294P EFFECT OF ANTAGONISM OF 5-HT1A AND 5-HTlB RECEPTORS ON RESPONSE TO 5-HT1 RECEPTOR AGONISTS AND IMIPRAMINE IN THE FORCED SWIM TEST IN MICE O'Neill, M F, Moore, NA, Dobson, DR, Steggles, D and RU24969 (0.6-2.5mgkg-') significantly increased time spent Conway, M W. Lilly Research Centre, Erl Wood Manor, swimming in the FST. The effect of anpirtoline (1.25mgkg-') Sunninghill Rd, Windlesham, Surrey GU20 6PH. was reversed by GR127935 (1.25mgkg-') and isamoltane (Smgkg-') but not by WAY100635. GR127935 (1.25mgkg-') 8-OH-DPAT induces antidepressant-like effects in the forced also reversed the effect of the mixed agonist RU24969 swim test (FST) in mice (Luscombe et al, 1993) while the (0.6mgkg-') but WAY 100635 had no effect. The effect of mixed 5HTIA/B agonist RU24969 decreases immobility in imipramine (5mgkg-') was significantly reversed by the tails suspension test in mice (O'Neill et al, 1996). We set isamoltane (5mgkg-') while WAY100635 (0.1-0.5mgkg-') out to compare the effect of 8-OH-DPAT with the mixed was without effect. 5HTIA/B agonist RU24969 and the more selective 5HT1B agonist anpirtoline in the FST in mice. We also set out to These results confirm previous findings that direct stimulation characterise the effects of antagonists selective for these of 5HT1A and 5HT1B receptors induces antidepressant-like subtypes alone and their interaction with the agonists effects in the FST. These results further suggest that the effects described above. Finally we examined the effect of the of RU24969 in the forced swim test are mediated by 5HTlB WAY100635 and isamoltane on the actions of imipramine in rather than 5HT1A receptors. The doses of 5HT1B receptor this test. Female BKTO mice (25±3g) were housed under agonists used increased locomotor activity in mice, while 8- standard conditions. The animals received a subcutaneous OHDPAT does not (data not shown) suggesting that the effects injection 30 min prior to testing. Where a pretreatment was of 5HT1B agonists in this test may be due to their effects on used it was given 30 min prior to the main treatment and the locomotor activity. Finally these results support previous animals were tested 30 min later. Swimming was measured in findings that blockade of 5HTiB receptors but not 5HT1A a IL beaker. Activity was measured for the last 4 min of a 5 receptors attenuates the anti-immobility effects of imipramine min test session. N was minimum of6 for all groups. suggesting that activity at these receptors may be an important mediator ofits behavioural effects in this test. 8-OH-DPAT induces a 40% decrease in immobility in the FST [minimum effective dose MED 0.25mgkg-'(p < 0.01)]. Luscombe G, Martin, KF, Hutchins, LJ, et al, (1993) Br J Pindolol reversed the effect of 8-OH-DPAT over a dose range Pharmacol. 108, 669-677 that did not alter swimming when given alone (1-5mgkg-') as O'Neill MF, Fernandez AG, and Palacios JM, (1996) did buspirone (1-5mgkg-') and WAY100635 (0.1-0.5mgkg-') Pharmacol Biochem Behav. 53, 535-539 but not GR127935. Both the selective 5HT1B agonist anpirtoline (1.25-5mgkg-') and mixed 5HT1A/B agonist 295P THE EFFECT OF CHRONIC PAROXETINE ON 20 kHz ULTRASOUND-INDUCED DEFENCE BEHAVIOUR IN THE RAT M. Graham', I.F. Tulloch2 and C.A. Marsden', 'Department of Physiology and Pharmacology, University of Nottingham, Queen's 20. Medical Centre, Nottingham NG7 2UH and 2 SmithKline Beecham Pharmaceuticals, Harlow, Essex. Aversive situations, such as predator threat, result in the production of ultrasonic vocalisations from rats in the range of 20-32kHz (Blanchard et al 1993). Rats exposed to artificially generated 20kHz ultrasound exhibit defence-like behaviour that is associated with activation of the brain Exposure aversive system (Beckett et al 1997). This behaviour has previously been shown to be sensitive to pharmacological manipulation (Beckett et al Eigure 1:L Effect of paroxetine (-l10mg/kg) on maximum speed values 1996), and may be a model of panic. The present study aims to look at obtained during 1 minute of 20kHz ultrasound (101dB) (mean ± s.e. mean) the effect of chronic treatment with the selective serotonin reuptake compared to saline (U*) * p<O.05 vs saline ** p<0.O1 vs saline. One-way inhibitor paroxetine, which is used clinically to treat panic disorder ANOVA with post-hoc Duncan's NMR. (Oehrberg et al 1995), on the expression of this response. These results demonstrate that chronic treatment with paroxetine caused a Male hooded Lister rats (190-250g, n=5-8) received daily I.P. injections small, but significant, increase in the response to 20kHz ultrasound. As of paroxetine (10mg/kg) or saline for 6 weeks, and were exposed to 20kHz paroxetine is an effective treatment for human panic disorder (Oehrberg et a! ultrasound twice weekly during this period. On test days, 30 minutes 1995), this result may question the validity