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Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens
European Journal of Pharmacology, 140 (1987) 179-185
179
Elsevier EJP 00857
Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens Jerzy Maj *, Krzysztof W~dzony and Violetta Klimek Institute of Pharmacology, Polish Academy of Sciences, Smqtna Street 12, 31-343 Krakbw, Poland
Received30 October 1986,revisedMS received20 February 1987, accepted12 May 1987
The effect of desipramine (DMI) was studied after its repeated administration (10 mg/kg p.o., twice daily, 14 days) to rats, on the action of dopamine and d-amphetamine injected bilaterally into the nucleus accumbens. DMI, applied repeatedly but not acutely, prevented the sedative effect of dopamine and enhanced its stimulating action, as assessed by the open-field test, Repeated administration of DMI also enhanced d-amphetamine-induced locomotor hyperactivity. The number of [3H]SCH 23390 binding sites (D-l) in the limbic system decreased while the number of [3H] spiperone ones (D-2) remained unchanged. The results indicate that, like other antidepressant drugs studied earlier, DMI enhances neurotransmission in the dopamine mesolimbic system (nucleus accumbens) of the rat. Desipramine; Dopamine; d-Amphetamine; Nucleus accumbens; Dopamine receptors; (Behaviour)
1. Introduction
As we found previously, repeated but not single administration of antidepressants enhances the locomotor hyperactivity evoked in rats by injection of d-amphetamine into the nucleus accumbens (W~dzony and Maj, 1983; Maj and Wfxlzony, 1985; Maj, 1986). Moreover, antidepressants, like electroshock applied repeatedly, enhance the stimulation of the exploratory behaviour evoked in rats by injection of dopamine into the nucleus accumbens (Maj et al., 1985; Maj, 1986). Sedation, observed in the first phase after dopamine injection, is prevented by antidepressants and electroshock applied repeatedly (Maj et al., 1985). These, as well as other data (see Discussion) permit the assumption that antidepressants administered repeatedly increase the responsiveness of the mesolimbic dopamine system.
* To whom all correspondenceshould be addressed.
The increase in d-amphetamine and dopamine behavioural stimulation was observed after repeated administration of imipramine and amitriptyline, inhibitors of noradrenaline and 5hydroxytryptamine uptake (Maj and Wf~dzony, 1985; Maj, 1986). Citalopram, a selective inhibitor of the 5-hydroxytryptamine uptake (Hyttel, 1982), exhibited no such effect (Maj, 1986). The question arises whether the noradrenaline uptake inhibitor has an action similar to that of imipramine and amitriptyline which inhibit the uptake of both amines. Therefore, in the present study, we used desipramine (DMI), which has practically no action on the uptake of 5-hydroxytryptamine. We investigated its effect on the action of dopamine and d-amphetamine injected into the nucleus accumbens after estimation in the open-field test and the locomotor activity test. Moreover, we studied the effect of DMI on the binding to dopamine receptors in the limbic system with [3H] SCH 23390 and [3H]spiperone used as ligands for D-1 and D-2 receptor sites, respectively.
0014-2999/87/$03.50 © 1987 ElsevierSciencePublishers B.V. (BiomedicalDivision)
180
2. Materials and methods
The experiments were performed on male Wistar rats (200-250 g), treated repeatedly with saline or DMI. DMI (10 mg/kg p.o. dissolved in 0.9% NaC1) was given twice a day for 14 days. The effect of a single dose of DMI was investigated in rats that received saline (p.o.) for 14 days. All the results are compared with those from a control group treated with saline according to the same schedule. This treatment procedure was applied to avoid any possible differences between groups (1 day vs. 14 days) that could result from a two-week handling. The rats were housed on a constant light/dark cycle (12/12) during drug administration. At the time of surgery the rats were fixed in a David Kopff stereotaxic frame under hexobarbital sodium (100 mg/kg i.p.) anaesthesia. Steel guide cannulae (o.d. 0.4 mm) were then implanted bilaterally in the upper border of the nucleus accumbens septi (coordinates: A 9.5; L 1.8; H 6.1 from the surface of the skull, Krnig and Klippel, 1963). The cannulae were fixed to the skull with acrylic dental cement, d-Amphetamine sulfate or dopamine hydrochloride, dissolved in distilled water or vehicle, was injected bilaterally into the nucleus accumbens septi with internal cannulae (o.d. 0.3 mm) protruding from the guide cannula by 0.5 mm and attached to a Hamilton syringe with a teflon tube. The internal cannula was left in situ for 30 s after injections. The injection volume was always 0.5 #1.
second parameter is presented since we found a very high correlation between the time of walking and the number of ambulations. Locomotor activity was measured in photoresistor actometers (two light beams) in which the rats were placed individually and habituated for 60 min before intracerebral drug administration. d-Amphetamine in a dose of 5 /~g/0.5 /~1 was given 2 and 72 h after the single or the last dose of desipramine. Locomotor activity was measured for 60 rain, starting immediately after the injection of d-amphetamine. At the end of the experiment the rats were killed by an overdose of hexobarbital sodium and the injection sites were identified histologically. The data on the animals in which the sites of injections were not clearly within the nucleus accumbens septi have been discarded.
2.2. Binding studies
2.1. Behaoioural studies
The rats used in [3H]SCH 23390 and [3H] spiperone binding studies were killed 24 h after the last dose of DMI and the limbic system (containing the olfactory tubercle, preoptic area, nucleus accumbens, septum and amygdala) was dissected and rapidly frozen. The tissue was homogenized in 100 volumes (w/v) of an ice-cold potassium phosphate buffer (50 mM, pH 7.4) in a Polytron homogenizer. The homogenates were centrifuged at 25 000 × g for 10 min. The pellets were rehomogenized in another portion of the buffer and centrifuged. The final pellets were resuspended in 40 volumes of potassium phosphate buffer (50 mM, pH 7.4).
