second series of experiments, unitary recordings of 5-HT neurons were obtained from themesencephalic dorsal raphe nucleus. After 2 days of zimelidine treatment (5 mg/kg, i.p., q.d.), thenumber of 5-HT units discharging spontaneously was greatly reduced. After 7 days of treatment, thenumber of active 5-HT neurons had returned to normal values, but their firing rate was slower thanin control animals. After a treatment of 14 days, both the number of active 5-HT units and theirmean firing rate were within normal range. At this time, the responsiveness of 5-HT neurons tointravenous lyserg ic acid diethylamide (LSD) was assessed: the EDbO of LSD was 2- to 3-fold greaterthan in control rats, indicating that their autoreceptors had desensitized.It is concluded that long-term zimel idine treatment enhances the efficacy of 5-HT neurotransmis-sion in the hippocampus. However, the reuptake blockade by zimelidine cannot result in an enhanced5-HT neurotransmission until 5-HT neurons resume a normal electrica l activity. This sequence ofevents may well account for the delayed antidepressant effect of zimelidine in major depression.

Serotonin (5-HT) has long been thought to be impl i-cated in the clinical effect of antidepressant treatments(Lapin and Oxenkriig, 1969). By means of microionto-phoresis, several groups of investigators have evidenceda sensitization of rat forebrain neurons to 5-HT followingchronic administration of different types of tricy clic an-tidepressant (TCA) drugs (De Montigny and Aghajanian, We thank D. Tardif for technical assistance, D. Cyr and G. B. Filosi

for preparing the illustrations, M. Lerebours for typing the manuscript,and G. Blanchette and S. Rossignol for making available the computeranalyses. This research was supported, in part, by Canadian MedicalResearch Council Grant MA-6444. C. De M. is a recipient of a scholar-ship from the Fonds de la Recherche en Sante du Quebec.

To whom correspondence should be addressed.

1978; Gallagher and Bunney, 1979; Menkes et al., 1980;Wang and Aghajanian, 1980; De Montigny et al., 1981a;Menkes and Aghajanian, 1981). This sensitiza tion has atime course consistent with the delayed c linica l effect ofthese drugs and is obtained with doses falling in the rangeof clinical dosage. Furthermore, it seems to be specific tothis class of drugs. These observations suggest that thissensi tization to 5-HT might be implicated in the thera-peutic effect of these drugs. This hypothesis is in keepingwith the reversal of the therapeutic effect of imipramineby the administration of a 5-HT synthesis inhibitor(Shopsin et al., 75).Chronic electroconvulsive shock treatment has beenshown to enhance the behaviora l response to 5-HT ago-nists in rats (Evans et al., 1976; Green et al., 1977;1270


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The Journal of Neuroscience Effect of Zimelidine on 5-HT Neurotransmission 1271Grahame-Smith et al., 1978; Costain et al., 1979) and toinduce an enhanced responsiveness of forebrain neuronsto microiontophoretically applied 5-HT (De Montigny,1980). Thus, two very different types of treatments, TCAdrugs and electroconvulsive shock treatment, both effec-tive in major depression, share this neurobiological effect.This further suggests that enhancing 5-HT neurotrans-miss ion might have an antidepressant effect in majordepression.The addition of lithium to the therapeutic regimens ofpatients presenting a major depression treated with butnot responding to a TCA drug brings a rapid and pro-found amelioration of depression in most cases (De Mon-tigny et al., 1981b; Heninger and Charney, 1982). Giventhe enhancement of the acti vity of 5-HT neurons byshort-term lithium (Grahame-Smith and Green, 1974),this clinical phenomenon might be due to an amplifica-tion of the effect of lithium on the 5-HT system by theTCA-induced sensitization of postsynaptic neurons.Zimelidine is a selective 5-HT reuptake blocker (Rossand Renyi, 1977) and a clin icall y effective antidepressant(Aberg and Holmberg, 1979; Coppen et al., 1979; Mont-gomery et al., 1981; Gershon et al., 1982). Its demethy-lated metabolite, norzimelidine, is an even more potent5-HT reuptake blocker (Ross and Renyi, 1977). However,the rapid action of zimelidine on 5-HT reuptake was inapparent discrepancy with its delayed clinic al efficacy(Montgomery et al., 1981; Gershon et al., 1982). Further-more, the net effect of its chron ic administra tion on 5-HT neurotransm ission has never been documented.In order to assess the net effect of zimelidine treatmenton 5-HT neuro transmiss ion, four aspects of the function-ing of the 5-HT system were investigated electrophysio-logically in the present study: (I) the responsiveness offorebrain neurons to microiontophoretically applied 5-HT; (2) the response of the same neurons to electrica lstimulation of the ascending 5-HT pathway; (3) theactivity of the 5-HT neurons; and (4) the sensitiv ity ofthe 5-HT autoreceptor.

