Psychomotor slowing, neuroendocrine responses, and behavioral changes after oral administration of meta-chlorophenylpiperazine in normal volunteers

Psychiatry Research 105 Ž2001. 151᎐163

Psychomotor slowing, neuroendocrine responses, and behavioral changes after oral administration of meta-chlorophenylpiperazine in normal volunteers Bernard Sabbe a,b,U , Wouter Hulstijn c , Michael Maes d, Marielle Pier e, Simon Scharpe ´f , Frans Zitman g a

Department of Psychiatry, Uni¨ ersity of Nijmegen, Reinier Postlaan 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands b Uni¨ ersity of Antwerp, Antwerp, Belgium c Nijmegen Institute for Cognition and Information, Uni¨ ersity of Nijmegen, Nijmegen, The Netherlands d Department of Psychiatry, Uni¨ ersity of Maastricht, Maastricht, The Netherlands e Department of Psychiatry, Uni¨ ersity of Nijmegen, Nijmegen, The Netherlands f Laboratory for Clinical Biochemistry, Uni¨ ersity of Antwerp, Antwerp, Belgium g Department of Psychiatry, Uni¨ ersity of Leiden, Leiden, The Netherlands Received 15 September 2000; received in revised form 24 August 2001; accepted 19 September 2001

Abstract The mixed 5-HT receptor agonistrantagonist meta-chlorophenylpiperazine Ž mCPP. is known to suppress locomotor activity in mice and rats. This study aimed: Ž1. to determine whether mCPP induces cognitive and motor changes in normal human volunteers and how these changes relate to the neuroendocrine effects of mCPP; and Ž2. to compare these cognitive and motor changes to the known cognitive and motor slowing patterns in depression and schizophrenia. A computerized method Žused in previous research . analyzed fine motor behavior during figure-copying tasks. In 14 normal male volunteers behavioral responses, body temperature, plasma levels of prolactin and cortisol, and cognitive and motor performance during figure-copying tasks were measured after a single oral dose of mCPP Ž0.5 mgrkg.. mCPP-induced prolongation of the reaction times in all copying tasks, parallel to increases in cortisol and prolactin and some self-reported behavioral effects. There were no changes in the movement times or the velocities of the writing movements. In conclusion, mCPP induced cognitive, but not motor slowing, in normal male volunteers. This indicates that the human serotonin system is also implicated in psychomotor behavior. This pattern of slowing was different from that in depressed and schizophrenic patients. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cognition; Motor; Psychomotor retardation; Cortisol; Prolactin; Depression; Schizophrenia

U

Corresponding author. Tel.: q31-24-361-5327; fax: q31-24-354-0561. E-mail address: [email protected] ŽB. Sabbe..

0165-1781r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 1 . 0 0 3 2 6 - 2

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1. Introduction In recent years, the mixed serotonin Ž5-HT. receptor agonistrantagonist meta-chlorophenylpiperazine Ž m-CPP. has been used to investigate serotonergic function in healthy subjects ŽMurphy et al., 1989; Kahn et al., 1990a,b; Seibyl et al., 1991; Kahn and Wetzler, 1991; Asnis et al., 1992; Silverstone et al., 1994; Meltzer and Maes, 1995; Benjamin et al., 1996; Maes and Meltzer, 1996; Terao et al., 1997; Broocks et al., 1997; Gijsman et al., 1998. and in patients with anxiety disorders Žpanic disorder: Charney et al., 1987; Kahn et al., 1991; Asnis et al., 1992; Wetzler et al., 1996; Broocks et al., 2000; obsessive᎐compulsive disorder: Kahn et al., 1988; Pigott et al., 1991, 1993., depression ŽAsnis et al., 1992; Maes et al., 1997a,b., schizophrenia ŽKahn et al., 1992; Maes and Meltzer, 1996., depersonalization ŽSimeon et al., 1995., pedophilia ŽMaes et al., 2001. and Alzheimer’s disease ŽLawlor et al., 1989.. Psychomotor disturbances are important symptoms in many neuropsychiatric disorders such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s syndrome; psychomotor changes occur during treatment with anti-psychotic, antidepressant and sedative, hypnotic and anxiolytic pharmacological agents. A great deal of evidence indicates involvement of the serotonin system in psychomotor activity in general ŽJacobs, 1991; Wallis, 1994; Jacobs and Fornal, 1997.. Important neural circuits related to the motor system may be serotonergically mediated or modulated; it is well established that the striatum receives a primary serotonergic projection from the dorsal raphe nucleus and that there is complex interdependency between the serotonergic and dopaminergic systems ŽSobin and Sackeim, 1997.. Serotonin may also play a role in cognitive performance in the execution of motor acts, particularly in learning and memory ŽRiedel et al., 1999.. Furthermore, it is well known that selective serotonin reuptake inhibitors ŽSSRIs. may occasionally induce extrapyramidal side effects andror akathisia. This may be a consequence of serotonergically-mediated inhibition of the dopaminergic system. The propensity for the SSRIs to induce

