- Email: [email protected]
P.1.116 Antidepressant-like effects of citalogoam, antagoniste and amodel of receptor antagonist in an animal model of depression
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•
P1, Affectiue disorders and antlclepre~sa~t~
Behavioural profiles of H/Rouen and NH/Rouen mice in different tests evaluating anxiety
M. E1 Yacoubi, J. l~lot, J. @onzfi,lez, Y. Costentin, J.-M. Vaugeois. Fi{E 2735 CNSS, Yacu#d de Mddecine & Plcarmacie, ~o~en,
Eranc e Pro'pose: Mice differing in their behaviour in the tail suspension test, a screening procedure for potential antidepressants, have been selectively bred. The helpless line (H/Rouen), which may represent a new genetic model of depression (El Yacoubi et al., 2003), is much more immobile in the TST than the so-called non helpless CNH/Rouen) line. The response profiles elicited by helpless and non-helpless mice (generations $10 to $20) in different tests evaluating to anxiety were compared in drug-free conditions. Resets: At generation S17 the percentages of mice reaching the selection criteria for classification as non-helpless (immobility time ~<35 sec) and helpless (immobility time ) 1 1 5 sec) were: NIURouen males: 100%; NK/Rouen females: 98%; N/Rouen males: 99%; K/Rouen females: 100%. In the tail suspension test, that lasted 360 seconds, immobility times were higher (P<0.001) in female N/Rouen mice (2494-4 sec, n=121) than in male H/Rouen mice (2184-4 sec, n=107). Immobility times were 1.84-0.1 (n=137) and 3.94-0.6 (n=99) for males and females NIURouen mice respectively. Concerning the elevated plus-maze and light/dark box tests, no differences in anxiety levels were found in mice from both s ~ e s belonging to generations $10 and S17. Exploratory behaviour during the first minutes in the open field test is considered to represent the result of a motivational conflict between a tendency to explore (motivated by curiosity) and that (induced by fear) of staying in close contact with the walls. At generation $20, H/Rouen mice (males: 49164-201; females: 43944-165) showed a decrease in motor activity counts as compared to NK/Rouen mice (males: 90924-330; females: 116534-1288) as measured using an automated Digiscan. On the other hand, in another experimental setting using a videotracking technique, the index of thigmotaxis did not differ between H/Rouen males: 464-2; females: 404-2 and N1-1/Rouen (males: 444-2; females: 404-2). In the holeboard test which provides independent measures of exploration and locomotor activity, numbers of dips were higher (P<0.001) in NH/Rouen than in N/Rouen male and female mice. However, F2 mice derived from cross-breeding between the parental strains K/Rouen and NH/Rouen, did not differ between each other in the holeboard test. Using a 6-man maternal separation procedure male and female H/Rouen mouse pups (1 to 21 day-old) produced less ultrasonic vocalisations (USV) than NH/Rouen pups. Diazepam (3 mg/kg i.p.) did not modify USV in N/Rouen and NI-I/Rouen pups. In the resident-intruder test (mice isolated for 4 weeks), aimed at stu@ing aggressiveness, no differences in aggressiveness towards a CD1 intruder were observed between male N/Rouen and NH/Rouen mice. However, less frequent social grooming behaviour was observed in I-I/Rouen mice than in N-K/Rouen mice. Another social interaction test between male and female mice of the same line revealed a decrease in social and aggressive grooming behaviour in N/Rouen mice, as compared to NN/Rouen mice. C~nel~ion-" Taken together, compared to NH/Rouen, H/Rouen mice do not show signs of important anxiety in a variety of behavioural tests, l)ehavioural parameters associated with anxiety should be explored more thoroughly in F2 intercroases in order to check their relevance in the present model.
References E1Yaooubi et al., Pro~ Natl Aoad sea U S A. 2003;100, 6227-6232.