Materia ls and MethodsExperiments on postsynaptic neurons. Ten maleSprague-Dawley rats (150 to 250 gm) were treated for 14days with daily injections of zimelidine (5 mg/kg, i.p.).Twenty-four hours after the last injection, rats wereanesthetized with chloral hydrate (400 mg/kg, i.p.) andmounted in a stereotaxic apparatus. Five-barrel led glass

micropipettes were prepared in a conventiona l manner(Haigler and Aghajanian, 1974). The central barre l usedfor recording was filled with a 2 M NaCl solution satu-rated with Fast Green FCF and the side barre ls werefilled with the following solutions: 5-HT creatinine sulfate(2 or 0.5 mM in 200 mM NaCl, pH 4; Regis), y-aminobu-tyric acid ( GAB A) (50 mM in 50 mM NaCl, pH 4; Calbi-ochem) and acetylcholine chloride (ACh) (20 mM in 200mM NaCl, pH 4.0; Calbiochem), and NaCl (2 M). Thislatter barrel was used for automatic current balancing.CAs hippocampal pyramidal neurons were identified bytheir large amplitude (0.5 to 1.2 mV) and long duration(0.8 to 1.2 msec) action potentials, and their character-istic complex spike discharge, alternating with simple

spike activity (Kandel and Spencer, 1961). Fast Greenwas deposited at the last recording site with a - 26 PAcurrent for subsequent histological verification. Sincemost hippocampal pyramidal neurons are not sponta-neously active in chloral hydrate-anesthetized rats, asmall current of ACh was used to obtain a firing rate inthe physiological range (8 to 12 Hz). The mean currentsof ACh used in controls and zimelidine-treated rats weresim ilar (3.7 f 0.6 and 3.3 + 0.4 nA, respective ly). Theneuronal responsiveness to microiontophoretic applica-tions was assessed using the previously described I-T50method (De Montigny and Aghajanian, 1977). Brie fly,neuronal sensitiv ity is estimated from the charge (currentI in n4 by time T50 in seconds) required to obtain a 50%depression of firing rate from base line.A bipolar concentric electrode (NE-loo, David KopfInstruments) was positioned on the midline at a back-ward angle of 10 in the ventromedial tegmentum (VMT)at A = 2.0; V = 2.3 according to Konig and Klippel(l963).At the end of each experiment a current of 0.5 mA waspassed for 10 set through the stimulating electrode tomake a lesion. This permitted the subsequent local izationof the electrode tip from histological sections (Fig. 1).Square pulses of 0.5 msec were delivered at 0.8 Hz withintensities of 40, 80, 160, and 300 PA. Pulses were gener-ated by a Grass S8 stimulator and were delivered througha direct-coupled isolation unit (model SIV478A). Theunitary acti vity was recorded on magnetic tapes andsubsequently was analyzed on a PDP-11 computer. Per-istimulus time histograms of hippocampal cell firing weregenerated to measure the period of suppression of firing.Raphe neuron recordings. Given that both dorsal andmedial raphe nuclei send 5-HT projections to the hip-pocampus (Kohler, 1982; Kohler and Steinbusch, 1982)and that the properties of these two populations of 5-HTneurons are similar (Aghajanian and Haigler, 1974), re-cordings were obtained from the dorsal raphe nucleuswhere the density of 5-HT neurons is greater and thuslends itself more readily to a systematic investigation.Twelve rats received daily injections of zimelidine (5mg/kg, i.p.) for 2, 7, or 14 days. Twenty-four hours afterthe last injection, they were anesthetized with chloralhydrate (400 mg/kg, i.p.) and mounted in a stereotaxicapparatus. 5-HT raphe neurons were recorded using sin -gle-barrelled glass micropipettes filled with a 2 M NaClsolution saturated with Fast Green. Theta micropipetteswith one barrel filled with glutamate (0.1 M, pH 8; Sigma)were used to activate silen t 5-HT neurons in the 2-daypretreatment group. 5-HT neurons were identified usingthe crite ria established by Aghajanian (1978): a slow (0.5to 2.5 Hz) and regular firing rate, a long duration (0.8 to1.2 msec), and posit ive action potential. The electrodewas first lowered at 0.8 mm anterior to lambda on mid-line, and four other tra jectories were performed 200 pmanterior, 200 pm posterior, and 200 pm on each side. Theelectrode descent was terminated 1 mm below the ventralborder of the Sylvian aqueduct (Fig. 5A). Each 5-HTneuron encountered was recorded for at least 1 min toestablish its basal firing rate. A t the end of the experi-ment in control and 14-day pretreated animals, 10 pg/kgof lyserg ic acid diethylamide (LSD) (see Fig. 7) were