Exploratory activity was investigated in a slightly modified open-field test of Janssen et al. (1960). After intracerebral injections of dopamine, 2.5 or 15 /~g/0.5 /tl on each side, the rats were gently placed in a black circular arena (without walls; 1 m in diameter) divided into 6 symmetrical sectors. During the 9 (3 × 3) min experimental session the following parameters were analysed by direct observation: the time of walking, the number of ambulations (number of sectors crossed) and the number of rearing and peeping episodes (looking under the edge of the arena). Only the
2.2.1. [31-1] SCH 23390 binding Tissue suspension, 100 /d, and 600 /~1 of the buffer (potassium phosphate 50 raM, pH 7.4), 200 /~1 of 1/xM cis-flupentixol (displacer) or H20, and 100 F1 of [3H] SCH 23390 were incubated together at 30 °C for 60 min. The incubation was followed by a rapid vacuum filtration through Whatman G F / C glass filters. The filters were washed twice with 10 ml portions of a potassium phosphate buffer (50 mM, pH 7.4) and tritium was estimated by conventional liquid scintillation counting. The specific binding of [3H]SCH 23390 was
181 about 90% of the total binding. [3H]SCH 23390 concentrations ranging from 0.01 to 2 nM were used for Scatchard plots.
2.2.2. [3HI Spiperone binding Membrane suspension 200 /xl, and 1600 /~1 of potassium phosphate buffer (50 mM, pH 7.4), 100 /~l of [3H] spiperone (non-specific binding was obtained by adding 100 pl of I ttM ( - ) sulpiride) were incubated at 37°C for 15 min, followed by 10 min in an ice-cold bath. The total incubation volume (2 ml) was filtered through Whatman G F / C glass filters and the filter was rinsed twice with 10 ml of potassium phosphate (50 mM, pH 7.4) poured on the filters. Radioligand concentrations ranging from 0.01 to 4 nM were used for Scatchard plots. The Bm~, and K D values were calculated individually for each rat by Scatchard analysis for 6-7 concentrations of the ligands; the assays were performed in duplicate. Statistical significance was calculated by means of Student's t-test.
tory activity and rearing + peeping (in saline rats) but had no effect on the behavioural alternation induced by dopamine (fig. 1). DMI administered repeatedly (10 mg/kg p.o., twice daily, 14 days) did not change behaviour. Repeated administration of DMI antagonized sedation (in the first phase) and enhanced hyperactivity (in the second one), both effects having been induced by dopamine (fig. 2). Dopamine, 2.5 #g, administered bilaterally into the nucleus accumbens of rats, decreased ambulation and rearing + peeping in the first observation period (data not given). The behaviour of the rats in the second phase did not differ from that of the AMBULATION 20]
0 - 3 rain
6 - groin
=1
2.3. Drugs d-Amphetamine (sulfate, Smith Kline and French), desipramine (hydrochloride, Ciba Geigy), dopamine (hydrochloride, Sigma), cis-flupentixol (Lundbeck), hexobarbital (sodium, Germed), sulpiride (Sigma), [3H]spiperone (NEN, spec. act. 16.7 Ci/mmol), [3H]SCH 23390 (Novo Pharmaceuticals R.D. Lab., sp. act. 85 Ci/mmol).
_
3m
NG
PEEPI
9
.|
i,o
3. Results
3.1. Behavioural studies 0 J
3.1.1. Effect of dopamine Dopamine, 15 ttg, administered bilaterally into the nucleus accumbens of control rats, diminished ambulation and rearing + peeping in the first phase of observation (0-3 min) and increased both those parameters in the second phase (6-9 rain) (fig. 1). Similar effects were evoked by dopamine given to rate pretreated with a single dose of DMI (10 mg/kg p.o.). DMI, administered as a single dose (10 mg/kg p.o.) attenuated both the ambula-
dopamine - - +
-- + OMI x 1
-- + DMI x 1
Fig. 1. The influenceof a single dose of DMI (10 mg/kg p.o.) on the open-field behavioural effectsof dopamine (15 pg per side) injected into the nucleus accumbens of rats. The data represent the means (±S,E.M.) for 9 rats in each group. Dopamine was given 2 h after DMI. a, A significant difference between the rats treated with dopamine and those receiving saline; B, a significant differencebetweenthe rats treated with a single dose of DMI and those treated with saline (Duncan test, after the two-wayANOVA; level of significance, at least 0.05).
182 TABLE 1
0 - 3 rain
i
Saline× 14
DMIxl (2 h)
DMI×14 (2 h)
DMI×14 (72 h)
133.84- 5.1
78.7+13.8 a
130.04- 8.4
114.0+14.1
361.04-32
10-
c
j
0
After d-amphetamine (AMP)
-+
clopomlfle
Saline × 14 + DMI × 1 + AMP (2 h)
DMI×14 + AMP (2 h)
326.04-29.1
1230.04-46.5 b 677.04-42b
6 - 9 rnin
20-
During habituation to actometers
Saline× 14 + AMP
AMBULATION
30.
Effect of a single dose on repeated treatment with DMI on the spontaneous locomotor activity measured during habituation to actometers, and on the locomotor hyperactivity induced by d-amphetamine given into the nucleus accumbens (5/~g/0.5/~1 per side). The data represent the means ( + S.E.M.) for 9 rats in each group. DMI was given p.o. in a dose of 10 mg/kg, acutely (DMI × 1) or twice daily for 14 days (DMI X 14). d-Amphetamine was given 2 h after a single dose of DMI (acute treatment) and 2 or 72 h after the last dose of DMI (repeated treatment).
-+
DMIx14 + AMP (72 h)
-+
DMIxl/.