~ T h e
1~3 adrenoceptor agonist, SR58611A, displays antidepressant-like effects in rodents
J. Stemmelin j , P. Keane 2, Q. Griebel j , B. Scatton j, G. Le Fur 3, 1Sanofi-@nthelabo, CNS Research, Bagneux, France; 2Sanofi-
Syntiqelabo, CNS 2eseare~, Toulouse, France; ~Sano,fi-Synthelabo, R&D, Paris, France [3-adrenoceptors are known to be involved in the modulation of stress-related behaviors. Earlier experiments in rodents have demonstrated that the stimulation of the [33 receptor subtype by 8R58611A, the first selective [33 receptor agonist, resulted in antidepressant-like effects (Simiand et al. 1992). To Nrther explore the antidepressant potential of SR58611A, the drug was tested in two different rodent models of depression with high predictive validity, the forced swimming test in rats and the chronic mild stress procedure in mice. In the forced swimming test, SR58611A induced a significant decrease in immobility time from 1 mg/kg, pc, an effect which is indicative of antidepressantlike activity. This effect was comparable to that observed with fluoxetine. The chronic mild stress procedure in mice involves the chronic sequential application of a variety of mild stressors for six weeks, leading to the appearance of physical and behavioral symptoms similar to those observed during human depression. In this test, SR58611A (3 mg/kg, pc) significantly attenuated stressinduced degradation of the physical state (coat appearance) of mice after one week of treatment, an effect which was comparable to that observed with the protoihnpical antidepresssant, fluoxetine. This effect lasted until the end of the 28-day injection procedure. These results confirm the antidepressant-like potential of SR58611A and suggest further that [33 receptor agonists may be useful in the treatment of depression.
References Simiand J et al. (1992) EarJ Pharmaool219: 193-201.
IP.1.1151 Changes in regional ~-[11C]methylL-tryptophan trapping in patients with major depression treated with citalopram augmented with pindolol A. Berney I ,M. Nishikawa 2, G. Gobbi 1, P. Gravel 1, G. Debonnel 1, M. Diksic 2, C. ]~enkelfat 1 . 1MoG#I University. 2sy~hi~ry.
Me.real, Canada; 2McGitl University, Neurology a~d Neurc~urger)A, Montreal, Canada B a ¢ I c g a ~ & Positron emission tomography (-PET) coupled with the use of ~-[I IC]-methyl-L-tryp~ophan (11 C-c~Mtrp), is believed to provide an index of the brain regional rates of 5-HT synthesis, through the measure of l]C<~Mtrp brain trapping constant ZK*, Recently, decreased regional trapping was reported in the Anterior Cingulate Cortex in unmedicated patients with Major Depression, relative to controls (I), In this study, we inv~tigated prospectively the effects on 1 IC-alVitrp regional trapping of citalopram, augmented with the mixed 5-HTIA and b-adrenoceptor antagonist pindolol, in patients treated for acute Major Depression, l~letheds: A 24 days, two-arm, randomized, double-blind study was conducted in patients with NDD. All patients received citalopram 20 mg/day augmented with either pindolol 2.5 mg tad or
.Pl, Affection disorders and ant~de.pre~saut~ placebo from day 11 to 24. t-IDRS-17 mood scores, as well as PET estimates of 11C-aMtrp trapping were obtained at baseline, and after 10 and 24 days of treatment, respectively. A voxel-wise approach (SPM99), as well as an a priori selected Volume-OfInterest (VOI) based analysis were applied, focusing on the brain areas/5-HT pathways previously identified as the sites of regional differences in 11C-aMtrp trapping between unmedicated patients with MDE and controls: dorsolateral prefrontal cortex (DLPFC), Anterior Cingulate Cortex, Mesial Temporal Cortex, Thalamus, and Caudate Nucleus (1). Results: results obtained at