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1272 Blier and De Montigny Vol. 3, No. 6, June 1983

Figure 1. Histological section o f the mesen cephalon (at approx imately A = 1.8 according to Konig and Klippel (1963)) showinga lesion m ade at the tip of the stimulating electrode (arrow). This lesion is in the VMT in which the ascending 5-HT bundletravels (Anden et al., 1966). It is notew orthy that in three rata where the tip of the stimulating electrode was outside of this region,there wa s no response to the electrical st imulat ion even at the highest intensity (300 PA).injected in a tail vein while a recording was made froma dorsal raphe 5-HT neuron exhibiting a stable firingrate. A Fast Green deposit was left at the bottom of thelast electrode track and a mesencephalic block was cutfor subsequent histologica l verification of the area ofrecording.Experiments in SHT-denervated animals. 5,7-Dihy-droxytryptamine (5,7-DHT; 200 pg free base in 20 ~1 of a0.9% NaCl and 0.1% ascorbic acid solution) was injectedin the lateral ventricule in rats under chloral hydrateanesthesia to destroy the 5-HT neurons (Baumgartenand Lachemnayer, 1972). Thir ty minutes before the ad-ministration of 5,7-DHT, desipramine hydrochloride (25mg/kg; Merrel l) was injected intraperitoneally to protectthe noradrenergic system (B jorklund et al., 1975; Gersonand Baldessar ini, 1975). Two weeks after the denerva-tion, systematic electrode tracks were done in the dorsalraphe, and the response of the CA3 pyramida l neurons toVMT stimulation was assessed as previously described.The destruction of 5-HT neurons was subsequently con-firmed by histofluorescence.

ResultsResponsiveness of CA3 pyramidal neurons to mi-croiontophoretic applications of 5-HT. The 14-day pre-treatment with zimelidine (5 mg/kg, i.p.) did not modifythe responsiveness of CA, hippocampal pyramidal neu-rons to microiontophoreticahy applied 5-HT as measuredby the I-T50 method (Fig. 2, Table I). Neither was theresponsiveness of the same neurons to GABA modified.