-+ DMIxl&
REARING * PEEPING 0 - :3rain
6 - 9 rnin ",B
20
a A significant difference between the effects induced by DMI × 1 and saline; b A statistically significant difference between the effects of d-amphetamine in rats treated repeatedly with saline and DMI. (Duncan test, after the two-way analysis of variance (ANOVA); level of significance, at least 0.05).
controls. Repeated, but not single, treatment with DMI (10 mg/kg p.o., twice daily, 14 days) counteracted the above sedative effect of dopamine (data not given).
c 0
0opom,°e
-
+
~ -+ DMI
3.1.2. Effect of d-amphetamine
_
xl/.
+ £)MI x I/~
Fig. 2. The influence of repeated treatment with DMI (10 mg/kg p.o., twice daily, for 14 days) on behavioural effects of dopamine (15 #g per side) injected into the nucleus accumbens of rats. The data represent the means (+S.E.M.) for 9 rats in each group, a, A significant difference between the effects induced by dopamine and saline; /3, a statistically significant difference between the effects of dopamine in rats treated repeatedly with DMI and saline (Duncan test, after the two-way ANOVA; level of significance, at least 0.05).
DMI (10 mg/kg p.o.) attenuated the locomotor activity measured at the time of habituation (table 1). Repeated administration of DMI (10 mg/kg p.o. twice daily, 14 days) did not change this activity, as assessed 2 or 72 h after the last dose. d-Amphetamine, 5 /~g, administered bilaterally into the nucleus accumbens, enhanced locomotor TABLE 2
Effect of repeated treatment with DMI (10 mg/kg p.o., twice daily, 14 days) on the specific binding of [3H] SCH23390 and [3H] spiperone to rat limbic membranes. The number of binding sites, Bm~ (mean values+ S.E.M.), and the binding affinity constants, K D values (means + S.E.M.) were calculated separately for each rat by Scatchard analysis. Treatment
Saline DMI
[3H]SCH 23390
[3H]spiper0ne
Bm~x (pmol/g tissue)
K D (nM)
na
Bra~ (pmol/~ tissue)
K D (nM)
n
18.9 4- 0.99 14.9 4- 0.67 b
0.53 + 0.05 0.54 + 0.05
4 4
4.95 + 0.12 4.87 + 0.23
0.14 + 0.01 0.15 _+0.01
2 2
a n = number of Scatchard plots, b p < 0.01 vs. saline control (Student's t-test)
183
activity (table 1). This effect was not altered by pretreatment with a single dose of DMI (10 mg/kg p.o.). Repeated treatment with DMI (10 mg/kg p.o., twice daily, 14 days) enhanced the hyperactivity induced by d-amphetamine. The enhancement was observed both 2 and 72 h after the last dose of DMI but was strongest at 2 h. 3.2. Biochemical studies
The results given in table 2 show that repeated treatment with DMI decreased the number of [3H] SCH 23390 binding sites (Bronx) by about 21% in rat limbic membranes. The K o value was not changed. DMI given repeatedly to the rats did not influence [3H]spiperone binding to membranes prepared from the limbic system.
4. Discussion
The results obtained indicate that repeated, but not single, administration of DMI enhanced the behavioural stimulation induced by dopamine or d-amphetamine injected into the nucleus accumbens. The enhanced stimulating action of damphetamine persisted for at least 72 h (after the last dose of DMI). The behavioural stimulation induced by a local injection of dopamine or d-amphetamine into the nucleus accumbens is mediated by dopamine postsynaptic receptors (Pijnenburg et al., 1975; 1976). Therefore it may be assumed that a dopaminergic mechanism is involved in the effect evoked by repeated treatment with DMI. The behavioural inhibition observed after a low dose of dopamine or in the first phase after a higher dose is antagonized by repeated treatment with DMI. The above sedative effect of dopamine c a n be regarded as a result of stimulation of dopamine presynaptic receptors (Wachtel et al., 1979; Svensson and Ahlenius, 1983; Maj et al. in press). Hence the antagonistic effect of DMI administered repeatedly could be due to a diminished sensitivity of the above receptors. DMI administered repeatedly does not affect the binding to dopamine D-2 receptors in the limbic system. Martin-Iverson et al. (1983) re-
ported a similar absence of changes in the nucleus accumbens, and other authors found this for other structures (see: Charney et al., 1981). However, our results indicate that repeated administration of DMI decreases the density of dopamine D-1 receptors in the limbic system. We had observed a similar decrease in the number of D-1 receptors in the limbic system and striatum after repeated administration of other antidepressants such as imipramine, amitriptyline, citalopram, mianserin, iprindole and bupropione, with [3H]SCH 23390 also used as a specific ligand (Klimek and Nielsen, in press). A decreased density of dopamine receptors in the striatum after repeated DMI administration was also reported by Lee and Tang (1982), who used [3H] dopamine - which binds to dopamine presynaptic receptors - as a ligand. We found previously that the stimulating action of dopamine and d-amphetamine, injected into the nucleus accumbens, was also enhanced by repeated administration of imipramine and amitriptyline but not of citalopram - a selective inhibitor of the 5-hydroxytryptamine uptake (Maj and W~dzony, 1985; Maj, 1986). The fact that DMI has an action similar to that of imipramine and amitriptyline indicates that inhibition of noradrenaline uptake may be essential for the appearance of the reported effects. On the other hand, mianserin, which has practically no effect on noradrenaline uptake, also enhances the stimulating action of dopamine and d-amphetamine when it is administered repeatedly (Maj, 1986). Therefore it is likely that another effect common to DMI, imipramine, amitriptyline and mianserin - could be of some importance here. As was found earlier, a number of antidepressants administered repeatedly also enhance the locomotor hyperactivity induced by d-amphetamine, injected systemically to rats and mice (Maj et al., 1984; 1985). Other authors have reported a similar potentiation for some antidepressants in the rat (e.g. Spyraki and Fibiger, 1981; MartinIverson et al., 1983; Arnt et al., 1984). Antidepressants administered repeatedly also potentiate the locomotor hyperactivity induced by l-amphetamine and nomifensine (Maj, 1984), and the exploratory stimulation induced by apomorphine (Spyraki and Fibiger, 1981; Maj et
184