baseline and at day 24 in 9 lvIDD patients (5F/4M, mean4-SD age:4 3,14-11,7, citalopram+pindolol: n=5; citalopram+placebo: n=4) are presented, Repeated Measure ANOVA on I-IDRS-17 scores revealed a significant decrease over time (mean4-SD score at entry=23.34-3.9, at day 24=13.24-5.4, P=35.27; df=2; p<0.0001), with no significant treatment condition effect or Time x trea~nent interaction. VOI's were submitted to Repeated Measure ANOVA, using hemisphere (R, L) and time (baseline, day-24), as repeated measures, revealing a Time x Treatment interaction in the DLPFC (F=6.27 (1,7); p<0.05), and a Timex hemisphere x Treatment interaction in the Caudate Nucleus (F=13.06 (1,7); p<0.01). Post-hoe comparisons (Newman-Keuls test) indicated that the addition of pindolol, relative to placebo, resulted in a significant increase in l l C - a M t r p trapping in all these structures (p<0.02). SPM maps were obtained using proportional scaling to examine whether regional changes in 11C-aMtrp trapping correlated with clinical improvement: in the group as a whole, increases in trapping correlated with a reduction of HDRS17 in the Cingulate Cortex (BAs 32 and 24), Precentral Gyrus (BA40), and the Medial Frontal @yrus (p<0.05; corrected). Conclusion-" pindolol augmentation as a therapeutic strategy in the pharmaootherapy of Major Depression, may rely upon the enhancement of aspects of 5-HT neurotransmission/5-HT synthesis, in pathways believed to regulate mood. Supported by the Canadian Institutes of Health Research (MOP-42438) and a Swiss National Science Foundation grant to the first author.
References [1 ] Rosa-Nero P, Diksie M, Okazawa H, Leyton M, Ghadirian N, Mzenge~a S, Nakai A, Debormel @, Bli~ P and Benkdfat C. Measurement of Brain Regional o;-[11C]Methyl-L-Tryptophan Trapping, as a Measure of Serotonin Synthesis, in Medication-free Patients with Major Depression. Arch Gen Psy&iatry (In press)
•
Antidepressant-like effects of citalopram, desJpramJne and a vasopressinlb receptor antagonist in an animal model of depression
D.H. Overstreet 1, A. Mork 2, J.P. Redrobe 3 . 1University of]lortH
Carolina, .psycHiatry, CHapel Hill, NC. U S.A: 2H Lundbeck A/S, NeurocHemi~try, Val~y, Denmar&' SH, Lundbe& A/E, .psycHiatry &TaNet PHarmacology, Valby, Denmark Vasopressin has been implicated in the response to stress in animals, just as has corticotropin releasing factor (CRF). Therefore, interest has increased in the possibility that vasopressin receptor antagonists, like CRY receptor antagonists, will have antidepressant like-effects in animal models. The present investigation sought to determine whether treatment of Flinders Sensitive Line (PSL) rats, a genetic animal model of depression, with the V l b receptor antagonist SSR149415 would reduce the exaggerated swim test immobility exhibited by the FSL rats. Rats were treated chronically i.p. with vehicle, SSR149415 (5 mg/kg,
S225
twice dally) or reference antidepressants citalopram (10 ms/ks, twice dally) or desipramine (5 ms/kS, once daily) for 10 days. The social interaction and forced swim tests were conducted 22 and 24 h after the last treatment. All active treatments significantly reduced the exaggerated swim test immobility of the FSL rats. In contrast, none of the treatments increased the abnormally low social interaction behavior of the ZPSL rats. Thus, the V1 b receptor antagonist SSR149415, like citalopram and desipramine, has selectNe antidepressant-like effects following chronic treatment for 10 days. The results of an ongoing study with a dose of 10 mg/kg will be reported at the meeting.
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Serotonin and lhe 5HTtAreceptor in the signalling of taste: A novel human surrogate marker?