these effects may depend on their affinity to the 5-HT2c receptor ŽLane, 1998.. In mice ŽGleason and Shannon, 1998. and in rats ŽLucki et al., 1989; Ulrichsen et al., 1992., mCPP induced a dose-related decrease in locomotor activity, probably caused by the summative effects of agonist activity at the 5-HT2c receptor as well as at the 5-HT1 receptor family ŽGleason and Shannon, 1998.. It is unclear whether mCPP also induces psychomotor changes in humans. Studies on this issue are scarce, mainly because sensitive measuring methods are lacking. The following effects have been observed in normal volunteers after a single oral or i.v. dose of mCPP ŽBroocks et al., 1997.: 䢇

䢇

䢇

neuroendocrine effects, such as elevations in ACTH, plasma cortisol and prolactin; physiological effects, such as increases in temperature, pupil size and diastolic blood pressure; behavioral effects: after i.v. administration increased anxiety and functional deficit, altered self-reality, changes in mood, increased activation-euphoria and dysphoria.

These anxiogenic, mood and cognitive effects were greater when mCPP was administrated intravenously rather than orally ŽMurphy et al., 1989.. After oral mCPP, only ‘nausea’ was rated significantly higher than placebo values on a somatic symptom check-list or visual analogue scale. In contrast, the subjects who received i.v. mCPP reported significant increases in comparison with those who received placebo in feeling ‘flushed’, ‘dizzy’, ‘stressed’, ‘unpleasant’, and ‘slowed’ and in experiencing ‘nausea’, ‘physical difficulties’ and ‘mental difficulties’. It was also observed that daily administration of mCPP in healthy human volunteers led to the rapid attenuation of many of its behavioral, hormonal and physiological effects ŽBenjamin et al., 1996.. Based on studies of second messenger system effects, antagonist profiles and cross-tolerance investigations with 5-HT1a , 5-HT2a and 5-HT2c . Broocks et al. Ž1997. concluded that the effects of

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mCPP on prolactin, CRHrACTHrcortisol and temperature, as well as its anorectic, anxiogenic and other behavioral responses, have most commonly been attributed to actions mediated by 5-HT2c receptors, where mCPP acts as a partial agonist. In healthy human volunteers and neuropsychiatric patients, pre-treatment with the 5HT1,2 antagonists metergoline and methysergide, the 5-HT2ar2c antagonist ritanserin, or the 5-HT3 antagonist ondonsetron ŽBroocks et al., 1997. has been reported to attenuate some, but not all, of the physiological, neuroendocrine and behavioral effects of mCPP ŽMueller et al., 1986; Kahn et al., 1990a,b; Pigott et al., 1991, 1993; Seibyl et al., 1991.. In recent years, we have developed a sensitive computerized registration method and detailed analysis techniques to measure fine motor behavior: by recording and analyzing writing and drawing movements. Using this method, we have analyzed and differentiated the patterns of cognitive and motor slowing in depression ŽSabbe et al., 1996a,b, 1997, 1999; Van Hoof et al., 1998., schizophrenia ŽVan Hoof et al., 1998; JogemsKosterman et al., 1999, 2001. and Parkinson’s disease ŽHulstijn, 1996.. The computerized system has also been used to analyze the effects of the administration of psychopharmacological agents, e.g. benzodiazepines ŽHulstijn, 1996.. In depressed patients treated for 6 weeks with fluoxetine 20 mg a day, we found that slowing on the more cognitive aspects of the tasks, e.g. reaction time, had significantly decreased or disappeared, while slowing on the motor aspects, the movement time pen-down and the velocity, had only diminished slightly at the end of treatment ŽSabbe et al., 1996b, 1997.. Thus, serotonergic activity might be expected to modulate the psychomotor tasks used in this study. This study aimed: Ž1. to determine whether the oral administration of mCPP induces cognitive and motor slowing in healthy human male subjects, and if so, how these changes relate to the neuroendocrine effects of mCPP; and Ž2. to compare any cognitive and motor changes to the known cognitive and motor slowing patterns in depression and schizophrenia.