al., 1984). On the other hand, the d-amphetamineor apomorphine-induced stereotypy is not intensified by repeated treatment with various antidepressants (Delini-Stula and Vassout, 1979; Maj et al., 1979; 1985; Spyraki and Fibiger, 1981). All these data, together with the present results, indicate that antidepressants administered repeatedly enhance the responsiveness of the dopamine mesolimbic system. The mechanism of the changes induced by antidepressants is unclear. The binding of [3H]SCH 23390 and [3H]spiperone to dopamine receptors in the limbic system is not increased by DMI, nor is it enhanced by other antidepressants (Klimek and Nielsen, in press). The level of DA and its metabolites in the rat nucleus accumbens and tuberculum olfactorium is also not modified by repeated administration of imipramine (Maj, 1984). Some earlier data pointed to the lack of changes in the level, synthesis and turnover of dopamine in whole brain or in its different regions (the mesolimbic one was not studied) after administration of various antidepressants (see: Charney et al., 1981). Therefore it may be assumed that the increased responsiveness of the dopamine mesolimbic system results from changes in the membrane substrate coupled with the postsynaptic dopamine receptor, or from changes occurring beyond the postsynaptic dopamine receptor. It is also not clear what the decreased density of dopamine D-1 receptors means for function. If this decrease concerned presynaptic receptors, it might be the cause of the abolition of the sedative effect of dopamine. A presynaptic mechanism of the sedative action of dopamine or dopaminomimetics has been postulated by a number of authors (e.g. Serra et al., 1979), though other results are controversial in this respect (e.g. Spyraki and Fibiger, 1981; Diggory and Buckett, 1984). However, it should be mentioned that D-1 receptors have not been demonstrated on DA terminals or cell bodies as yet. It is also possible that the behavioural changes after repeated antidepressant treatment and the down-regulation of D-1 receptors are not related. Moreover, it should be stressed that in the behavioural studies DA was applied locally to the nucleus accumbens while the whole limbic system was used in the binding studies.
Irrespective of the mechanism of action, DMI administered repeatedly facilitates - as a net effect - like some antidepressants, dopamine neurotransmission in the nucleus accumbens or mesolimbic system. Such a facilitation of dopamine transmission is supported by the results obtained in other experimental models (Fibiger and Philips, 1981; Borsini et al., 1985; De Ceballos et al., 1985; Smialowski and Maj, 1986). Irrespective of the involvement of other mechanisms, this facilitation may be of importance to the therapeutic action of antidepressants.
Acknowledgements The authors express their thanks for a generous gift of desipramine (Ciba-Geigy) and [3H] SCH 23390 (Novo Pharmaceuticals R.D. Lab.).
References Arm, J., J. Hyttel and K. Fredericson Over~, 1984, Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: effect on dopaminergic and serotonergic functions, Pol. J. Pharmacol. Pharm. 36, 221. Borsini, F., L. Pulvirenti and R. Samanin, 1985, Evidence of dopamine involvement in the effect of repeated treatment with various antidepressants in the behavioural despair test in rats, European J. Pharmacol. 110, 253. Charney, D.S., D.B. Menkes and G.R. Heninger, 1981, Receptor sensitivity and the mechanism of action of antidepressant treatment, Arch. Gen. Psychiat. 38, 1160. De Ceballos, M.L., A. Benedi, C. De Felipe and J. Del Rio, 1985, Prenatal exposure of rats to antidepressants enhances agonist affinity of brain dopamine receptors and dopamine-mediated behaviour, European J. Pharmacol. 116, 257. Delini-Stula, A. and A. Vassout, 1979, Modulation of dopamine-mediated behavioural response by antidepressants. Effect of single and repeated treatment, European J. Pharmacol. 58, 443. Diggory, G.L. and W.R. Buckett, 1984, Chronic antidepressant administration fails to attenuate apomorphine-induced decrease in rat striatal dopamine metabolites, European J. Pharmacol. 105, 257. Fibiger, H.C. and A.G. Philips, 1981, Increased intracranial self-stimulation in rats after long-term administration of desipramine, Science 214, 683. Hyttel, J., 1982, citalopram - pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity, Prog. Neuropsychopharmacol. Biol. Psychiat. 6, 277. Janssen, P.A.J., A.H.M. Jagenan and K.H.C. Schellekens, 1960,
185 Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. Part IV. Influence of haloperidol (R-1625) and chlorpromazine on the behaviour of rats in an unfamiliar open field situation, Psychopharmacologia (Berlin) 1,389. Klimek, V. and M. Nielsen, Chronic treatment with antidepressants decreases the number of 3H-SCH 23390 binding sites in rat striatum and the limbic system, European J. Pharmacol. (in press). Kt~nig, J.F.R. and R.A. Klippel, 1963, The Rat Brain. A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem, The Williams and Wilkins Company, Baltimore. Lee, T. and S.W. Tang, 1982, Reduced presynaptic dopamine receptor density after chronic antidepressant treatment in rats, Psychiat. Res. 7, 111. Maj, J., 1984, Mechanism of action of antidepressant drugs given repeatedly: changes in the responses mediated by noradrenaline (al) and dopamine receptors, in: IUPHAR 9th International Congress of Pharmacology, London, Proceedings, eds. W. Paton, J. Mitchell, P. Turner (Macmillan Press) Vol. 3, 137. Maj, J., 1986, Repeated treatment with antidepressant drugs: responses mediated by brain dopamine receptors, in: New Results in Depression Research, eds. H. Hippius, G.L. Klerman, N. Matussek (Springer-Verlag, Berlin, Heidelberg) p. 90. Maj, J., E. Mogilnicka and A. Kordecka, 1979, Chronic treatment with antidepressant drugs: potentiation of apomorphine-induced aggressive behaviour in rats, Neurosci. Lett. 13, 337. Maj, J., Z. Rog6~, G. Skuza and H. Sowihska, 1984, Repeated treatment with antidepressant drugs increases the behavioural response to apomorphine, J. Neural Transm. 60, 273. Maj, J., Z. Rog6~, G. Skuza and H. Sowifiska, 1985, The effect of repeated treatment with antidepressant drugs on the action of d-amphetamine and apomorphine in rats, in: Neuropharmocology 85, eds. K. Kelemen, K. Magyar and E.S. Vizi, Akademiai Kiado, Budapest, p. 133. Maj, J. and K. Wfxtzony, 1985, Repeated treatment with imipramine or amitriptyline increases the locomotor response of rats to (+)-amphetamine given into the nucleus accumbens, J. Pharm. Pharmacol. 37, 362.