of the ultrasound paradigm as a post-injection, the rats were placed in an open field arena containing a model of panic disorder. It may be that 20kHz ultrasound-induced behaviour wall-mounted speaker. After a 2 minute basal period they received a 1 is analogous to a panic attack, and not the underlying panic disorder. The minute ultrasound pulse (91, 98 or 101dB SPL) followed by 2 minutes introduction of a conditioning procedure to this model may improve its without sound. This was repeated for each sound intensity with an inter- value for the detection of potential drug treatments for panic disorder. procedure interval of 1 minute. Animal behaviour was analysed using a computer tracking system as distance travelled and speed (Beckett et at We thank SmithKline Beecham for financial support. 1995). Beckett, S. & Marsden, C. (1995) J. Neurosci. Meths. 58 157-61 20kHz ultrasound exposure produced an intensity related defence response Beckett, S., Aspley, S., Graham, M., et a! (1996) Psychopharmacol. 127 characterised by hyperlocomotion. Chronic administration of paroxetine 384-90 (10mg/kg) had no significant effect on maximum speed values obtained Beckett, S., Duxon, M., Aspley, S., eta! (1997) Brain Res. Bull. 42 421- during 12 exposures to ultrasound at the 91dB intensity when compared to 26 saline treated controls. Paroxetine treatment increased this response at the Blanchard, R., Yudko, E., Rodgers, R., et a! (1993) Behav. Brain Res. 58 98dB intensity, reaching statistical significance on exposures 4, 7 and 8. 155-65 Exposure to 101dB ultrasound also resulted in an augmentation of this Oehrberg, S., Christiansen, P., Behnke, K., et a! (1995) Br. J. Psychiatry response, with exposures 6 and 12 reaching statistical significance (figure 167 374-9 1). 296P EFFECT OF ACUTE FLUOXETINE AND YOHIMBINE ON BRAIN DEHYDROEPIANDROSTERONE (DHEA) S. Nayak, G.W. Bennett & CA.lMarsden DHEA was measured in 4 brain regions,with the Department of Physiology and Pharmacology, University of highest control levels in the hippocampus (3.3 ± 0.2 x 10-2 Nottingham Medical School, Queen's Medical Centre, ng/mg tissue) followed by the hypothalamus (2.3 ± 0.2), the Nottingham, NG7 2UH. striatum (1.9 ± 0.2) and the cortex (0.1 ±0.3). Exposure to the elevated plus maze had no effect on the levels of DHEA in any Dehydroepiandrosterone (DHEA) is one of several of the brain regions. Fluoxetine (n=6-8 ) significantly (p< neurosteroids released from the adrenal cortex and 0.05, Student t test) decreased hippocampal DHEA (30%h) and transported into the CNS, though recent studies have reduced hypothalamic levels by 38% but had no effect on suggested that DHEA may also be synthesised in the brain DHEA in the striatum and cortex. Yohimbine (n=6-8) also (Robel & Baulieu, 1994). In addition Melchior & Ritzman tended to decrease DHEA levels in brain regions (1994) have demonstrated that DHEA, has a dose dependent (hippocampus 17%; cortex 600/% and striatum 400/% ) but the anxiolytic property in animals but there is little changes were not significant. information about the effect of aversive situations and anxiogenic drug treatment on brain levels or cellular release While exposure to the elevated plus maze had no effect of DHEA. The present study investigated the effects of: on DHEA, acute fluoxetine, which has been shown to produce 1) exposure of rats to the elevated plus maze, an established anxiogenic behaviour, (Handley & McBlane, 1992), decreased animal model of anxiety (Lister, 1987) and 2) the acute DHEA. Since previous studies have shown that administration of fluoxetine and yohimbine on the levels of administration of DHEA produces anxiolytic behaviour DHEA in brain regions. (Melchior & Ritzman, 1994), it is possible that the present changes in DHEA may be associated with the anxiogenic Lister hooded rats were used for all experiments. In effects of fluoxetine and yohimbine. Further studies are the first experiment rats (n=8) were exposed to the plus maze required to identify the mechanisms involved in the change for 5 minutes and then immediately killed and brain regions in brain DHEA and to determine its role in aversive dissected and stored at -800C. Controls (n=8) were killed behaviour, directly after removal from the home cage. The second experiment looked at changes in DHEA in response to Robel, P. & Baulieu, E.E. Trends in Endocrine Metab., 1994, fluoxetine (10mg/kg) and yohimbine (0.5mg/kg) 5, 1-9. administered acutely (lh and 20min pretreatment respectively) . Controls were given saline (0.9%). In the Melchior, C.L., & Ritzman, RF., Pharmacol. Biochem. and analysis of DHEA, the brain regions were sonicated first in Behav., 1994, 47, 437-442. ethanol and then extracted with an equal volume of acetone followed by chloroform/methanol (1:1) and finally ethyl Lister RG., Psychopharmacology, 1987, 92, 180-185.