Could a performance measurement system embody the self-irony that less of the measurable performance variable may be preferred to more? It seems clear to me that answering these demands requires not so much the design of a new RAE as the design of a new society, based upon a discourse remote from our present obsession with self-transparent objectives (Strathern, 1997). This would be a society immune to the shrill hyperbole of ‘excellence’, ‘quality’, ‘international recognition’ and ‘innovation’ which has so corrupted the possibility of a nuanced evaluative discourse for academic life today. The fact also remains that research for many academics has become a basis for signalling reputation, a way of translating symbolic into financial capital as Bourdieu would put it. Research is profession not vocation. The RAE is not entirely to blame for this; it is the child of its time, a time in which the imperative to ‘add value’ in all aspects of life is part of the unquestionable mumbo jumbo that passes for common sense. As a head of department I am required to preside over this nonsense, adopting a discourse of non-decline and progress in which mediocrity masquerades as excellence, and in which the term scholarship has lost its meaning. However, I am skilled in management façade, and I remain confident that we may ‘do well’ in the next RAE.

GR127935 is the most potent 5-HT1A receptor antagonist yet described, possessing nanomolar affinity at human 5-HT1D receptors. Sumatriptan-induced contractions of the dog isolated basilar artery and saphenous vein are antagonised by GR127935 in an insurmountable manner indicative of its slow dissociation from the 5-HT1D receptor. 5-HT1D receptor-mediated hypothermia and rotational behaviour in guinea-pigs are antagonised potently, and with long duration, by GR127935, administered by a variety of routes. GR127935 also blocks central 5-HT1D autoreceptors in vitro and in vivo. GR127935 has much lower affinity at other 5-HT, and non-5-HT, receptors. In functional studies, GR127935 fails to affect 5-HT2 receptor-mediated 'wet dog shakes' in guinea-pigs and 5-HT1A receptor-mediated inhibition of 5-HT release in rat dorsal raphe nucleus. The compound has a good safety profile in all species tested. It is concluded that GR127935 is a useful pharmacological tool to characterise 5-HT1D receptor function.

Previous studies have shown that guinea-pigs handled daily from birth exhibit on exposure to the elevated plus maze similar behaviour to rats and increased cortical extracellular 5-HT determined by in vivo microdialysis. The present study investigates the effects of a non-selective 5-HT(1) agonist 5-carboxamidotryptamine (5-CT) and the 5-HT(1D) antagonist GR 127935 on behaviour and the release of cortical extracellular 5-HT both in a familiar environment and on exposure to the elevated plus maze. In the familiar environment of the home cage GR 127935 (0.3mg/kg i.p.) had no effect on extracellular 5-HT. The non-selective agonist 5-CT (0.1 mg/kg i.p) produced a prolonged decrease (-25%) in cortical 5-HT release, an effect noT antagonized by GR 127935 (0.3mg/kg). Under aversive conditions, exposure to the elevated plus maze, the release of extracellular 5-HT increased (155% of basal release), an effect abolished by 5-CT. Pre-treatment with the selective 5.HT(1D) antagonist GR 127935 antagonized the effect of 5-CT on the aversion-induced increase in extracellular 5-HT on exposure to the elevated plus maze, but did not change the effects of 5-CT on basal 5-HT release. The results suggest that GR 127935 is an effective antagonist at the 5 -HT(1D) terminal autoreceptor in vivo under conditions of increased 5- HT function. Furthermore, the results indicate that the 5-HT( 1D) receptor in the frontal cortex is functionally active under aversive conditions.