Maj, J., K. Wfxlzony and G. Skuza, Subsensitivity of presynaptic and supersensitivity of postsynaptic dopaminergic receptors as a result of repeated administration of antidepressant drugs. Proceedings of Fourth Congress of Hungarian Pharmacological Society, ed. Akademiai Kiado (Publishing House, Budapest) (in press). Martin-Iverson, M.T., J.-F. Leclere and H.C. Fibiger, 1983, Cholinergic interactions and the mechanisms of action of antidepressants, European J. Pharmacol. 94, 193. Pijnenburg, A.J.J., W.M.M. Honig and J.M. Van Rossum, 1975, Effects of antagonists upon locomotor stimulation induced by injection of dopamine and noradrenaline into the nucleus accumbens of nialamide-pretreated rats, Psychopharmacologia (Berhn) 41, 175. Pijnenburg, A.J.J., W.M.M. Honig, J.A.M. Van der Heyden and J.M. Van Rossum, 1976, Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity, European J. Pharmacol. 35, 45. Serra, G., A. Argiolas, V. Klimek, F. Fadda and G.L. Gessa, 1979, Chronic treated with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity, Life Sci. 25, 415. Smialowski, A. and J. Maj, 1985, Repeated treatment with imipramine potentiates the locomotor effect of apomorphine administered into the hippocampus in rats, Psychopharmacology 86, 468. Spyraki, C. and H.C. Fibiger, 1981, Behavioural evidence for supersensitivity of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine, European J. Pharmacol. 74, 195. Svensson, L. and S. Ahlenius, 1983, Suppression of locomotor activity by the local application of dopamine or 1-noradrenaline to the nucleus accumbens of the rat, Pharmacol. Biochem. Behav. 19, 693. Wachtel, H., S. Ahlenius and N.-E. And6n, 1979, Effects of locally applied dopamine to the nucleus accumbens on the motor activity of normal rats and following a-methyltyrosine or reserpine, Psychopharmacology 63, 203. Wsdzony, K. and J. Maj, 1983, The effect of repeated treatment with imipramine on the locomotor hyperactivity induced in rats by amphetamine administered into the nucleus accumbens (Abstr.) 8th Congress of the Pharmacological Society, Warsaw, p. 181.
179
Elsevier EJP 00857
Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens Jerzy Maj *, Krzysztof W~dzony and Violetta Klimek Institute of Pharmacology, Polish Academy of Sciences, Smqtna Street 12, 31-343 Krakbw, Poland
Received30 October 1986,revisedMS received20 February 1987, accepted12 May 1987
The effect of desipramine (DMI) was studied after its repeated administration (10 mg/kg p.o., twice daily, 14 days) to rats, on the action of dopamine and d-amphetamine injected bilaterally into the nucleus accumbens. DMI, applied repeatedly but not acutely, prevented the sedative effect of dopamine and enhanced its stimulating action, as assessed by the open-field test, Repeated administration of DMI also enhanced d-amphetamine-induced locomotor hyperactivity. The number of [3H]SCH 23390 binding sites (D-l) in the limbic system decreased while the number of [3H] spiperone ones (D-2) remained unchanged. The results indicate that, like other antidepressant drugs studied earlier, DMI enhances neurotransmission in the dopamine mesolimbic system (nucleus accumbens) of the rat. Desipramine; Dopamine; d-Amphetamine; Nucleus accumbens; Dopamine receptors; (Behaviour)
1. Introduction
As we found previously, repeated but not single administration of antidepressants enhances the locomotor hyperactivity evoked in rats by injection of d-amphetamine into the nucleus accumbens (W~dzony and Maj, 1983; Maj and Wfxlzony, 1985; Maj, 1986). Moreover, antidepressants, like electroshock applied repeatedly, enhance the stimulation of the exploratory behaviour evoked in rats by injection of dopamine into the nucleus accumbens (Maj et al., 1985; Maj, 1986). Sedation, observed in the first phase after dopamine injection, is prevented by antidepressants and electroshock applied repeatedly (Maj et al., 1985). These, as well as other data (see Discussion) permit the assumption that antidepressants administered repeatedly increase the responsiveness of the mesolimbic dopamine system.
* To whom all correspondenceshould be addressed.
The increase in d-amphetamine and dopamine behavioural stimulation was observed after repeated administration of imipramine and amitriptyline, inhibitors of noradrenaline and 5hydroxytryptamine uptake (Maj and Wf~dzony, 1985; Maj, 1986). Citalopram, a selective inhibitor of the 5-hydroxytryptamine uptake (Hyttel, 1982), exhibited no such effect (Maj, 1986). The question arises whether the noradrenaline uptake inhibitor has an action similar to that of imipramine and amitriptyline which inhibit the uptake of both amines. Therefore, in the present study, we used desipramine (DMI), which has practically no action on the uptake of 5-hydroxytryptamine. We investigated its effect on the action of dopamine and d-amphetamine injected into the nucleus accumbens after estimation in the open-field test and the locomotor activity test. Moreover, we studied the effect of DMI on the binding to dopamine receptors in the limbic system with [3H] SCH 23390 and [3H]spiperone used as ligands for D-1 and D-2 receptor sites, respectively.