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2. Methods 2.1. Subjects

Fourteen healthy normal male volunteers, mean Ž"S.D.. age 29.5 years Ž"8.2. who all gave written informed consent, participated in this study. They underwent physical and clinical investigations we.g. blood tests such as sedimentation rate, serum electrolytes, thyroid function Žthyroid secreting hormone., renal and liver function, radiograph of the heart and lungs and electrocardiogram to exclude any major medical illnesses x. All the subjects had been free from medication for at least 1 month before blood testing. No one was a regular drinker or had ever taken psychotropic drugs. The volunteers were screened for present, past and family history of mental disorders by means of a self-rating scale followed by a semi-structured interview. Those with a current or past history of psychiatric disorders and those with a family history in first-degree relatives were excluded from the study. All the subjects were toxicologically screened by urine tests. By means of a power analysis, based on earlier measurements of reaction times during figure-copying tasks in normal volunteers before and after a 15-mg oral dose of diazepam, it was determined that at least 12 subjects were required ŽHulstijn 1996; alpha s 0.05; H 0 s 1.57; H 1 s 2.68; sigma 0 s 0.32; sigma 1 s 0.76; powers 0.80.. 2.2. Procedures

Each subject was tested on two occasions: during the placebo and mCPP conditions, separated by at least 1 day. Subjects arrived at the University Research Centre at 08.00 h. After insertion of an intravenous cannula at 08.15 h Ž1 h before baseline T 0., two blood samples were collected 30 and 45 min later ŽT 0.. Psychomotor tests were performed at baseline ŽT 0.. Immediately after blood sampling and psychomotor testing at T 0, subjects received either a single oral dose of

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mCPP Ž0.5 mgrkg. or an identical placebo capsule in a randomized single-blind crossover design. Then blood samples were taken and psychomotor tests were performed every 30 min over a 3-h period. Psychomotor tests consisted of test 1 Žsee below. at T 0, T 30, T 60, T 90, T 120, T 150 and T 180 and test 2 Žsee below. at T 0 and T 120. These periods were chosen because, in normal volunteers, plasma peak values of mCPP and plasma peak values of prolactin and cortisol were reached 120 min after oral intake of mCPP ŽMaes and Meltzer, 1996.. Blood was stored in plastic tubes at y20 ⬚C until it was thawed for plasma cortisol and prolactin assay. Subjects remained half supine during the test period and were not allowed to sleep or eat. They wore street clothes during the study. Cortisol was assayed by means of a fluorescence immunoassay ŽAbbott NV, Diagnostic Division, Belgium. method with the TDx ŽAbbott, Belgium.. The sensitivity of the assay was 0.2 ␮grdl. The cross-reactivity of this assay was: 11deoxycortisol 9.9%; corticosterone 6.3%; corti-

sone 2.3%; and tetrahydrocortisol 1.1%. Prolactin was determined by means of an ELISA method ŽAbbott NV, Diagnostic Division, Belgium. on an Imx analyzer. The sensitivity of the assay was 0.60 ngrml. Body temperature was recorded with an electronic thermometer ŽVital Check Monitor 4200; IVAC, CA, USA. just before the blood was sampled for cortisol and prolactin assays. Self-reports of behavioral effects and side effects were obtained using a 15-item visual analogue scale ŽVAS.. For every item, participants had to indicate on a scale from 0 to 10 how they were feeling. The VAS was completed at baseline and at 30-min intervals for 3 h. 2.3. Psychomotor tasks The psychomotor tasks were the same as those used in previous studies ŽSabbe et al., 1996a,b, 1997, 1999.. 2.3.1. Test 1 Test 1 consisted of two tasks: a line-copying

Fig. 1. The stimulus figures of tasks 1, 2, 3 and examples of the stimulus figures of task 4.

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task Žtask 1. and a variant of the Fitts’ task Žtask 2.. In task 1, the subjects had to copy four straight lines Žone vertical, one horizontal and two diagonals. ŽFig. 1.. All the stimuli were presented six times in a fixed random order. Both tasks were preceded by some practice trials. Task 2, a variant of a Fitts’ task ŽMagill, 1993., required more precise planning and programming processes than those in the previous task: two vertically placed open circles had to be connected with a line of "10 mm from the centers of the circles. Per trial, six lines had to be drawn. The accuracy of movement was varied by changing the circle diameter from 0.50 cm in trials 1 and 4 to 0.25 cm in trials 2 and 3. Examples of ‘good’ trials and of ‘wrong’ trials Žall trials not ending in the circle. were given.