This absence of any down- or up-regulation of respon-siveness to 5-HT by zimelidine pretreatment confirms anearlier report from our laboratory (De Montigny et al.,1981a).Responsiveness of CAS pyramidal neurons to electri-cal stimulation of the ascending 5-HT pathway. Re-sponses to the electrica l stimulation of the ascending 5-HT pathway in the VMT were measured from the sameneurons tested microiontophoretically in control and zi-melidine-pretreated rats. The latency from the stimula-t ion to the onset of suppression ranged from 4 to 12 mse c.The peristimulus time histogram of Figure 3B showslatencies of 6 msec. Given the distance of approximate ly6 mm travelled by the impulse, these latencies indicatea conduction velocity of 0.5 to 1.5 m/set. This i s fullyconsistent with the slow conduction velocity of the smallunmyelinated 5-HT fibers. Moreover, the marked reduc-tion of the effect of VMT stimulation in 5,7-DHT-pre-treated animals (Fig. 4) is a further indication that theeffect of the VMT stimulation on CA3 pyramida l neuronsis mediated by 5-HT axons.The 40-d stimulations had no detectable effect on theprobab ility of firing of CA3 hippocampal neurons in bothgroups (Fig. 4). With an BO-PA current, the mean durationof suppression of firing was longer in zimelidine-pre-treated rats, but this difference failed to reach statisticalsignif icance due to the wide variation of the responses(Fig. 4). More constant effects were produced by stimu-lations of 160 PA. Figure 3 shows the effect of 160~PAstimulations in a control animal (A) and a zimelidine-


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The Journal of Neuroscience Effect of Zimelidine on 5-HT Nenrotransmission 1273pretreated animal (B) : there was no effect in the control group (Fig. 4); however, it was more difficult to assessrat, whereas a 20-msec reduction of the firing probab ility prec isely the duration of the inhibitory effect of thewas obtained in the zimelidine-pretreated rat. At 300 PA, stimulation since, in many cells, the period of suppressionthe period of suppression was also longer in the zimelidine was followed by an increased probability of firing.These results show that the response of the postsyn-aptic element to the electrica l stimulation of the ascend-ing 5-HT pathway is augmented by chronic zimelidineadministration , whereas the responsiveness of the samepostsynaptic neurons to microiontophoretically applied5-HT was not modified. Hence, the enhanced effect ofthe activation of the ELHT pathway under zimelidinemust be due to a presynaptic modification, most probablyto the impairment of the 5-HT reuptake process.

SALINE

ZIMELIDINE1201

G 5-HT Gg5 7

5-HT G G5 3 5am a

1 minFigure 2. Histograms of the integrated f iring rate of pyram-idal hippocam pal neurons recorded in the CA3 region of acontrol and a zimelidine-pretreated rat (5 mg /kg, i.p., q.d. x 14days) showing the responses of these neurons to microionto-phoret ic applications of 5-HT and GABA (G). Solid barsindicate the duration of applications ; cm-re nt is given innanoamperes; the t ime base applies to both traces.

A

-25TIME (ms)

Firing rate of 5-HT neurons. If 5-HT reuptake block-ade were responsible for the antidepressant effect ofzimel idine, it could be expected to exert its antidepressanteffect rapidly. However, zimelidine, like TCA drugs, re-quires a long-term administration before a full antide-pressant effect is obtained (Montgomery et al., 1981;Gershon et al., 1982). How can this delayed clinic al actionbe reconciled with the rapid blockade of 5-HT reuptake?Since the rate of firing of 5-HT neurons is a critical factorfor the release of the neurotransmitter (Aghajanian etal., 1975), we studied the activ ity of 5-HT neurons in thedorsal mesencephalic raphe nucleus during the course ofzimelidine treatment.In control rats, a mean number of 4.2 f 0.6 5-HTneurons was recorded per l-mm electrode track (see Fig.

TABLE IResponsiveness of CA3 hippocampal pyramidal neurons tomicroiontophoretic applications of 5-HT and GABA in control andzimelidine-treated ratsControl Zimel idine

5-HT 168 + 11 185 f 11m3Y (33)GABA 200235 169 + 24(15) (17)

a Zimelidine was administered at a daily dose of 5 mg/kg , i .p. , for 14days; values are expressed as mean I . T50 -t SE M. I . T W values for 5-HT and GABA in zimelidine-pretreated rats were not signif icant lydifferent ( p > 0.05) from control values.b Numbers in parentheses, number of unite tested.