The involvement of 5-HT1D receptors in the regulation of 5-HT release in the guinea-pig brain was examined using the novel 5-HT1D receptor blocking drug GR127935. Levels of 5-HT were measured in frontal cortex of anaesthetized guinea-pigs using microdialysis. The infusion of GR127935 (100 nM) through the dialysis probe into frontal cortex caused a significant increase (61 +/- 8%) in cortical extracellular levels of 5-HT. The increase was transient (approximately 40 min) even in the continuous presence of GR127935. The transient increase was abolished by tetrodotoxin (1 microM). The 5-HT1 receptor agonist GR46611 (10 mg/kg s.c.) caused a significant and sustained (> 100 min) reduction in extracellular levels of 5-HT (65 +/- 5%). This response was abolished in animals pre-treated with GR127935, 0.05 mg/kg i.p. Paradoxically, systemic administration of higher doses of GR127935 (0.1-1 mg/kg i.p.) in naive anaesthetized guinea-pigs caused significant and sustained (> 120 min) decreases (> 65%) in cortical levels of 5-HT. The increase in extracellular 5-HT seen following infusion of GR127935 into frontal cortex may be due to GR127935 blocking 5-HT terminal autoreceptors causing a subsequent increase in the outflow of 5-HT from pre-synaptic terminals. This conclusion is supported by the ability of GR127935 to block the decrease in 5-HT induced by the 5-HT1 receptor agonist GR46611.(ABSTRACT TRUNCATED AT 250 WORDS)

Since their discovery in the late 1980s, 5-HT1D receptors have aroused considerable interest, not least because they represent the most abundant 5-HT1 receptor subtype in the CNS. Until recently, studies of the 5-HT1D receptor have relied upon poorly selective agents and this has seriously hampered efforts to define their physiological and potential pathological role in the CNS. Now, a series of centrally active, selective 5-HT1D receptor antagonists have become available which should add an important dimension to the study of 5-HT1D receptors. This review provides background biology on 5-HT1D receptors and the current status of novel chemical entities.

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The 5-HT1 receptor agonist GR46611 (3-30 mg/kg s.c.) caused a dose-related decrease in rectal temperature in the adult guinea-pig. A lower dose (20 μg) administered directly into the lateral cerebral ventricle also caused a hypothermic response, suggesting that this effect is centrally mediated. GR46611-induced (10 mg/kg s.c.) hypothermia was not attenuated by WAY100135 (3-10 mg/kg s.c.), ritanserin (0.3-1 mg/kg s.c.), spiperone (0.1-0.3 mg/kg s.c.) and ondansetron (0.1-1 mg/kg s.c.), suggesting that 5-HT1A, 5-HT2A, 5-HT 2C and 5-HT3 receptors are unlikely to be involved in this response. In contrast, the poorly selective 5-HT receptor antagonist, metergoline (1-10 mg/kg s.c.), and the potent 5-HT1D receptor antagonist, GR127935 (0.1-1 mg/kg p.o.), antagonized the effects of GR46611. The present data suggest that antagonism of GR46611-induced hypothermia may be useful for assessing the potency and duration of action of centrally-acting 5-HT 1D receptor antagonists in the guinea-pig.

5-Hydroxytryptamine (5-HT) release was measured by fast cyclic voltammetry in guinea-pig dorsal raphé nucleus slices. Release was reproducibly evoked by a single 0.1 msec pulse of electrical stimulation. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH DPAT) produced a concentration-related inhibition of the stimulated 5-HT release, with 50% inhibition at 47 nM. This inhibition was competitively antagonized by N-tert-butyl 3-4-(2-methoxypheny)piperazin-1-yl-2- phenylpropanamide dihydrochloride [(+/-)WAY 100135], a selective 5-HT1A receptor antagonist (pA2 = 7.9). The 5-HT1D receptor agonist sumatriptan also produced a concentration-related inhibition of 5-HT release, with 50% inhibition at 40 nM. The effect of sumatriptan on 5-HT release was antagonized by the 5-HT1D receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR127935) (pA2 = 8.7). Both (+/-)WAY 100135 and GR127935 increased the 5-HT release evoked by a train of 5 pulses at 1 Hz, suggesting that they were antagonizing the feedback of endogenously released 5-HT onto its autoreceptors. These findings demonstrate for the first time the presence of functional 5-HT1D as well as 5-HT1A autoreceptors in the guinea-pig dorsal raphé nucleus.