J.I(_.Melichar 1, T. Heath 2, L.N. Jackson 2, ]~. Watson 2, D.I Nutt,1
L.F. Donaldson 2 , 1 University of Bristol, .psycHopHarmacology
Unit, Bristol, United Ki~gdom; 2 U~ioer~ity of Bristo4 Departme~ of,Physiology, Bristol, United Kingdom Purpose of stud N Appetite is usually reduced and weight loss is common in biological depression. We hypothesised that this altered appetite in depression may be attrbutable to altered taste thresholds as a consequence of altered serotonin levels, either at the level of the taste receptor cell or in the taste transmission pathway, where one of the key modulatory receptors is the 5HT1Areceptor. Metheds/Stntisfies: We used a blind cross-over trial design to investigate the effect of serotonin reuptake inhibition on the thresholds to salt and sucrose in 10 healthy normal volunteers, who were non-smokers. The threshold for salt and sweet tastes were determined at the tip of the tongue, using standard protocols and concentrations of each solute from 1M to 0.02M. Solutions were applied to the tongue in a pseudorandom order, and the number of positive responses to each concentration was recorded until two negative responses were obtained. The taste tests were repeated 2 hours after administration of either venlafaxine (75 ms) or caffeine (50 ms), an active placebo. We used venlafaxine, as at this dose it is primarily a serotonin reuptake inhibitor. Mean thresholdss0o/; for salt and sugar were calculated from curvee of best fit before and after drug and placebo. Thresholdsh0% before and after drug/placebo were compared using a paired t-test. All procedures were approved by the Local Ethics Committee. Results: Caffeine administration resulted in no change in the thresholds0% value for either salt or sucrose, despite having a significant alerting effect equal to that of venlafaxine (p=0.03, Wilcoxon test). Venlafaxin6 had no effect on the thresholdh0o4 for salt, but significantly reduced the thresholds0% for sucrose (Table 1 ). Table Taste
Salt Sweet
1
Thi'eshold~% Before venlafaxine
After venlafaxine
p-value
0.16M 0.29M
0.18M 0.24M
0.3 0.02
Conclusions: These data support the hypothesis that serotonin is involved in either the determination of sucrose taste threshold,
or in the perception of natural sweet tastes, This suggest8 that
•
P1, Affectiue disorders and antlclepre~sa~t~
Behavioural profiles of H/Rouen and NH/Rouen mice in different tests evaluating anxiety
M. E1 Yacoubi, J. l~lot, J. @onzfi,lez, Y. Costentin, J.-M. Vaugeois. Fi{E 2735 CNSS, Yacu#d de Mddecine & Plcarmacie, ~o~en,
Eranc e Pro'pose: Mice differing in their behaviour in the tail suspension test, a screening procedure for potential antidepressants, have been selectively bred. The helpless line (H/Rouen), which may represent a new genetic model of depression (El Yacoubi et al., 2003), is much more immobile in the TST than the so-called non helpless CNH/Rouen) line. The response profiles elicited by helpless and non-helpless mice (generations $10 to $20) in different tests evaluating to anxiety were compared in drug-free conditions. Resets: At generation S17 the percentages of mice reaching the selection criteria for classification as non-helpless (immobility time ~<35 sec) and helpless (immobility time ) 1 1 5 sec) were: NIURouen males: 100%; NK/Rouen females: 98%; N/Rouen males: 99%; K/Rouen females: 100%. In the tail suspension test, that lasted 360 seconds, immobility times were higher (P<0.001) in female N/Rouen mice (2494-4 sec, n=121) than in male H/Rouen mice (2184-4 sec, n=107). Immobility times were 1.84-0.1 (n=137) and 3.94-0.6 (n=99) for males and females NIURouen mice respectively. Concerning the elevated plus-maze and light/dark box tests, no differences in anxiety levels were found in mice from both s ~ e s belonging to generations $10 and S17. Exploratory behaviour during the first minutes in the open field test is considered to represent the result of a motivational conflict between a tendency to explore (motivated by curiosity) and that (induced by fear) of staying in close