Biomedical subjects
Publications and source records attributed to C T Dourish.
The effects of the serotonin agonist MK-212, on rat plasma ACTH were examined. MK-212 significantly increased plasma ACTH levels, and this effect was blocked by the 5-HT1C antagonists mesulergine and metergoline but not by spiperone, ketanserin, or (-)-pindolol. The results suggest that MK-212 activates the 5-HT1C receptor subtype to increase ACTH.
Exogenous cholecystokinin (CCK) decreases food intake and causes satiety in animals and man. However, it has not been established that endogenous CCK causes satiety or whether the response is mediated by peripheral-type (CCK-A) or brain-type (CCK-B) receptors. The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed. The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety. These results suggest that endogenous CCK causes satiety by an agonist action on CCK-B receptors in the brain.
Sensorimotor function and the behavioural responses to a range of doses of subcutaneous apomorphine were assessed in mature (6-8 months) and old (23-26 months) Sprague-Dawley rats of comparable weight. In addition, the locomotor activity response of 12-month-old and 24-month-old rats to continuous infusions (14 days by osmotic minipump) of a selective dopamine D2 agonist. (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 10 micrograms/h) was investigated. Measures of spontaneous locomotor activity and motor coordination revealed impairments in the aged animals. Low doses of apomorphine (10-50 micrograms/kg), which preferentially activate dopamine autoreceptors, induced yawning, chewing mouth movements and penile grooming. The frequency of yawning and duration of penile grooming were significantly decreased in the old animals. In contrast, 200 micrograms/kg of apomorphine induced stereotyped sniffing and licking or gnawing, and these responses were significantly increased in the aged animals. There was a 25% decrease in striatal dopamine levels in the aged animals in this experiment. PHNO increased the amplitude of the circadian rhythms in locomotor activity exhibited by mature rats, and daytime tolerance to the stimulant effects of PHNO was reversed by stress in these animals. Both of these effects were attenuated in the aged rats. These findings suggest that (1) the dopamine receptors mediating yawning and stereotypy have different anatomical locations (2) ageing is associated with decreased responsiveness to stimulation of dopamine autoreceptors, consequent upon the loss of dopaminergic nerve terminals, and (3) while the functional response to selective stimulation of postsynaptic D2 receptors decreases with age, the postsynaptic response to a mixed D1/D2 agonist increases.
The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examined. The 5-HT2 antagonists ritanserin and ketanserin and the selective 5-HT3 antagonists ICS 205-930 and MDL 72222 had no effect on food intake. In contrast, the non-selective 5-HT antagonists metergoline, methiothepin, mesulergine, mianserin and methysergide (all of which have high affinity for various 5-HT1 receptor subtypes), dose-dependently increased food intake during a 4-h daytime test. Furthermore, metergoline dose dependently increased food intake over a 24-h period. Surprisingly, mesulergine decreased food intake over a 24-h period at the same doses that increased daytime food intake. This may indicate that the increase in daytime feeding produced by mesulergine is a non-specific response. Although the antagonists used have varying degrees of selectivity for 5-HT receptor subtypes, the pattern of results suggests that postsynaptic 5-HT1 receptors (possibly of the 5-HT1C type) play an important role in the control of feeding in rats.
Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.
The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, penile grooming and mouth movements induced by small doses of apomorphine in male rats were examined. Yawning induced by 0.05mg/kg apomorphine was dose dependently blocked by (+)-AJ-76, significant decreases being observed at 0.86 and 3.5mg/kg of the drug. A dose of 0.86mg/kg (+)-AJ 76 caused a two fold shift to the right of the apomorphine dose response curve for yawning. In contrast, (+)-AJ 76 had no effect on penile grooming and vacuous mouth movements induced by small doses of apomorphine. This pattern of results is similar to that observed after bilateral 6-hydroxydopamine-induced lesions of the substantia nigra which also blocked apomorphine-induced yawning but spared penile grooming and mouth movements. Previous studies have suggested that (+)-AJ 76 is a selective dopamine autoreceptor antagonist that has little or no effect on behaviour mediated by post-synaptic dopamine receptors. Therefore, these data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors.
The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.
Using autoradiography, 'peripheral type' or cholecystokinin-A (CCK-A) receptor binding was measured in the interpeduncular nucleus (IPN) of rats which had received electrolytic lesions of the habenular nucleus. Presynaptic GABAB receptor binding was also determined in the IPN in order to verify the loss of input to the nucleus. In animals which showed almost total loss of GABAB receptors. 125I-Bolton Hunter CCK binding in the IPN was reduced from 1.83 +/- 0.28 pmol/g wet weight to 0.87 +/- 0.16 pmol/g wet weight. This was not significantly different from non-specific levels, determined in the same region using 10(-7) M L-365,031 (0.97 +/- 0.14 pmol/g wet weight). These data suggest that CCK-A receptors in rat IPN are localized on presynaptic terminals within the nucleus.