B15 -

10 -

5-

O--50 -i5 25 5.0

TIME (ms)Figure 3. Perist imulus t ime histograms of CA3 hippocampal pyramidal neurons recorded in a control rat (A) and in a rattreated with zimelidine (5 mg/kg, i .p. , q.d. x 14 days) (B). Each histogram was constructed from 150 st imuli of 0.5 msec deliveredat 0.8 Hz with an intensity of 160 ).LA in the VMT . Bin width is 2 mse c, the total o bservat ion period being 100 mse c. Thest imulat ion pulse was delivered at t ime 0.


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1274 Blier and De Montigny No. 6, 1983

I-

*

CONTROLR= 0.64

5,7-DHT (8)I

(5) (6)T I I I I I I I40 80 120 160 200 240 280 320

CURRENTFigure 4. Relationship between the duration of suppression of CA3 hippo-campal pyramidal neuron firing and the intensi ty of the current used tostimulate the ascending 5-HT pathway in control and zimelidine-pretreatedrats (5 mg/kg, i.p., q.d. x 14 days). Values are expressed as means & SEM; thenumber of cells tested is indicated in parentheses. *, p < 0.05; **, p < 0.001(Students t test, comparing control and zimelidine groups).

5A); their mean firing rate was 1.2 + 0.1 Hz (Fig. 6).Using the same procedure, no 5-HT neurons were re-corded in 5,7-DHT-denervated animals. This is consist-ent with the total disappearance of 5-HT somata in thedorsal raphe in sections prepared for histofluorescence.Twenty-four hours after a 2-day treatment with zimeli-dine (5 mg/kg, i.p., q.d.), hardly any 5HT neurons weredischarg ing spontaneously (Table II). When probing wasdone with a leak of glutamate from a two-barrelledmicropipette, the number of 5-HT units recorded pertract was within the normal range (Table II), confirmingthat most of the 5-HT units were silent. A fter 7 days oftreatment, the number of active 5-HT neurons per trackhad returned to normal values (Table II), but their meanfiring rate was lower than in control animals. Figure 6illustrates the time course of the progressive restorationof the firing rate of these neurons under prolonged zi -melidine treatment.

Sensitivity of the 5-HT autoreceptor. 5-HT autorecep-tors located on the somata of 5-HT neurons play a majorrole in regulating their rate of discharge (Aghajanian etal., 1975). We used LSD, a potent agonist of the 5-HTautoreceptor (Aghajanian and Haigler, 1974), to deter-mine the sensitivity of these receptors following chroniczimelidine treatment. Figure 7 illustrates the response oftwo dorsal raphe units to the intravenous inject ions of 10pg/kg of LSD. In all control animals, this dose produceda complete cessation of firing within 60 sec. Following a14-day treatment with zimelidine , the effect of the samedose of LSD was much smaller (control: 100 & 0% n = 5vs. zimelidine: 49 + 7%, n = 5; p < 0.001). The EDso ofLSD in zimelidine-pretreated rats was increased 2.5-foldbased on the prev iously obtained EDs0 of 4 pg/kg in naiverats (Bl ier and De Montigny, 1980).This indicates that long-term zimelidine treatmentleads to a desensi tization of the 5-HT receptor. The


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The Journal of Neuroscience Effect of Zimelidine on 5-HT Neurotransmission 1275

-250

-1000 pm

I 220 320 490 710 820 910 990 pm

20 300 370 720 840 930 960 pm

2 minFigure 5. A, The area from which the 5-HT units were recorded (shaded area) isrepresented on the reproduction of a histologica l section prepared by radioautographyfollowing intraventricular injection of [3H]5-HT. Each dot represents a 5-HT neuron.This section was kindly loaned to us by L. Descarries, K. C. Watkins, S. Garcia, and A.Beaudet (1982). B and C, Integrated fining rate histograms of 5-HT neurons recordedduring one electrode descent in the area delineated in A from a control rat (B) and arat pretreated with zimelidine (5 mg/kg, i.p., q.d.) for 7 days (C). The depth of recording

for each neuron is indicated in micrometers from the Sy lvius aqueduct.prolonged exposure of the autoreceptor to an increasedamount of 5-HT resulting from the sustained blockade of5-HT reuptake by zimelidine probably leads to the de-sensitization of these receptors as witnessed by the de-creased effectiveness of LSD.