mm. The following movement variables were obtained: 䢇

䢇

䢇

2.3.2. Test 2 Subjects had to complete two figure-copying tasks in which the degree of complexity and familiarity was manipulated. In task 3, four simple figures, presented six times in a fixed random order, had to be copied. The figures consisted of simple figures Žcircle and angle. and of more complex figures Ždiamond and spiral. ŽFig. 1.. In task 4, twelve figures had to be copied. The figures were divided into three categories, varying in familiarity: combinations of capital letters, familiar figures and unfamiliar, nonsense patterns ŽFig. 1.. Furthermore, each category was divided into two ‘complexity’ groups, consisting of stimuli of either four or eight strokes. For all tasks, subjects were instructed to draw the figures as fast and as accurately as possible. 2.4. Recording and analyses The drawing movements were recorded using a WACOM digitizer connected to a PC and a normal pen that had been specially designed to measure pen pressure, with a precision of 0.24 N ŽMaarse et al., 1988.. The position of the pen on the digitizing tablet Žaxial pen force. was recorded with a frequency of 206 Hz and a precision of 0.2

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In tasks 1, 3 and 4, the reaction time ŽRT., defined as the time interval between the onset of stimulus presentation and the moment the pen touched the paper and the pressure threshold was exceeded. In all tasks, the movement time ŽMT., defined as the time interval between the first and last moment that the pressure threshold was exceeded. Movement time ŽMT. was divided into the time that the pen was moving on the paper and the pressure threshold was exceeded ŽMTmove., the time that the pen was on the paper but not moving ŽPause. and the time that the pen was above the paper and the pressure was below threshold ŽMTup.. In addition, the mean velocity Žcmrs. during MTmove was calculated for all tasks.

2.5. Data analysis Delta values for T 30᎐T 180 were calculated by subtracting the baseline value from the T 30, T 60, T 90, T 120, T 150 and T 180 values for the neuroendocrine measures and for the kinematic variables. A repeated-measures ŽRM. analysis of variance ŽANOVA. was performed on the delta values of the neuroendocrine and kinematic variables of tasks 1 and 2, with two within-subject factors: Drug Ž mCPP or placebo condition. and Time ŽT 30, T 60, T 90, T 120, T 150, T 180.. Effects of stimulus factors in tasks 3 and 4 were analyzed by performing RM ANOVAs on the raw data. Three within-subject factors were used in task 3 Žfactor 1: mCPPrplacebo condition; factor 2: time and factor 3: complexity.. In task 4, four withinsubject factors were used: mCPPrplacebo condition, time, complexity and familiarity. For every RM ANOVA, Pillai’s Trace is reported. On the basis of the known plasma peak values of mCPP and plasma peak values of prolactin and cortisol 120 min after oral intake of mCPP, tasks 3 and 4 were administered only at T 120 and planned Student’s t-tests Žone-tailed. were car-

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ried out on delta values at T 120. In addition, the baseline-corrected areas under the curve ŽAUC. were calculated after mCPP and placebo for the neuroendocrine measures and the kinematic variables of tasks 1 and 2. Paired t-tests Žone-tailed. were performed to detect differences in AUC following mCPP or placebo. Paired t-tests with Bonferroni corrections were performed to detect differences between mCPP and placebo on the delta values at T 30, T 60, T 90, T 150 or T 180. After correction, P-values of less than 0.01 were considered to be significant. Spearman’s rho Ž␳; one-tailed. was calculated to evaluate the relationship between the double delta values of cortisol, prolactin and RT in task 1. These double delta values corresponded to the placebo-corrected delta values at T 120 Ždelta value for mCPP at T 120 minus delta value for placebo at T 120.. The total VAS score was calculated by adding up all the item scores, except for items 5 Žcalm., 6 Žactive., 11 Žgood overall. and 15 Žmellow., which were subtracted from the total score.

3. Results 3.1. Post-mCPP beha¨ ioral responses (VAS) All 14 subjects tolerated the oral administration of mCPP well, although two subjects suffered from fairly severe nausea and reported the urge to vomit. Table 1 presents the mean scores averaged over T 30᎐T 180 as well as the results of RM ANOVAs and paired t-tests at T 120 per VAS item. After taking mCPP, the subjects felt more nauseated, dizzy, restless and aroused, and less active and mellow than they felt after placebo. It was only at T 120 that the subjects also felt slightly more strange and irritable. The curve of the sum of the double delta scores of the items that showed significant differences between the mCPP and placebo condition = time ŽT 30᎐T 180. followed approximately the same course as the curve of the delta prolactin values = time ŽFig. 2.. 3.2. Prolactin responses to mCPP Fig. 2 shows the time = concentration curves of

