B Cox’s research while affiliated with University of Manchester and other places

A series of 2-[(2-aminoethyl)thio]quinolines substituted at the 3-position with alkyl, aryl, or heteroaryl groups has been prepared in the search for novel and selective 5-HT2 antagonists. The affinity of the compounds for 5-HT1 receptor sites was measured by their ability to displace [3H]-5-HT from rat brain synaptosomes whereas the affinity for 5-HT2 receptor sites was measured by their ability to displace [3H]spiperone from synaptosomes prepared from rat brain cortex. The 5-HT2 antagonist properties of the compounds were measured in vivo by their antagonism of 5-hydroxytryptophan-induced head twitches in the mouse and by their antagonism of hyperthermia induced by fenfluramine (N-ethyl-alpha-methyl-m-(trifluoromethyl)phenethylamine hydrochloride) in the rat. The structure-activity relationships in this series are discussed and the properties of 2-[[2-(dimethylamino)ethyl]thio]-3-phenylquinoline hydrochloride (70) are highlighted.

1. Intrahypothalamic injection of either 5‐hydroxytryptamine (5‐HT) (20 μg) or tryptamine (1 μg) caused hypothermia and hyperthermia respectively in lightly restrained rats maintained at an ambient temperature of 20 ± 1 °C. 2. Both the 5‐HT‐ and the tryptamine‐sensitive sites were located within the same region of the preoptic area. 3. When rats were tested at different ambient temperatures (4, 20 and 29 °C), intrahypothalamic injection of 5‐HT caused a marked fall in core temperature (‐1·3 °C) in rats maintained at 4 °C, but smaller responses were obtained at 20 and 29 °C (‐0·9 and ‐0·5 °C respectively). Tryptamine caused a significant hyperthermia in rats kept at 20 °C, but had no significant effect in rats maintained at either 4 or 29 °C. 4. The hypothermic effect of 5‐HT was selectively antagonized by systemic pre‐treatment with cyproheptadine (2·5 mg/kg), but not by methergoline (0·625 mg/kg) and methysergide (0·2 mg/kg). In contrast, the hyperthermic effect of tryptamine was blocked by methergoline and methysergide, but not by cyproheptadine. 5. Cyproheptadine (2·5 mg/kg) reduced the ability of rats to cope with a heat load but had no effect on the response to cold. In contrast, methergoline (0·625 mg/kg) and methysergide (0·2 mg/kg) reduced the ability to cope with cold but the rats' ability to cope with a heat load remained intact. 6. These results suggest the existence of two indoleamine pathways within the preoptic anterior hypothalamus involved in the control of body temperature: a serotonergic pathway mediating heat loss and a non‐serotonergic pathway mediating heat gain. The non‐serotonergic system may exert its effects by modulating the activity of a central serotonergic system.

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) (7.5 mg/kg SC) caused a contralateral turning in rats with a unilateral lesion of the dorsal raphe nucleus (DRN). This turning behaviour was blocked by pretreatment with putative 5-HT antagonists, methysergide, cyproheptadine and cinanserin. The peripheral 5-HT antagonist, xylamidine, also prevented the response to 5-MeODMT. Of the other neurotransmitter antagonists, only haloperidol was active, hyoscine, picrotoxin, naloxone and strychnine were ineffective. Pretreatment with alpha-methyl-p-tyrosine (alpha-MT) also significantly reduced the turning response to 5-MeODMT. These results indicate that a central dopaminergic system is involved in 5-MeODMT-induced turning behaviour. This suggestion is supported by the finding that an ipsilateral turning in response to 5-MeODMT was observed in the rats with additional 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle (MFB). The possible mechanisms by which 5-MeODMT induced turning in DRN lesioned rats are discussed.

The effect of a series of indoleamines on the potassium-evoked release of previously accumulated [3H]serotonin from slices of rat raphe nuclei has been studied. Indoleamine agonists produced a dose-related inhibition of potassium-evoked tritium release which was reversed by methiothepin, metergoline, mianserin and methysergide but not cyproheptadine or cinanserin. The relative order of antagonist potency for this effect was different from that obtained for the antagonism of indoleamine-induced inhibition of potassium-evoked tritium release from rat striatal slices previously loaded with [3H]-dopamine. The results show that the serotonin-autoreceptor located on cell bodies and dendrites in the raphe nucleus is different from the postsynaptic serotonin receptor located on dopamine nerve terminals in the striatum.

The turning behaviour induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) has been investigated in rats with lesions of the dorsal raphé nucleus (DRN). 5-MeODMT caused a dose-related contralateral turning in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions of the substantia nigra and a similar effect was observed in DRN-lesioned rats. In contrast, a dose-related ipsilateral turning was observed when 5-MeODMT was injected into rats with 5,7-DHT lesions of the striatum. These results suggest that the effects of 5-MeODMT in DRN-Lesioned rats are mediated via the substantia nigra. The contralateral turning induced by 5-MeODMT in rats with a 5,7-DHT lesion of the DRN was significantly reduced when a second 5-hydroxydopamine lesion was placed in the striatum, but not when it was placed in the nucleus accumbens. Thus the nigrostriatal dopaminergic system seems to be involved in 5-MeODMT-induced turning. The release of tritium from slices of substantia nigra previously labelled with [3H]-dopamine was inhibited by 5-MeODMT (10(-7) to 10(-5) M) and this effect was blocked by methysergide in a concentration-related manner. Tetrodotoxin (10(-7) M) failed to antagonise 5-MeODMT. These results suggest that 5-MeODMT can inhibit dopamine release from nigral dendrites, which could in turn enhance nigrostriatal activity by reducing the auto-inhibitory actions of dopamine, thereby causing contralateral turning in DRN-lesioned rats.

The aim of this chapter is to review the published evidence which suggests that central neurotransmitters play a role in fever. As such it relies heavily on two basic assumptions. Firstly that thermoregulation involves central neurotransmitter pathways and secondly that fever is a disturbance of thermoregulation. The second assumption will be discussed in full in other chapters of this book; the first has been the subject of a number of recent reviews and symposia (Cox and Lomax 1977; Milton 1978; Lomax and Schönbaum 1979; Cox et al. 1980).

This chapter discusses the dopaminergic involvement in thermoregulatory deficits in elderly rodents. In an experiment described in the chapter, rats subjected to either heat or cold stress were tested at different ages. Under the cold stress, the core temperature of rats of 18 and 24 months was significantly lower than that recorded from the 2-month-old rats. An abnormal rise in core temperature was observed in elderly rats under heat stress; this hyperthermic effect was accompanied by a reduction in tail blood vessel dilation. The loss of vasodilatory mechanisms appears to be the explanation of the inability of elderly rats to cope with an imposed heat load. Blockade of central dopaminergic transmission also produced an inability to cope with heat stress. Therefore, it is possible that a deficit in central dopamine pathways may be the mechanism underlying this deficit. This idea was supported by the finding that the elderly rat was less susceptible to apomorphine, a dopamine agonist, than was the young adult rat.