contact with the walls. At generation $20, H/Rouen mice (males: 49164-201; females: 43944-165) showed a decrease in motor activity counts as compared to NK/Rouen mice (males: 90924-330; females: 116534-1288) as measured using an automated Digiscan. On the other hand, in another experimental setting using a videotracking technique, the index of thigmotaxis did not differ between H/Rouen males: 464-2; females: 404-2 and N1-1/Rouen (males: 444-2; females: 404-2). In the holeboard test which provides independent measures of exploration and locomotor activity, numbers of dips were higher (P<0.001) in NH/Rouen than in N/Rouen male and female mice. However, F2 mice derived from cross-breeding between the parental strains K/Rouen and NH/Rouen, did not differ between each other in the holeboard test. Using a 6-man maternal separation procedure male and female H/Rouen mouse pups (1 to 21 day-old) produced less ultrasonic vocalisations (USV) than NH/Rouen pups. Diazepam (3 mg/kg i.p.) did not modify USV in N/Rouen and NI-I/Rouen pups. In the resident-intruder test (mice isolated for 4 weeks), aimed at stu@ing aggressiveness, no differences in aggressiveness towards a CD1 intruder were observed between male N/Rouen and NH/Rouen mice. However, less frequent social grooming behaviour was observed in I-I/Rouen mice than in N-K/Rouen mice. Another social interaction test between male and female mice of the same line revealed a decrease in social and aggressive grooming behaviour in N/Rouen mice, as compared to NN/Rouen mice. C~nel~ion-" Taken together, compared to NH/Rouen, H/Rouen mice do not show signs of important anxiety in a variety of behavioural tests, l)ehavioural parameters associated with anxiety should be explored more thoroughly in F2 intercroases in order to check their relevance in the present model.
References E1Yaooubi et al., Pro~ Natl Aoad sea U S A. 2003;100, 6227-6232.
~ T h e
1~3 adrenoceptor agonist, SR58611A, displays antidepressant-like effects in rodents
J. Stemmelin j , P. Keane 2, Q. Griebel j , B. Scatton j, G. Le Fur 3, 1Sanofi-@nthelabo, CNS Research, Bagneux, France; 2Sanofi-
Syntiqelabo, CNS 2eseare~, Toulouse, France; ~Sano,fi-Synthelabo, R&D, Paris, France [3-adrenoceptors are known to be involved in the modulation of stress-related behaviors. Earlier experiments in rodents have demonstrated that the stimulation of the [33 receptor subtype by 8R58611A, the first selective [33 receptor agonist, resulted in antidepressant-like effects (Simiand et al. 1992). To Nrther explore the antidepressant potential of SR58611A, the drug was tested in two different rodent models of depression with high predictive validity, the forced swimming test in rats and the chronic mild stress procedure in mice. In the forced swimming test, SR58611A induced a significant decrease in immobility time from 1 mg/kg, pc, an effect which is indicative of antidepressantlike activity. This effect was comparable to that observed with fluoxetine. The chronic mild stress procedure in mice involves the chronic sequential application of a variety of mild stressors for six weeks, leading to the appearance of physical and behavioral symptoms similar to those observed during human depression. In this test, SR58611A (3 mg/kg, pc) significantly attenuated stressinduced degradation of the physical state (coat appearance) of mice after one week of treatment, an effect which was comparable to that observed with the protoihnpical antidepresssant, fluoxetine. This effect lasted until the end of the 28-day injection procedure. These results confirm the antidepressant-like potential of SR58611A and suggest further that [33 receptor agonists may be useful in the treatment of depression.
References Simiand J et al. (1992) EarJ Pharmaool219: 193-201.
IP.1.1151 Changes in regional ~-[11C]methylL-tryptophan trapping in patients with major depression treated with citalopram augmented with pindolol A. Berney I ,M. Nishikawa 2, G. Gobbi 1, P. Gravel 1, G. Debonnel 1, M. Diksic 2, C. ]~enkelfat 1 . 1MoG#I University. 2sy~hi~ry.