the delta prolactin values following placebo or mCPP. Mean values at baseline, T 30᎐T 180 and at T 120 are presented in Table 2. Prolactin values at T 0 did not differ between the two conditions Ž t s 1.20, d.f.s 1,13, Ps 0.25.. For the delta Žbaseline-corrected . prolactin values, there was a significant main effect of Drug Ž F s 6.03, d.f.s 1,13, Ps 0.029., but no significant effect of Time Ž F s 2.37, d.f.s 1,13, Ps 0.123. or Drug= Time interaction Ž F s 1.56, d.f.s 1,13, Ps 0.26.. The administration of mCPP had a significant stimulatory effect on AUC prolactin Ž t s 2.65, d.f.s 1,13, Ps 0.010. and on delta values at T 120 Ž t s 2.046, d.f.s 1,13, Ps 0.031.. 3.3. Cortisol responses to mCPP Mean delta values are displayed in Fig. 2 and presented in Table 2. Cortisol levels did not differ significantly between the mCPP and placebo condition at T 0 Ž t s 0.67, d.f.s 1,13, Ps 0.95.. For the overall baseline-corrected Ždelta. cortisol values, RM ANOVA revealed a significant effect of Drug Ž F s 8.42, d.f.s 1,13, Ps 0.012. and Time Ž F s 6.88, d.f.s 1,13, Ps 0.007.. There was no significant Drug = Time interaction Ž F s 1.63, d.f.s 1,13, P s 0.25.. The administration of mCPP had a significant stimulatory effect on baseline-corrected AUC cortisol secretion Ž t s 2.95, d.f.s 1,13, Ps 0.006. and at T 120 Ž t s 2.86, d.f.s 1,13, Ps 0.007.. 3.4. Post-mCPP temperature responses Delta temperature values are displayed in Fig. 2 and presented in Table 2. The effects of Drug Ž F s 0.42, d.f.s 1,13, Ps 0.53., Time Ž F s 2.73, d.f.s 5,9, Ps 0.09. and Drug= Time Ž F s 2.11, d.f.s 5,9, Ps 0.16. were not significant. Furthermore, there were no significant differences in baseline-corrected AUC temperature Ž t s 0.57, d.f.s 1,13, Ps 0.29. and at T 120 Ž t s 0.31, d.f.s 1,13, Ps 0.383.. Fig. 2 suggests a difference between the two conditions at T 150, but post-hoc tests did not reveal any significant difference after

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Table 1 VAS score per item: means Ž"S.D.. over T 30 to T 180, RM ANOVAs on the baseline-corrected values of T 30 to T 180 and paired t-tests Žone-tailed. on the baseline-corrected values at T 120 Item

Mean Ž"S.D.. mCPP

1 Žhungry. 2 Žsleepy. 3 Žnauseated. 4 Ždizzy. 5 Žcalm. 6 Žactive. 7 Žanxious. 8 Žirritable . 9 Ždepressed. 10 Žhigh. 11 Žgood overall. 12 Žrestless . 13 Žstrange. 14 Žaroused. 15 Žmellow. U

3.95 Ž2.12. 3.11 Ž2.14. 1.21 Ž1.46. 1.23 Ž1.50. 6.89 Ž2.14. 4.30 Ž2.89. 0.28 Ž0.80. 0.29 Ž0.72. 0.33 Ž0.95. 1.90 Ž2.48. 6.78 Ž2.32. 1.17 Ž1.69. 1.64 Ž1.72. 1.08 Ž1.48. 6.84 Ž2.33.

RM ANOVA Placebo

4.85 Ž2.62. 3.10 Ž1.99. 0.1 Ž0.26. 0.19 Ž0.37. 7.86 Ž2.08. 5.61 Ž3.13. 0 Ž0. 0.08 Ž0.18. 0.06 Ž0.17. 2.35 Ž2.88. 7.93 Ž2.26. 0.94 Ž1.43. 0.54 Ž0.71. 0.67 Ž1.42. 7.81 Ž1.86.

Drug F1,13

Drug= Time F5,9

t-test ŽT 120 y T 0. t y1.8

2.09

3.25

3.92

2.38

0.77

2.19

2.88

7.51

1.67

2.81

0.26

0.54

y0.98

9.02

1.84

y2.86

0.80

1.00

1.00

2.29

1.00

1.88

1.66

1.00

1.61

0.01

1.04

0.59

0.43

2.46

y1.18

5.69

0.34

1.58

3.40

1.16

2.09

1.64

1.26

3.40

y4.07

UU

10.13

U

U

U

U

4.77

UU

15.73

UU

UU

UU

U

U

UUU

P- 0.05. P- 0.01. P- 0.001.

UU

UUU

Bonferroni correction Ž t s 2.14, d.f.s 1,13, Ps 0.026.. 3.5. Psychomotor tasks The results are summarized in Table 2. The table shows quite clearly that the results of the three figure-copying tasks Žtasks 1, 3 and 4. were very similar.