0014-2999/87/$03.50 © 1987 ElsevierSciencePublishers B.V. (BiomedicalDivision)
180
2. Materials and methods
The experiments were performed on male Wistar rats (200-250 g), treated repeatedly with saline or DMI. DMI (10 mg/kg p.o. dissolved in 0.9% NaC1) was given twice a day for 14 days. The effect of a single dose of DMI was investigated in rats that received saline (p.o.) for 14 days. All the results are compared with those from a control group treated with saline according to the same schedule. This treatment procedure was applied to avoid any possible differences between groups (1 day vs. 14 days) that could result from a two-week handling. The rats were housed on a constant light/dark cycle (12/12) during drug administration. At the time of surgery the rats were fixed in a David Kopff stereotaxic frame under hexobarbital sodium (100 mg/kg i.p.) anaesthesia. Steel guide cannulae (o.d. 0.4 mm) were then implanted bilaterally in the upper border of the nucleus accumbens septi (coordinates: A 9.5; L 1.8; H 6.1 from the surface of the skull, Krnig and Klippel, 1963). The cannulae were fixed to the skull with acrylic dental cement, d-Amphetamine sulfate or dopamine hydrochloride, dissolved in distilled water or vehicle, was injected bilaterally into the nucleus accumbens septi with internal cannulae (o.d. 0.3 mm) protruding from the guide cannula by 0.5 mm and attached to a Hamilton syringe with a teflon tube. The internal cannula was left in situ for 30 s after injections. The injection volume was always 0.5 #1.
second parameter is presented since we found a very high correlation between the time of walking and the number of ambulations. Locomotor activity was measured in photoresistor actometers (two light beams) in which the rats were placed individually and habituated for 60 min before intracerebral drug administration. d-Amphetamine in a dose of 5 /~g/0.5 /~1 was given 2 and 72 h after the single or the last dose of desipramine. Locomotor activity was measured for 60 rain, starting immediately after the injection of d-amphetamine. At the end of the experiment the rats were killed by an overdose of hexobarbital sodium and the injection sites were identified histologically. The data on the animals in which the sites of injections were not clearly within the nucleus accumbens septi have been discarded.
2.2. Binding studies
2.1. Behaoioural studies
The rats used in [3H]SCH 23390 and [3H] spiperone binding studies were killed 24 h after the last dose of DMI and the limbic system (containing the olfactory tubercle, preoptic area, nucleus accumbens, septum and amygdala) was dissected and rapidly frozen. The tissue was homogenized in 100 volumes (w/v) of an ice-cold potassium phosphate buffer (50 mM, pH 7.4) in a Polytron homogenizer. The homogenates were centrifuged at 25 000 × g for 10 min. The pellets were rehomogenized in another portion of the buffer and centrifuged. The final pellets were resuspended in 40 volumes of potassium phosphate buffer (50 mM, pH 7.4).
Exploratory activity was investigated in a slightly modified open-field test of Janssen et al. (1960). After intracerebral injections of dopamine, 2.5 or 15 /~g/0.5 /tl on each side, the rats were gently placed in a black circular arena (without walls; 1 m in diameter) divided into 6 symmetrical sectors. During the 9 (3 × 3) min experimental session the following parameters were analysed by direct observation: the time of walking, the number of ambulations (number of sectors crossed) and the number of rearing and peeping episodes (looking under the edge of the arena). Only the
2.2.1. [31-1] SCH 23390 binding Tissue suspension, 100 /d, and 600 /~1 of the buffer (potassium phosphate 50 raM, pH 7.4), 200 /~1 of 1/xM cis-flupentixol (displacer) or H20, and 100 F1 of [3H] SCH 23390 were incubated together at 30 °C for 60 min. The incubation was followed by a rapid vacuum filtration through Whatman G F / C glass filters. The filters were washed twice with 10 ml portions of a potassium phosphate buffer (50 mM, pH 7.4) and tritium was estimated by conventional liquid scintillation counting. The specific binding of [3H]SCH 23390 was
181 about 90% of the total binding. [3H]SCH 23390 concentrations ranging from 0.01 to 2 nM were used for Scatchard plots.
2.2.2. [3HI Spiperone binding Membrane suspension 200 /xl, and 1600 /~1 of potassium phosphate buffer (50 mM, pH 7.4), 100 /~l of [3H] spiperone (non-specific binding was obtained by adding 100 pl of I ttM ( - ) sulpiride) were incubated at 37°C for 15 min, followed by 10 min in an ice-cold bath. The total incubation volume (2 ml) was filtered through Whatman G F / C glass filters and the filter was rinsed twice with 10 ml of potassium phosphate (50 mM, pH 7.4) poured on the filters. Radioligand concentrations ranging from 0.01 to 4 nM were used for Scatchard plots. The Bm~, and K D values were calculated individually for each rat by Scatchard analysis for 6-7 concentrations of the ligands; the assays were performed in duplicate. Statistical significance was calculated by means of Student's t-test.
tory activity and rearing + peeping (in saline rats) but had no effect on the behavioural alternation induced by dopamine (fig. 1). DMI administered repeatedly (10 mg/kg p.o., twice daily, 14 days) did not change behaviour. Repeated administration of DMI antagonized sedation (in the first phase) and enhanced hyperactivity (in the second one), both effects having been induced by dopamine (fig. 2). Dopamine, 2.5 #g, administered bilaterally into the nucleus accumbens of rats, decreased ambulation and rearing + peeping in the first observation period (data not given). The behaviour of the rats in the second phase did not differ from that of the AMBULATION 20]
0 - 3 rain
6 - groin
=1
2.3. Drugs d-Amphetamine (sulfate, Smith Kline and French), desipramine (hydrochloride, Ciba Geigy), dopamine (hydrochloride, Sigma), cis-flupentixol (Lundbeck), hexobarbital (sodium, Germed), sulpiride (Sigma), [3H]spiperone (NEN, spec. act. 16.7 Ci/mmol), [3H]SCH 23390 (Novo Pharmaceuticals R.D. Lab., sp. act. 85 Ci/mmol).