Me.real, Canada; 2McGitl University, Neurology a~d Neurc~urger)A, Montreal, Canada B a ¢ I c g a ~ & Positron emission tomography (-PET) coupled with the use of ~-[I IC]-methyl-L-tryp~ophan (11 C-c~Mtrp), is believed to provide an index of the brain regional rates of 5-HT synthesis, through the measure of l]C<~Mtrp brain trapping constant ZK*, Recently, decreased regional trapping was reported in the Anterior Cingulate Cortex in unmedicated patients with Major Depression, relative to controls (I), In this study, we inv~tigated prospectively the effects on 1 IC-alVitrp regional trapping of citalopram, augmented with the mixed 5-HTIA and b-adrenoceptor antagonist pindolol, in patients treated for acute Major Depression, l~letheds: A 24 days, two-arm, randomized, double-blind study was conducted in patients with NDD. All patients received citalopram 20 mg/day augmented with either pindolol 2.5 mg tad or
.Pl, Affection disorders and ant~de.pre~saut~ placebo from day 11 to 24. t-IDRS-17 mood scores, as well as PET estimates of 11C-aMtrp trapping were obtained at baseline, and after 10 and 24 days of treatment, respectively. A voxel-wise approach (SPM99), as well as an a priori selected Volume-OfInterest (VOI) based analysis were applied, focusing on the brain areas/5-HT pathways previously identified as the sites of regional differences in 11C-aMtrp trapping between unmedicated patients with MDE and controls: dorsolateral prefrontal cortex (DLPFC), Anterior Cingulate Cortex, Mesial Temporal Cortex, Thalamus, and Caudate Nucleus (1). Results: results obtained at baseline and at day 24 in 9 lvIDD patients (5F/4M, mean4-SD age:4 3,14-11,7, citalopram+pindolol: n=5; citalopram+placebo: n=4) are presented, Repeated Measure ANOVA on I-IDRS-17 scores revealed a significant decrease over time (mean4-SD score at entry=23.34-3.9, at day 24=13.24-5.4, P=35.27; df=2; p<0.0001), with no significant treatment condition effect or Time x trea~nent interaction. VOI's were submitted to Repeated Measure ANOVA, using hemisphere (R, L) and time (baseline, day-24), as repeated measures, revealing a Time x Treatment interaction in the DLPFC (F=6.27 (1,7); p<0.05), and a Timex hemisphere x Treatment interaction in the Caudate Nucleus (F=13.06 (1,7); p<0.01). Post-hoe comparisons (Newman-Keuls test) indicated that the addition of pindolol, relative to placebo, resulted in a significant increase in l l C - a M t r p trapping in all these structures (p<0.02). SPM maps were obtained using proportional scaling to examine whether regional changes in 11C-aMtrp trapping correlated with clinical improvement: in the group as a whole, increases in trapping correlated with a reduction of HDRS17 in the Cingulate Cortex (BAs 32 and 24), Precentral Gyrus (BA40), and the Medial Frontal @yrus (p<0.05; corrected). Conclusion-" pindolol augmentation as a therapeutic strategy in the pharmaootherapy of Major Depression, may rely upon the enhancement of aspects of 5-HT neurotransmission/5-HT synthesis, in pathways believed to regulate mood. Supported by the Canadian Institutes of Health Research (MOP-42438) and a Swiss National Science Foundation grant to the first author.