3.5.1. Reaction time (RT) RT in all three copying tasks Žtasks 1, 3 and 4; see Table 2. at T 120 after mCPP showed relative slowing of 59, 60 and 107 ms, respectively. Only the line-copying task Žtask 1. was administered every 30 min. Fig. 3 shows the time = baselinecorrected RT curve after placebo and mCPP for the line-copying task. The curve follows a similar course ᎏ albeit a mirror image due to learning effects ᎏ to the time = cortisol and time =

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interactions were found in this task. Also, there were no significant differences in baseline-corrected AUC RT after mCPP or placebo in task 1 Ž ⌬ AUC RT: t s 1.53, d.f.s 1,13, Ps 0.076.. In tasks 3 and 4, the complexity of the figures was manipulated. An increase in complexity resulted in a significant increase in RT in both tasks, but the Drug Ž mCPP and placebo. = Complexity interactions were not significant. In task 4, the familiarity of the figures significantly influenced RT, but as with complexity, no Drug= Familiarity interaction was found. 3.5.2. Mo¨ ement time (MT) In general, mCPP did not have any significant effects on movement time. In the tasks that were done every 30 min, i.e. tasks 1 and 2, no significant effects of Drug, Time and Drug= Time were found. In addition, there were no significant differences in baseline-corrected AUC MT after mCPP or placebo for these tasks wAUC MT in task 1: t s 0.48, d.f.s 1,13, Ps 0.32; task 2: t s y0.36, d.f.s 1,13, Ps 0.36 Žlarge targets. and t s y0.28, d.f.s 1,13, Ps 0.39 Žsmall targets.x. Comparisons between the delta values at T 120 did not show any significant differences between the two conditions for these four tasks ŽTable 2..

Fig. 2. Mean delta values and S.D. of prolactin Župper panel., cortisol Žmiddle panel. and temperature Žlower panel. in the mCPP and placebo conditions. RM ANOVAs revealed no significant Drug effect for temperature, but showed a significant effect of Drug for prolactin, F s 6.03, d.f.s 1,13, Ps 0.029, and cortisol, F s 8.42, d.f.s 1,13, Ps 0.012. There were no significant Drug= Time interactions. Significant effects of Time were only found for cortisol, F s 6.88, d.f.s 1,13, Ps 0.007. Student’s t-tests revealed significant differences between the mCPP and placebo conditions for prolactin and cortisol only at T 120 ŽU P- 0.05..

prolactin ŽFig. 2. curves. However, no significant effects of Drug and no significant Drug= Time

3.5.3. Velocity Drug, Time and Drug= Time did not have any significant effects on velocity in all tasks. There were no significant differences in baseline-corrected AUC velocity between the mCPP and placebo condition w ⌬ AUC velocity in the copying of lines Žtask 1.: t s y0.59, d.f.s 1,13, Ps 0.28 and in the Fitts’ task Žtask 2.: t s y0.27, d.f.s 1,13, P s 0.40 Žlarge targets. and t s y0.20, d.f.s 1,13, Ps 0.43 Žsmall targets.x. Comparisons between delta values at T 120 did not show any significant differences between the two conditions for these four tasks. 3.6. Correlations between neuroendocrine, beha¨ ioral and psychomotor changes The psychomotor variables that showed significant differences between mCPP and placebo,

Table 2 Means and S.D. of the baseline value, delta value averaged over T 30 to T 180 and delta value at T 120 for the mCPP and placebo condition in relation to the neuroendocrine measures, the total VAS score and RTrMT Mean Baseline ŽS.D.. mCPP

RT task 1 Žms. RT task 3 Žms. RT task 4 Žms. MT task 1 Žms. MT task 2 Žms. MT task 3 Žms. MT task 4 Žms.

9.24 5.42 14.80 4.85 36.17 0.68 y7.93 8.75 740 198 731 191 1811 586 240 81 169 68 596 155 2416 608

8.15 3.08 14.09 4.75 36.31 0.54 y4.79 11.21 789 280 796 239 1856 576 255 77 169 35 656 175 2590 598

RM ANOVA

mCPP

Drug F1,13

5.81 9.42 2.02 4.55 0.04 0.24 9.24 11.27 y8 68 ᎐ ᎐ 15 47 y7 32 ᎐ ᎐

Placebo y0.81 2.16 y2.05 3.59 y0.02 0.20 y0.36 4.60 y35 114 ᎐ ᎐ 6 43 y2 36 ᎐ ᎐

U

6.03

U

Delta value at T 120 ŽS.D.. Drug= TimeF5,9 1.56

8.42

1.63

0.42

2.11

UU

15.83

1.59

1.92

2.34

᎐ ᎐

᎐ ᎐

0.25

0.74

0.14

0.47

᎐

᎐ ᎐

᎐

mCPP 9.73 16.75 3.59 5.91 0.04 0.41 12.57 15.99 y6 85 y6 65 55 171 22 55 y1 25 y13 y84 106 348

t-test

Placebo y0.85 2.59 y2.47 4.89 0.00 0.23 0.29 5.20 y65 130 y66 95 y52 278 6 46 y4 26 y48 92 7 324