_
3m
NG
PEEPI
9
.|
i,o
3. Results
3.1. Behavioural studies 0 J
3.1.1. Effect of dopamine Dopamine, 15 ttg, administered bilaterally into the nucleus accumbens of control rats, diminished ambulation and rearing + peeping in the first phase of observation (0-3 min) and increased both those parameters in the second phase (6-9 rain) (fig. 1). Similar effects were evoked by dopamine given to rate pretreated with a single dose of DMI (10 mg/kg p.o.). DMI, administered as a single dose (10 mg/kg p.o.) attenuated both the ambula-
dopamine - - +
-- + OMI x 1
-- + DMI x 1
Fig. 1. The influenceof a single dose of DMI (10 mg/kg p.o.) on the open-field behavioural effectsof dopamine (15 pg per side) injected into the nucleus accumbens of rats. The data represent the means (±S,E.M.) for 9 rats in each group. Dopamine was given 2 h after DMI. a, A significant difference between the rats treated with dopamine and those receiving saline; B, a significant differencebetweenthe rats treated with a single dose of DMI and those treated with saline (Duncan test, after the two-wayANOVA; level of significance, at least 0.05).
182 TABLE 1
0 - 3 rain
i
Saline× 14
DMIxl (2 h)
DMI×14 (2 h)
DMI×14 (72 h)
133.84- 5.1
78.7+13.8 a
130.04- 8.4
114.0+14.1
361.04-32
10-
c
j
0
After d-amphetamine (AMP)
-+
clopomlfle
Saline × 14 + DMI × 1 + AMP (2 h)
DMI×14 + AMP (2 h)
326.04-29.1
1230.04-46.5 b 677.04-42b
6 - 9 rnin
20-
During habituation to actometers
Saline× 14 + AMP
AMBULATION
30.
Effect of a single dose on repeated treatment with DMI on the spontaneous locomotor activity measured during habituation to actometers, and on the locomotor hyperactivity induced by d-amphetamine given into the nucleus accumbens (5/~g/0.5/~1 per side). The data represent the means ( + S.E.M.) for 9 rats in each group. DMI was given p.o. in a dose of 10 mg/kg, acutely (DMI × 1) or twice daily for 14 days (DMI X 14). d-Amphetamine was given 2 h after a single dose of DMI (acute treatment) and 2 or 72 h after the last dose of DMI (repeated treatment).
-+
DMIx14 + AMP (72 h)
-+
DMIxl/.
-+ DMIxl&
REARING * PEEPING 0 - :3rain
6 - 9 rnin ",B
20
a A significant difference between the effects induced by DMI × 1 and saline; b A statistically significant difference between the effects of d-amphetamine in rats treated repeatedly with saline and DMI. (Duncan test, after the two-way analysis of variance (ANOVA); level of significance, at least 0.05).
controls. Repeated, but not single, treatment with DMI (10 mg/kg p.o., twice daily, 14 days) counteracted the above sedative effect of dopamine (data not given).
c 0
0opom,°e
-
+
~ -+ DMI
3.1.2. Effect of d-amphetamine
_
xl/.
+ £)MI x I/~
Fig. 2. The influence of repeated treatment with DMI (10 mg/kg p.o., twice daily, for 14 days) on behavioural effects of dopamine (15 #g per side) injected into the nucleus accumbens of rats. The data represent the means (+S.E.M.) for 9 rats in each group, a, A significant difference between the effects induced by dopamine and saline; /3, a statistically significant difference between the effects of dopamine in rats treated repeatedly with DMI and saline (Duncan test, after the two-way ANOVA; level of significance, at least 0.05).
DMI (10 mg/kg p.o.) attenuated the locomotor activity measured at the time of habituation (table 1). Repeated administration of DMI (10 mg/kg p.o. twice daily, 14 days) did not change this activity, as assessed 2 or 72 h after the last dose. d-Amphetamine, 5 /~g, administered bilaterally into the nucleus accumbens, enhanced locomotor TABLE 2
Effect of repeated treatment with DMI (10 mg/kg p.o., twice daily, 14 days) on the specific binding of [3H] SCH23390 and [3H] spiperone to rat limbic membranes. The number of binding sites, Bm~ (mean values+ S.E.M.), and the binding affinity constants, K D values (means + S.E.M.) were calculated separately for each rat by Scatchard analysis. Treatment
Saline DMI
[3H]SCH 23390
[3H]spiper0ne
Bm~x (pmol/g tissue)
K D (nM)
na
Bra~ (pmol/~ tissue)
K D (nM)
n
18.9 4- 0.99 14.9 4- 0.67 b
0.53 + 0.05 0.54 + 0.05
4 4
4.95 + 0.12 4.87 + 0.23
0.14 + 0.01 0.15 _+0.01
2 2
a n = number of Scatchard plots, b p < 0.01 vs. saline control (Student's t-test)
183
activity (table 1). This effect was not altered by pretreatment with a single dose of DMI (10 mg/kg p.o.). Repeated treatment with DMI (10 mg/kg p.o., twice daily, 14 days) enhanced the hyperactivity induced by d-amphetamine. The enhancement was observed both 2 and 72 h after the last dose of DMI but was strongest at 2 h. 3.2. Biochemical studies
The results given in table 2 show that repeated treatment with DMI decreased the number of [3H] SCH 23390 binding sites (Bronx) by about 21% in rat limbic membranes. The K o value was not changed. DMI given repeatedly to the rats did not influence [3H]spiperone binding to membranes prepared from the limbic system.