References [1 ] Rosa-Nero P, Diksie M, Okazawa H, Leyton M, Ghadirian N, Mzenge~a S, Nakai A, Debormel @, Bli~ P and Benkdfat C. Measurement of Brain Regional o;-[11C]Methyl-L-Tryptophan Trapping, as a Measure of Serotonin Synthesis, in Medication-free Patients with Major Depression. Arch Gen Psy&iatry (In press)
•
Antidepressant-like effects of citalopram, desJpramJne and a vasopressinlb receptor antagonist in an animal model of depression
D.H. Overstreet 1, A. Mork 2, J.P. Redrobe 3 . 1University of]lortH
Carolina, .psycHiatry, CHapel Hill, NC. U S.A: 2H Lundbeck A/S, NeurocHemi~try, Val~y, Denmar&' SH, Lundbe& A/E, .psycHiatry &TaNet PHarmacology, Valby, Denmark Vasopressin has been implicated in the response to stress in animals, just as has corticotropin releasing factor (CRF). Therefore, interest has increased in the possibility that vasopressin receptor antagonists, like CRY receptor antagonists, will have antidepressant like-effects in animal models. The present investigation sought to determine whether treatment of Flinders Sensitive Line (PSL) rats, a genetic animal model of depression, with the V l b receptor antagonist SSR149415 would reduce the exaggerated swim test immobility exhibited by the FSL rats. Rats were treated chronically i.p. with vehicle, SSR149415 (5 mg/kg,
S225
twice dally) or reference antidepressants citalopram (10 ms/ks, twice dally) or desipramine (5 ms/kS, once daily) for 10 days. The social interaction and forced swim tests were conducted 22 and 24 h after the last treatment. All active treatments significantly reduced the exaggerated swim test immobility of the FSL rats. In contrast, none of the treatments increased the abnormally low social interaction behavior of the ZPSL rats. Thus, the V1 b receptor antagonist SSR149415, like citalopram and desipramine, has selectNe antidepressant-like effects following chronic treatment for 10 days. The results of an ongoing study with a dose of 10 mg/kg will be reported at the meeting.
•
Serotonin and lhe 5HTtAreceptor in the signalling of taste: A novel human surrogate marker?
J.I(_.Melichar 1, T. Heath 2, L.N. Jackson 2, ]~. Watson 2, D.I Nutt,1
L.F. Donaldson 2 , 1 University of Bristol, .psycHopHarmacology
Unit, Bristol, United Ki~gdom; 2 U~ioer~ity of Bristo4 Departme~ of,Physiology, Bristol, United Kingdom Purpose of stud N Appetite is usually reduced and weight loss is common in biological depression. We hypothesised that this altered appetite in depression may be attrbutable to altered taste thresholds as a consequence of altered serotonin levels, either at the level of the taste receptor cell or in the taste transmission pathway, where one of the key modulatory receptors is the 5HT1Areceptor. Metheds/Stntisfies: We used a blind cross-over trial design to investigate the effect of serotonin reuptake inhibition on the thresholds to salt and sucrose in 10 healthy normal volunteers, who were non-smokers. The threshold for salt and sweet tastes were determined at the tip of the tongue, using standard protocols and concentrations of each solute from 1M to 0.02M. Solutions were applied to the tongue in a pseudorandom order, and the number of positive responses to each concentration was recorded until two negative responses were obtained. The taste tests were repeated 2 hours after administration of either venlafaxine (75 ms) or caffeine (50 ms), an active placebo. We used venlafaxine, as at this dose it is primarily a serotonin reuptake inhibitor. Mean thresholdss0o/; for salt and sugar were calculated from curvee of best fit before and after drug and placebo. Thresholdsh0% before and after drug/placebo were compared using a paired t-test. All procedures were approved by the Local Ethics Committee. Results: Caffeine administration resulted in no change in the thresholds0% value for either salt or sucrose, despite having a significant alerting effect equal to that of venlafaxine (p=0.03, Wilcoxon test). Venlafaxin6 had no effect on the thresholdh0o4 for salt, but significantly reduced the thresholds0% for sucrose (Table 1 ). Table Taste
Salt Sweet
1
Thi'eshold~% Before venlafaxine
After venlafaxine
p-value
0.16M 0.29M
0.18M 0.24M
0.3 0.02
Conclusions: These data support the hypothesis that serotonin is involved in either the determination of sucrose taste threshold,
or in the perception of natural sweet tastes, This suggest8 that