U

2.26

UU

2.86

0.31 U

2.57

U

2.59

U

1.92

U

1.98

0.80 0.24 y1.02

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Prolactin Žngrml. Cortisol Ž␮grdl. Temperature Ž⬚C. VAS

Placebo

Mean Delta value for T 30᎐T 180 ŽS.D..

1.07

Note. F-values are reported for main effect of Drug and Drug= Time interactions on the baseline-corrected Ždelta. values for the neuroendocrine measures, VAS score and RT and MT of tasks 1 and 2. t-Values are reported for Student’s t-test on the differences between the mCPP and placebo condition for the baseline-corrected Ždelta. values at T 120. For tasks 3 and 4, only t-values are reported, because these tasks were administered only at baseline and T 120. U P- 0.05. UU P- 0.01.

159

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Fig. 3. Mean delta values and S.D. of RT in the mCPP and placebo condition for task 1. RM ANOVA revealed no significant main effect for Drug and Drug= Time interaction. However, Student’s t-test revealed a significant difference between the mCPP and placebo condition for delta RT in task 1 at T 120 Ž t s 2.59, d.f.s 1,13, Ps 0.012.

i.e. the RTs obtained in the three figure copying tasks, were correlated with changes in cortisol, prolactin and temperature. Of the nine possible correlations, only the correlation between the double delta values of cortisol and RT in task 1 was significant Ž␳ s 0.46, Ps 0.047.. Correlations were also calculated between the RTs in the three copying tasks and each of the eight items on the VAS Žnausea, dizzy, active, mellow, irritable, restless, strange and aroused. that showed significant differences between mCPP and placebo. Of the 24 possible correlations, only two were significant: RT in task 3 and item 6 Žactiveness: ␳ s y0.52, Ps 0.028. and item 15 Žmellowness: ␳ s y0.67, Ps 0.005.. However, the sum of the double delta values of the eight items at T 120 did not correlate with prolactin, cortisol and temperature double delta values at T 120.

4. Discussion This study on healthy male volunteers measured psychomotor changes after oral meta-chlorophenylpiperazine. Changes were correlated with neuroendocrine and behavioral effects. Oral mCPP induced prolongation of the reaction time ŽRT. in all three figure-copying tasks, i.e. the copying of lines, simple and complex figures. No changes were found in movement time ŽMT. or velocity.

Psychomotor slowing following mCPP intake has been observed in mice, rats and monkeys ŽKahn and Wetzler, 1991, Table 3; Gleason and Shannon, 1998.. Until now, only weak indications of psychomotor slowing have been described after mCPP in humans; in self-report questionnaires, subjects mentioned feeling less active. In the present study, the same feeling was reported, with the addition of nausea, dizzy, less mellow, irritable, restless, strange and aroused. Our findings in normal volunteers also clearly demonstrated fine motor slowing, i.e. prolongation of the reaction time when executing fine motor tasks after oral mCPP, despite wide variability in the clearance and bioavailability of mCPP ŽGijsman et al., 1998.. Both psychomotor slowing and the behavioral effects peaked at approximately 120 min after drug intake, but only two out of the 24 possible correlations were slightly above chance level. Therefore, these psychomotor changes could not be attributed to the behavioral changes mentioned in other studies ŽMurphy et al., 1989. and in neuropsychological studies that examined the effects of mCPP after pre-treatment with the selective 5-HT3 antagonist ondansetron ŽBroocks et al., 1998. and after the administration of anticholinergics ŽLittle et al., 1995.. In contrast with earlier research ŽKahn et al., 1991., none of our subjects demonstrated signs of a panic attack. The possible origins of psychomotor slowing can roughly be dichotomized into cognitive and motor processes. Earlier research has demonstrated that the separate contributions of cognitive and motor processes cannot be completely isolated by making a distinction between reaction time and movement time. Nevertheless, as a crude first approximation, it might be said that the reaction time reflects cognitive processing, while the movement time mainly reflects motor processing ŽSabbe et al., 1996a,b, 1997, 1999.. Cognitive processes encompass the detection of the stimulus, perceptual and attentional processes, storage in working memory and planning of the movement; and motor processes involve programming of the movement, its initiation, coordination of the agonist and antagonist muscle groups, and execution and feedback monitoring of the motor act. On the basis of this partitioning into cogni-