4. Discussion
The results obtained indicate that repeated, but not single, administration of DMI enhanced the behavioural stimulation induced by dopamine or d-amphetamine injected into the nucleus accumbens. The enhanced stimulating action of damphetamine persisted for at least 72 h (after the last dose of DMI). The behavioural stimulation induced by a local injection of dopamine or d-amphetamine into the nucleus accumbens is mediated by dopamine postsynaptic receptors (Pijnenburg et al., 1975; 1976). Therefore it may be assumed that a dopaminergic mechanism is involved in the effect evoked by repeated treatment with DMI. The behavioural inhibition observed after a low dose of dopamine or in the first phase after a higher dose is antagonized by repeated treatment with DMI. The above sedative effect of dopamine c a n be regarded as a result of stimulation of dopamine presynaptic receptors (Wachtel et al., 1979; Svensson and Ahlenius, 1983; Maj et al. in press). Hence the antagonistic effect of DMI administered repeatedly could be due to a diminished sensitivity of the above receptors. DMI administered repeatedly does not affect the binding to dopamine D-2 receptors in the limbic system. Martin-Iverson et al. (1983) re-
ported a similar absence of changes in the nucleus accumbens, and other authors found this for other structures (see: Charney et al., 1981). However, our results indicate that repeated administration of DMI decreases the density of dopamine D-1 receptors in the limbic system. We had observed a similar decrease in the number of D-1 receptors in the limbic system and striatum after repeated administration of other antidepressants such as imipramine, amitriptyline, citalopram, mianserin, iprindole and bupropione, with [3H]SCH 23390 also used as a specific ligand (Klimek and Nielsen, in press). A decreased density of dopamine receptors in the striatum after repeated DMI administration was also reported by Lee and Tang (1982), who used [3H] dopamine - which binds to dopamine presynaptic receptors - as a ligand. We found previously that the stimulating action of dopamine and d-amphetamine, injected into the nucleus accumbens, was also enhanced by repeated administration of imipramine and amitriptyline but not of citalopram - a selective inhibitor of the 5-hydroxytryptamine uptake (Maj and W~dzony, 1985; Maj, 1986). The fact that DMI has an action similar to that of imipramine and amitriptyline indicates that inhibition of noradrenaline uptake may be essential for the appearance of the reported effects. On the other hand, mianserin, which has practically no effect on noradrenaline uptake, also enhances the stimulating action of dopamine and d-amphetamine when it is administered repeatedly (Maj, 1986). Therefore it is likely that another effect common to DMI, imipramine, amitriptyline and mianserin - could be of some importance here. As was found earlier, a number of antidepressants administered repeatedly also enhance the locomotor hyperactivity induced by d-amphetamine, injected systemically to rats and mice (Maj et al., 1984; 1985). Other authors have reported a similar potentiation for some antidepressants in the rat (e.g. Spyraki and Fibiger, 1981; MartinIverson et al., 1983; Arnt et al., 1984). Antidepressants administered repeatedly also potentiate the locomotor hyperactivity induced by l-amphetamine and nomifensine (Maj, 1984), and the exploratory stimulation induced by apomorphine (Spyraki and Fibiger, 1981; Maj et
184
al., 1984). On the other hand, the d-amphetamineor apomorphine-induced stereotypy is not intensified by repeated treatment with various antidepressants (Delini-Stula and Vassout, 1979; Maj et al., 1979; 1985; Spyraki and Fibiger, 1981). All these data, together with the present results, indicate that antidepressants administered repeatedly enhance the responsiveness of the dopamine mesolimbic system. The mechanism of the changes induced by antidepressants is unclear. The binding of [3H]SCH 23390 and [3H]spiperone to dopamine receptors in the limbic system is not increased by DMI, nor is it enhanced by other antidepressants (Klimek and Nielsen, in press). The level of DA and its metabolites in the rat nucleus accumbens and tuberculum olfactorium is also not modified by repeated administration of imipramine (Maj, 1984). Some earlier data pointed to the lack of changes in the level, synthesis and turnover of dopamine in whole brain or in its different regions (the mesolimbic one was not studied) after administration of various antidepressants (see: Charney et al., 1981). Therefore it may be assumed that the increased responsiveness of the dopamine mesolimbic system results from changes in the membrane substrate coupled with the postsynaptic dopamine receptor, or from changes occurring beyond the postsynaptic dopamine receptor. It is also not clear what the decreased density of dopamine D-1 receptors means for function. If this decrease concerned presynaptic receptors, it might be the cause of the abolition of the sedative effect of dopamine. A presynaptic mechanism of the sedative action of dopamine or dopaminomimetics has been postulated by a number of authors (e.g. Serra et al., 1979), though other results are controversial in this respect (e.g. Spyraki and Fibiger, 1981; Diggory and Buckett, 1984). However, it should be mentioned that D-1 receptors have not been demonstrated on DA terminals or cell bodies as yet. It is also possible that the behavioural changes after repeated antidepressant treatment and the down-regulation of D-1 receptors are not related. Moreover, it should be stressed that in the behavioural studies DA was applied locally to the nucleus accumbens while the whole limbic system was used in the binding studies.
Irrespective of the mechanism of action, DMI administered repeatedly facilitates - as a net effect - like some antidepressants, dopamine neurotransmission in the nucleus accumbens or mesolimbic system. Such a facilitation of dopamine transmission is supported by the results obtained in other experimental models (Fibiger and Philips, 1981; Borsini et al., 1985; De Ceballos et al., 1985; Smialowski and Maj, 1986). Irrespective of the involvement of other mechanisms, this facilitation may be of importance to the therapeutic action of antidepressants.
Acknowledgements The authors express their thanks for a generous gift of desipramine (Ciba-Geigy) and [3H] SCH 23390 (Novo Pharmaceuticals R.D. Lab.).
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