278 P.2 Antidepressants." basic and clinical studies

trimipramlne: 27 ± 2 , n - 5) There was one dropout in the busp~rone, two in the fluvoxamine, and five in the deslpramlne groups.

After 7 days. 8 patients on busp~rone had a greater than 50% decrease m their HAM-D score and, after 14 days, 9 patients had a score smaller than 9 In the f luvoxamine group, a greater than 50% improvement was obtained in 4 patients after 14 days, and in 8 patients after 21 days. Only one patient on tr imipramme improved by 50% after 28 days Three patients who had received desipramine (HAM-D: 28 ± 2) were then given paroxetme and pindolol, and four patients who were on trimipramine (HAM-D: 21 ± 3) then received buspirone and pindolol. One week later, they were significantly improved [HAM-D: 17 ± 3 and 16 ± 1, respectively)

Although these results have to confirmed in double-blind studies, it ~s striking that the buspirone-pindolol combination resulted in a marked im- provement in the first week of treatment, whereas, in the other groups, the patients experienced such an improvement after only two or more weeks According to our hypothesis, m the presence of a blockade of 5-HT1A autoreceptors by pindolol, the selective activation by buspirone of postsy naptic 5-HT1A receptors would underlie the remarkably rapid and robust antidepressant observed

References

Artigas. E, Perez. V and Alvarez, E (1994) Pindolo' induces a rapid improvement of de pressed patients treated with serotonln reuptake inhibitor Arch Gen Psychlat 5 ~ 248-51

Blief. 13 and Bergeron, R (1995) Effectiveness of plndolol with selected antidepressant drugs m the treatment of maior depression J Clin 13sychopharmacol 15, in press

Blier, 13, Seletti, B r Bouchard, C, Artigas, F, and de Mont~gny, C., Functional evidence for the differential responsiveness of pre- and postsynaptic 5 HT1A receptors in the rat brain Society for Neuroscience Abstracts 20: 632.9. 1994

Pindolol potentiates the effect of paroxetine on 5-HT efflux in the rat dorsal raphe nucleus

Colin Davidson. Jonathan A. Stamford. Anaesthetics Unit (Neurotransmission Laboratory), London Hospital Medical College, Whitechapel, London Et 1BB, UK

An enduring criticism of antidepressants, mcluoing serotonm-selectwe re-. uptakeinhibitors(SSRIs), remains their slow onset of action Although the SSRIs act acutely on serotonin {5 HT) uptake, their clinical effect oPly be- comes apparent fol lowing 2-3 weeks of treatment, possibly due to dowm regulation of 5-HT autoreceptors in the dorsal raphe nucleus (DRN) [Chap~t et at, 1991}. This leads to diminished feedback control of 5-HT release and thus an enhanced (disinhiPited) response to the SSRI

This has led to attempts to mimic autoreceptor down-regulation clinically by blocking the autoreceptors. Artigas et al [1994] have shown that comoF nation of an SSRI {paroxetine) and the 5-HT1A receptor and /~-adrenoceotor antagonist pindolol rapidly (~5 days) alleviates depressive symptoms In the present study we investigated the effects of this drug combinatio q on 5 HT efflux in the DRN

Serotonin (5-HT) efflux in slices of rat DRN was evoked by electncal stim- ulation (20 pulses, 100 Hz, every 10 minutes) and measured by fast cyclic vo l tammetry(FCV) The t ime for peak 5-HT efflux to fall by half after the stimulation (tl/2} was used as a measure of the rate of 5-HT uptake. Parox.. etine (10 7 M), pindolol (10 -6 M) or the combination were administered after the third stimulation and their effects on peak 5-HT efflux monitored for a further 60 minutes. All values (60 minutes post-drug) are expressed as a percentage of the pre-drug penod All statistical comparisons wereoy one way ANQVA with posthoc Tukey-Kramer test

Drug 5-HT efflux 5 HT uptake t Vz

Control 98 ± 3 102 ± 6 Pindolol{] 0/zM) 125± 7 118± 6 Paroxetine (01 tiM) 147 ± 6 309 ± 29 tt Paroxetine ~ Pindolol 220 :l: 26** 385 ± 52 tt~

Means J_ s e m (n - 4/5) *" P < 0 0! vs p~ndolol, paroxetlne and controls, ~t p < 0 01, tt- p < 0001 vs controls

Table 1 shows the results Pindolol had no effect on 5-HT efflux or u~atake Paroxetine, on its own, slowed 5-HT uptake but did not significantly increase 5 HT efflux. However, m combination wGh pindolol, paroxetlne significantly/ increased 5-HTef f lux Pindolol did not increase the effect of paroxetmeon 5 HT uptake.