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tive and motor processes, it can be concluded that mCPP induces slowing of cognitive processes, but does not affect motor processes. Until now, only one study has measured the effect of mCPP or placebo on the cognitive performance of human volunteers. Silverstone et al. Ž1994. did not find any changes in scores on a digit span test, or in the raw scores of the Digit Symbol Substitution test or in a 15-word memory test. Combined with our results, this lack of changes, especially in Žworking. memory tasks, points rather more to perceptual and attentional alterations elicited by mCPP than to memory deficits. Reaction time slowing in our study ran parallel with increases in cortisol and prolactin, but only one of the six possible correlations between postmCPP psychomotor and neuroendocrine changes was above chance level. The neuroendocrine and behavioral changes in the present study were a replication of those found in earlier work ŽMaes and Meltzer, 1996.. These findings strongly implicate the 5-HT system in the pathophysiology of psychomotor slowing in humans. This confirms earlier animal research that emphasized the role of the 5-HT1 and 5-HT2c receptors in the decrease in locomotor activity after mCPP. Prolongation of reaction times when copying lines, simple and complex figures was found in patients with a Major Depressive Episode ŽMDE. Žmelancholic or psychotic subtype. and in schizophrenic patients ŽSabbe et al., 1996a,b; Van Hoof et al., 1998; Jogems-Kosterman et al., 1999, 2001.. However, the nature of the slowing in these two disorders ŽHulstijn, 1996. was different from the psychomotor slowing found in the present study on two aspects. Firstly, in patients with depression and in schizophrenic patients with severe negative symptoms, psychomotor retardation also has a strong motor component. Secondly, the reaction time in these patients became more prolonged when the task was made more difficult by increasing the stimulus complexity or unfamiliarity. In patients with an MDE, RT prolongation decreased significantly or nearly disappeared after treatment with a serotonin reuptake inhibitor, such as fluoxetine Ž20 mg a day; Sabbe et al., 1996b. or sertraline Ž50᎐100 mg a day; Sabbe et

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al., 2000.. This indicates that the 5-HT system, and especially 5-HT2c and 5-HT1 receptors, may play a role in the pathophysiology of the cognitive slowing observed in depressed and schizophrenic patients when performing fine motor tasks. Further research, and especially direct comparison between patient groups and normal control groups after mCPP, is required in order to confirm and differentiate the roles of the 5-HT system in psychomotor alterations in depression and schizophrenia. References Asnis, G.M., Wetzler, S., Sanderson, W.C., Kahn, R.S., Van Praag, H.M., 1992. Functional interrelationship of serotonin and norepinephrine: cortisol response to mCPP and DMI in patients with panic disorder, patients with depression, and normal control subjects. Psychiatry Research 43, 65᎐76. Benjamin, J., Greenberg, B.D., Murphy, D.L., 1996. Daily administration of m-chlorophenylpiperazine to healthy human volunteers rapidly attenuates many of its behavioral, hormonal, cardiovascular and temperature effects. Psychopharmacology 127, 140᎐149. Broocks, A., Briggs, N.C., Pigott, T.A., Hill, J.L., Canter, S.K., Tolliver, T.J., Baldemore, D., Murphy, D.L., 1997. Behavioral, physiological and neuroendocrine responses in healthy volunteers to m-chlorophenylpiperazine Ž m-CPP. with and without ondansetron pretreatment. Psychopharmacology 130, 91᎐103. Broocks, A., Little, J.T., Martin, A., Minichiello, M.D., Dubbert, B., Mack, C., Tune, L., Murphy, D.L., Sunderland, T., 1998. The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls. Biological Psychiatry 43 Ž6., 408᎐416. Broocks, A., Bandelow, B., George, A., Jestrabeck, C., Opitz, M., Bartmann, U., Gleiter, C.H., Meineke, I., Roed, I.S., Ruther, E., Hajak, G., 2000. Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder. International Clinical Psychopharmacology 15 Ž3., 153᎐161. Charney, D.S., Woods, S.W., Goodman, W.K., Heninger, G.R., 1987. Serotonin function in anxiety: effects of the serotonin agonist mCPP in panic disorder patients and healthy subjects. Psychopharmacology 92, 14᎐24. Gleason, S.D., Shannon, H.E., 1998. Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2c receptors in mice. European Journal of Pharmacology 341, 135᎐138. Gijsman, H.J., Van Gerven, J.M.A., Tieleman, M.C., Schoemaker, R.C., Pieters, M.S.M., Ferrari, M.D., Cohen, A.F., Van Kempen, G.M.J., 1998. Pharmacokinetic and

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