DiscussionThe present results show that chronic zimelidine ad-ministration fails to modify the responsiveness of hippo-campal pyramidal neurons to microiontophoretically ap-plied 5-HT, whereas it enhances their response to the

stimulation of the ascending 5-HT pathway. This differ-ential effect of zimel idine might be explained by thelocation of the 5-HT terminals in the stratum radiatum(Azmitia and Segal, 1978). The stimulation-inducedrelease of 5-HT from terminals would activate receptorslocated on remote dendrites, whereas the 5-HT ejectedfrom the micropipette acts direc tly on the soma. Hence,the blockade of the uptake process can affect the re-sponse of these cel ls to the stimulation without modifyingthat to microiontophoretically applied 5-HT. This inter-pretation is in agreement with the unchanged respon-


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1276 Blier and De Montigny Vol. 3 , No. 6, June 1983

g1 ,p 0.2

1/~

2 E p < 0.001

,z 0 Iz I 12 7 14IT DURATION OF ZIMELIDINE PRETREATMENT(DAYS)Figure 6. Graph showing the mean f ir ing rate (+ SEM) of 5-HT neurons recorded from the shaded area delineated in Figure5A in rats treated for 2, 7, and 14 days with zimelidine (5 mg/

kg, i .p. , q.d.). The shaded zone represents the range (SEM x 2)of the f iring frequency of 5-HT neurons recorded from the samearea in control rats.

TABLE IINumber of 5-HT neurons recorded per 1 -mm trajectory through themesencephalic dorsal raphe in controls, 5,7-DHT-treated, andzimelidine-pretreated rats

No. of 5-HT Neurons No. of TracksRecorded/TrackControl 4.2 f 0.6 135,7-DHT 0 8Zimelidine pretreated

2 days 0.8 + 0.4 152 days (with glutamate) 4.2 f 1.0 57 days 5.3 + 0.8 15

14 days 4.1 f 0.7 17a Zimelidine was administered at a daily dose of 5 mg/kg, i .p. , for thenumber of days indicated. Values are expressed as mean + SEM.*p c 0.001 (the Students t test, when compared with controls).A leak of glutamat e was allowed through one barrel of a thetamicropipette to act ivate si lent units.

siveness of these neurons to 5-HT applied by microion-tophoresis follow ing denervation with 5,7-DHT or acutereuptake blockade by fluoxetine (De Montigny et al.,1980).Fuxe et al. (1979) have reported a decreased density of[3H]5-HT-binding sites and the induction of new lowaffinity binding sites in the hypothalamus followingchron ic zimel idine treatment. However, both these in-vestiga tors and Ross et al. (1981) failed to detect anysigni ficant modification of [3H]5-HT high affinity bindingsites or low affinity binding site induction in the cerebralcortex. The absence of decrement in the neuronal re-sponsiveness to microiontophoretic application of 5-HT

