Introduction

1. Pindolol 20 mg Buspirone 30 mg or placebo or placebo 0 1:30 2:00 2:30 3:00 EEG EEG EEG EEG Temp Temp Temp Temp Blood Blood Blood Blood VAS VAS VAS VAS Buspirone and Pindolol Effects on the EEG Frequency Spectrum in Healthy MenR.H. McAllister-Williams* and A.E. MasseyDepartment of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK 1 4 7 Analysis of centroids - 8 sites Introduction 5-HT receptors may be of central importance l 1A in the pathophysiology and treatment of affective disorders 1 Current methods of examining their functional l Subjective effects rated using VAS scales integrity in man are limited: l No main effect of buspirone or pindolol on depressed, The neuroendocrine response to l-tryptophan and 5-HT F l 1A agonists may reflect postsynaptic hypothalamic 5-HT drowsy or restless VAS 1A receptor activation 2 Significant buspirone X time effect, but not pindolol, The hypothermic effect of 5-HT agonists is believed to l F 1A reflect a combination of somatodendritic and postsynaptic on ‘nausea’ ( F(2.52,30.23) = 4.86, p < 0.01) and Significant effect of buspirone and pindolol l 5- HT receptor activation 3 ‘ lightheaded’ ( F(2.06,26.82) = 10.32, p < 0.001) 1A Buspirone and pindolol effects on the EEG frequency Effect greater at posterior sites l The 5-HT agonist buspirone causes a leftward l l 1A Pindolol + buspirone significantly less than buspirone spectrum l shift of the EEG frequency spectrum 4,5 which is Pindolol + buspirone not significantly different from l ( F(2.26,27.11) = 4.80, p < 0.05 and F(2.42,29.08) = Relative power between 0.5 and 30Hz calculated from FFT (plotted to F hypothesised to reflect somatodendritic 5-HT buspirone alone 15Hz) 1A 3.03, p = 0.055 respectively) 8 5 2 receptor activation Correlation between effects Methods 14 healthy male volunteers l 4-way random order cross over, double blind l experiment Resting EEG recorded, plus temperature, l prolactin levels and VAS for ‘depressed’, ‘drowsy’, ‘restless’, ‘nausea’ and ‘lightheaded’ Weak correlation between shift in centroid (P7) and l restlessness and prolactin response Strongest correlation between prolactin response and Frequency spectrum analysis by bands l l Prolactin response to buspirone and pindolol l nausea and lightheadedness Using bands determined by factor analysis 6 F Main effect of drug (F(1.7,26.3) = 15.80, p < 0.001) l Analysis of theta band Conclusions l Main effect of buspirone (F(1.0,20.7) = 27.85, p < l Drug X AP effect for buspirone ( F(1,13) = 4.64, p = 0.051) F Buspirone (30 mg) causes a leftward shift of the EEG 0.001) l and pindolol (F(1,13) = 18.24, p < 0.001) frequency spectrum between 6 and 10.5 Hz in healthy Trend for effect of pindolol (F(1.0,16.6) = 4.61, p = No significant difference between pindolol+ buspirone and l F subjects buspirone alone 0.053) 6 : Pindolol (20 mg) causes a similar effect 10 min EEG recording Pindolol + buspirone significantly less than buspirone l l l 29 scalp electrodes The relative effects of buspirone and pindolol on the F (F(1.0,18.6) = 20.07, p < 0.001) l referenced to left mastoid, re- F EEG are different to the prolactin response which is 3 referenced off-line to linked known to reflect postsynaptic 5-HT activation mastoids 1A band width 0.1 - 100 Hz F Pindolol has been shown to be a partial agonist at l blink corrected using VEOG F somatodendritic 5-HT receptors in rodents 7 1A 10 s epochs generated F The shift in EEG spectrum with buspirone and rejected if voltage deflection l F ± m > 75 V (including HEOG) pindolol may reflect somatodendritic 5-HT receptor 1A FFT generated with bin width F activation of 0.1 Hz Post-hoc analysis used 8 References F colored sites to examine 1. McAllister-Williams R.H. & Young A.H. (1998) The pathology of depression. A synthesis of the role of serotonin and corticosteroids. In New models for depression ( ed . Ebert D. and ant/post and left/right Ebmeier K.), Vol . 19, pp. 170-198. Karger , Basel . differences 2. Smith C.E., Ware C.J., & Cowen P.J. (1991) Pindolol decreases prolactin and growth hormone responses to intravenous L-tryptophan. Psychopharm . 103, 140-142. Subjects 3. Blier P., Seletti B., Young S.N., Benkelfat C., & de Montigny C. (1994) Serotonin receptor 1A activation and hypothermia: Evidence for a postsynaptic mechanism in humans. Neuropsychopharm . 10, 92S (O-229-360). 4. Bogdanov N.N. & Bogdanov M.B. (1994) The role of 5-HT serotonin and D dopamine 1A 2 receptors in buspirone effects on cortical electrical activity in rats. Neurosci . Lett . 177, 1-4. Temperature response to buspirone and pindolol l 5. Anderer P., Barbanoj M.J., Saletu B., & Semlitsch H.V. (1993) Restriction to a limited set of EEG-target variables may lead to misinterpretation of pharmaco -EEG results. Neuropsychobiol . Main effect of drug (F(2.0,60.0) = 6.30, p < 0.01) 27, 112-116. l 6. Herrman W.M., Fichte K., & Kubicki S. (1980) Definition of EEG frequency bands based on the Main effect of buspirone (F(1.3,30.8) = 7.65, p < 0.05) interpretation of factor analysis with EEG power spectrum parameters. In Factor analysis and l EEG variables ( ed Kubicki S., et al.), pp 61-74. Gustav Fischer, Stuttgart. 7. Clifford E.M., Gartside S.E., Umbers V., Cowen P.J., Hajos M., & Sharp T. (1998) Main effect of pindolol (F(1.3,31.6) = 6.67, p < 0.05) l Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5- HT(1A) autoreceptor in vivo. Brit . J. Pharmacol . 124, 206-212. Pindolol + buspirone not significantly different to l Acknowledgements Centroid analysis of FFT between 6 and 10.5 Hz l buspirone alone This work was supported by an MRC (UK) Clinician l Scientist Fellowship award to RHMcAW