These data suggest that, fol lowing paroxetine, DRN 5-HT autoreceptors are activated and this partly counteracts the effect of uptake blockade Pindolol potentiates the effect of paroxetine on 5-HT efflux by blocking this autoinhibitory tone This may explain the rapid clinical improvement

seen w~th this combination and provide a basis for future antidepressant strategies.

Acknow/edgernents." We thank SmithKline Beecham and the Nuffie)d Foundation for support.

References

Artigas, F, Perez, V and Alvarez, E (1994) Pindolol induces a rapid improvement of de- pressed patients treated with serotonin reuptake inhibitors, Archives of General Psy- chiatry 51,248-251

Chaput, ¥. De Montigny, C and Blier, R {1991) 13resynaptic and postsynaptic modifica- tions of the serotonin system by long-term administration of antidepressant treat- ments Neuropsyehopharmacology 5,219-229

Acute and chronic effects of imipramine on serotonergic function. Microdialysis studies in conscious rats

F. Artigas, N Bel. Department of Neurochernisto4, CS/C. Jordi Girona 18-26, 08034 Barcelona, Spain

Selective 5-HT reuptake inhibitors (SSRI) and MAC inhibitors increase pref- erentially the extraceltular concentration of 5-HT (5-HText) in the midbrain raphe nuclei, as compared to forebrain regions. This regional selectivity is due to the higher density of 5-HT uptake sites and MAP in the dorsal raphe nucleus and to the activation of inhibitory 5-HT1A autoreceptors by the ex- cess 5-HT produced by these drugs. When given repeatedly, tow doses of SSRI or MAgi increase cortical 5-HTex t (Bel and Artigas, 1993; Ferret and Artigas. 1994). Yet, the information regarding the effects of non-selective inhbitors of uptake is limited to clomipramine (Adell and Artigas, 1991), a tncyclic drug with very high affinity for the 5-HT transporter, Therefore. we have examined the acute and chronic effects of imipramine on 5-HText in the brain of conscious rats, using microdialysis (see references for experi- mental details),

Locally applied, imipramine induced dose-dependent increases of 5-HText ,n both regions examined (data expressed as fmol/fraction).

Basal 1 #M 10/zM 33/zM 100 JAM

Cortex 5 4 ± 1 4 5 .7918 1 2 7 ± 0 8 4 1 1 ± 4.5 3 3 9 ± 6.3 Raphe 121 ± 2 9 1 3 9 ± 2 9 30 .9±36 746±16.9 77.2±144

The calculated EC50 were very similar (108 and 12.4/~M for FC and RN, respectively), suggesting a comparable mteractpon of imipramine with the 5-HT carner in both regions. Yet, when imipramine was given systemically, a totally different picture emerged. 5-HText in RN was similarly affected by all doses (4, 10 and 20 mg/kg) (ca. 190-210% of basal). In contrast, the effect in FC was clearly dose-dependent (no change at 4 mg/kg and 300 and 400% of basal at 10 and 20 mg/kg, respectively) When the 4 mg/kg dose was given daily for two weeks using osmotic mmipumps, 5-HText increased to 260% of controls in FC, but not in RN ( + 5 % )

These results show that imipramine inhibits 5-HT uptake and increases 5-HText with an z# vivo potency similar to that of clomipramine. Given the clear dose-effect relationship in RN after local administration, the flat- tened response obtained after systemic administration suggests transy~ naptic mechanisms that attenuate 5-HT release in this area. The reduced effect in RN probably accounts for the marked elevations observed in FC, although changes in noradrenergic transmission also may be involved. Also, as with other antidepressant drugs, the chronic treatment with a daily dose that is ineffective when given as a bolus, results in marked elevations of 5-HText in FC.

Supported by a grant from the Fondo de Investigaci6n Sanitaria {95/266)

References

,#*dell A and Artigas, F (1991) Differential effects of clomipramine given locally or sys- temically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex An in vivo microdialysis study. Naunyn-Schmied. Arch Pharmacol 343, 237-244

Bel N and Artigas, F (1993) Chronic treatment with fluvoxamine increases extracellular serotonln in frontal cortex but not in raphe nuclei Synapse 15, 243-245

Ferrer, A and Artigas, E (1994) Effects o1 single and chronic treatment with tranyl- cypromine on extracellular serotonin in rat brain. Eur. J Pharmacol. 263, 227-234