(present resu lts and De Montigny et al., 1981a) indicatesthat there is no down-regulation of the postsynaptic 5-HT-sensitive effector mechanism in the hippocampusfollowing chronic uptake blockade with zimelidine.The enhanced response of hippocampal pyramidalcells to the electrical stimulation of the ascending 5-HTpathway following chron ic zimelidine treatment must beattributed to the blockade of 5-HT uptake, since theresponsiveness of the same neurons to direct microion-tophoretic applica tions of 5-HT was not enhanced. Thus,in contrast with the postsynaptic sensitization inducedby TCA drugs (De Montigny and Aghajanian, 1978;Gallagher and Bunney, 1979; Menkes et al., 1980; Wangand Aghajanian, 1980; De Montigny et al., 1981a; Menkesand Aghajanian, 1981), zimelidine would increase 5-HTneurotransmission via a presynaptic effect.Sheard et al. (1972) and ScuvBe-Moreau and Dresse(1979) have shown that acute 5-HT reuptake blockadereduces the firing rate of 5-HT neurons. In keeping withthis observation we have previously reported that acuteadministration of zimelidine and norzimelidine depressesthe rate of discharge of 5-HT neurons (ED50 = 1.1 and0.8 mg/kg, i.v., respectively) (De Montigny et al., 1981a).This effect of 5-HT reuptake blockers is probably due toan increased availab ility of the neurotransmitter at theautoreceptor site (Aghajanian, 1978). Thus, the marked lydecreased activity of 5-HT raphe neurons at day 2 wasexpected, given the effectiveness of zimel idine and nor-zimelidine in blocking 5-HT reuptake (Ross and Renyi,1977) and the long half-life of norzimelidine (Brown etal., 1980). After 14 daily injections, the activity of 5-HTneurons i s back within the normal range. At this point intime, the responsiveness to LSD, a potent agonist of the5-HT autoreceptor (Aghajanian and Haigler, 1974), isreduced by 2- to 3-fold. Furthermore, ScuvBe-Moreau(1981) has reported a decreased efficacy of acute zimeli-dine in depressing the firing rate of 5-HT neurons follow-ing chron ic treatment with zimel idine. Consequently, theprogressive restoration of 5-HT neuronal activity underzimelidine treatment is attributable to the desensitizationof the auto receptor. These resu lts point to a majordifference between the 5-HT autoreceptor and the post-synaptic 5-HT receptor: the former but not the latterdesensitizes under long-term exposure to an increasedamount of the neurotransmitter.In contrast to zimelidine, chronic administration offemoxetine, chlorimipramine, or imipramine does notinduce desensitization of the 5-HT autoreceptor (Bl ierand De Montigny, 1980; ScuvBe-Moreau, 1981). Femox-etine and its metabolite, norfemoxetine, have a shorthalf-li fe (Mengel and Lund, 1982); tertiary amine TCAdrugs are rapid ly demethylated into their secdndaryforms which are weak 5-HT uptake blockers (Ross andRenyi, 1975a, b; Nagy and Johansson, 1977). This sug-gests that a sustained blockade of 5-HT reuptake isrequired for a desensitization of the 5-HT autoreceptorto occur.In conclusion, the data presented here show that long-term zimel idine treatment enhances the synaptic efficacyof the 5-HT system via reuptake blockade. However,during the firs t few days of zimel idine administration the


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The Journal of NeuroscienceA

B 25

Effect of Zimelidine on 5-HT Neurotransmission

LSD, 10 pglkg, i.v.4

1277

2 minFigure 7. Integrated f i ing rate histograms of dorsal raphe 5-HT neuronsshowing the effect of intravenous administrations of 10 pgg/kg of LSD(arrows) in a control rat (A) and a zimelidine-pretreated rat (5 mg /kg, i.p .,q.d. x 14 days) (B).

electrical act iv ity of 5-HT neurons is markedly slowed telencephalon and diencephalon. Acta Physiol. Stand. 67:down; after several days of t reatment, i t returns to nor- 313-326.ma1 levels. T his sequence of events may well account for Azm itia, E. C., and M. Segal (1978) An autoradiographic anal-the delayed clinical action of zimelidine: the 5-HT reup- ysis of the differential ascending projections of the dorsal andtake blockade cannot result in an enhanced 5-HT neu- median raphe in the rat. J. Comp . Neurol. 179: 641-668.rotransmission unt i l 5-HT neurons resume a normal elec- Baumgarten, H. G., and L. Lachenmayer (1972) 5,7-Dihydrox-tr ical act iv ity. This const itutes further evidence that ytryptamine: Improvement in chemical lesioning of in-doleamine neurons in the mamma lian brain. Z. Zell forsch.enhancing 5-HT neurotransmission might have a thera- 135: 399-414.peut ic effect in major depression. Bjorklund, A., H. G. Baumgarten, and A. Rensch (1975) 5,7-Dihydroxytryptamine: Improvemen t of i ts select iv ity for ser-

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