The effects of various 5‐hydroxytryptamine (5‐HT) receptor agonists were examined following unilateral infusion into the substantia nigra (SN) of the guinea‐pig. The 5‐HT1 receptor agonists, 5‐carboxamidotryptamine (5‐CT) (2–25 μg), sumatriptan (10–25 μg) and RU24969 (25 μg) all induced a marked contralateral rotation. In contrast, the selective 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH DPAT, 10–25 μg) produced only a very small response, whilst the selective 5‐HT1C/5‐HT2 receptor agonist (±)‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane hydrochloride ((±)‐DOI) (25 μg) and the 5‐HT3 receptor agonist, 2‐methyl 5‐HT (2‐Me5‐HT, 25 μg) were without effect. The contralateral rotation induced by 5‐CT (10 μg) was attenuated following pretreatment with the non‐selective 5‐HT1/5‐HT2 receptor antagonists methiothepin (1 mg kg−1, s.c.) and metergoline (5–10 mg kg−1, s.c.) but not the 5‐HT1C/5‐HT2 antagonist ritanserin (1 mg kg−1, s.c.) or the 5‐HT3 antagonist, ondansetron (0.5 mg kg−1, s.c). An involvement of dopaminergic systems in the rotational response to 5‐CT was implied by the antagonism of 5‐CT‐induced rotation by haloperidol (0.3 mg kg−1, s.c). At doses lower than those required to produce contralateral rotation, 5‐CT (0.08–0.4 μg) and sumatriptan (2 μg) induced a small, but nonetheless consistent, ipsilateral rotation. The data with agonists and antagonists taken together suggest that 5‐CT‐induced contralateral rotation may be mediated by 5‐HT1D receptor activation but definitive classification of the receptor will not be possible until selective 5‐HT1D‐antagonists become available. This may therefore represent the first model to study this receptor subtype in vivo.

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

The preferential 5-HT 2/5-HT1C receptor agonist DOI (0.1-4 mg/kg s.c.) caused an increase in locomotor activity, grooming and 'wet-dog' shakes (WDS) in the adult guinea-pig. The DOI-induced WDS behaviour was potently inhibited by several antagonists that have high affinity for the 5-HT2 binding site. The WDS response is likely to be centrally-mediated since the effects of peripherally administered DOI were poorly antagonized by the peripherally-acting 5-HT2 receptor antagonist BW501C67. Although these studies do not exclude an effect of DOI at 5-HT1C receptors, the high potency of ketanserin and spiperone in attenuating the effects of DOI would suggest an effect at the 5-HT2 receptor. The present data suggest that antagonism of the directly-acting agonist DOI may be useful for assessing the selectivity and duration of action of centrally-acting 5-HT2 receptor antagonists in the guinea-pig.

The present study attempts to determine whether the novel anti-migraine drug sumatriptan has antinociceptive activity in rodents. Sumatriptan had little or no antinociceptive activity against a range of noxious stimuli and we therefore conclude that it is unlikely that the beneficial effects of the drug in treating migraine are due to a non-specific analgesic action.

Migraine has long been considered as a "vascular headache" but clearly neurological mechanisms are involved. The pathophysiology appears to somehow involve serotonin, both peripherally and centrally, but its involvement may be just epiphenomenal. Adding to the enigma it is apparent that many of the presently available drugs for the treatment of migraine interact in one way or another with serotonin receptors. However, they tend to have a number of other unrelated actions and they are only of limited clinical value. Interestingly a promising new drug for the treatment of the acute attack, sumatriptan, has a very selective action as an agonist at a specific 5-HT1-like receptor sub-type, mediating vasoconstriction, which is localized on cranial blood vessels. Its action may, or may not, be independent of any involvement of serotonin in the genesis of migraine. Hopefully though, current attempts to determine sumatriptan's mechanism of action will shed further light on the pathology of migraine itself and the putative involvement of serotonin.