The 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) at a dose of 1 mg/kg s.c. increased food intake in free feeding rats. 8-OH-DPAT-induced feeding was blocked by metergoline which has comparable affinity for 5-HT1A, 5-HT1B, 5-HT1C and 5-HT2 receptors. This is consistent with the hyperphagia being mediated by an action at 5-HT receptors. Evidence against the involvement of 5-HT2 or 5-HT3 receptors was provided by the lack of effect of methysergide, ketanserin, MDL 72222 and ICS 205930 on the feeding response. Blockade of the hyperphagia by (-)- but not (+)pendolol which stereoselectively interacts with 5-HT1 receptors indicated an involvement of this receptor type. The lack of effect of ketanserin suggests that the 5-HT1C site is not involved as it has high affinity for both 5-HT2 and 5-HT1C receptors. Blockade of the hyperphagia by spiperone suggests mediation by 5-HT1A rather than 5-HT1B receptors. Although spiperone also blocks dopamine and alpha 2-adrenoreceptors, involvement of these sites is unlikely as neither the DA antagonist haloperidol nor the alpha 2-adrenoceptor antagonist idazoxan blocked 8-OH-DPAT-induced feeding. These results indicate that 8-OH-DPAT-induced feeding is mediated by 5-HT1A receptors.
The potent and selective non-peptide cholecystokinin (CCK) antagonist L-364,718 (0.5-2.0 mg/kg s.c.) enhanced the analgesia induced by acute morphine treatment in the rat tail flick test. Chronic treatment with L-364,718 (1.0 mg/kg) prevented the development of tolerance to morphine analgesia (after a 6 day period of morphine treatment) but did not influence the onset of opioid dependence. Since L-364,718 is considerably more potent in inhibiting CCK binding to peripheral tissues than to brain membranes its interaction with morphine is surprising. The exact locus of this interaction, or whether it involves 'peripheral-type' (CCK-A) or 'central-type' (CCK-B) receptors is not known.
The selective NK-3 tachykinin receptor agonist senktide elicited yawning, chewing mouth movements and sexual arousal following subcutaneous administration (0.1-1.0 mg/kg) in the rat. These responses were not significantly affected by the dopamine antagonist haloperidol (0.03 mg/kg) or by 6-hydroxydopamine lesions of the nigrostriatal projection. In contrast, the behaviours were markedly attenuated by the peripheral and central muscarinic antagonist scopolamine (1 mg/kg), but not by the peripheral muscarinic antagonist N-methylscopolamine (1 mg/kg). These findings suggest that stimulation of NK-3 receptors produces yawning, chewing and sexual arousal by directly activating central cholinergic neurons.
There have been recent claims that the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) elicits chewing and eating of solid but not liquid foods. Therefore, the effects of 8-OH-DPAT and another 5-HT1A agonist gepirone on the consumption of a liquid chow diet, by free feeding male rats, were examined. Both drugs produced a dose-dependent increase in the consumption of liquid diet during a 2 h test. The doses of 8-OH-DPAT and gepirone which increased liquid diet intake in this study were in the same range as those which were found previously to increase food pellet consumption by free feeding rats. The effects of 8-OH-DPAT were also examined in a feeding choice test in which free feeding animals were allowed to choose between food pellets and a liquid chow diet. In this test, 8-OH-DPAT significantly increased total food intake (liquid plus pellet) but had no significant effect on the consumption of either liquid or pellet diets when analysed separately. Thus, there were large individual differences in diet choice after 8-OH-DPAT injection. However, rats did not consistently choose to eat food pellets rather than the liquid diet, as would be predicted if the drug elicited chewing rather than eating. These results provide strong evidence that 8-OH-DPAT elicits a behaviourally specific hyperphagia and not chewing or gnawing.
The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5-120 micrograms/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 micrograms/kg, a D-1 receptor selective antagonist). Increasing "arousal" by disturbance associated with repeated food weighing also increased food pellet consumption, but did not diminish PHNO-elicited feeding. However, the same range of doses of PHNO (7.5-120 micrograms/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.
The 5-HT1A agonist 8-OH-DPAT, at a dose of 30 micrograms/kg, enhanced the consumption of sweetened wet mash and sweetened milk in non-deprived rats. In partially satiated rats, sensitivity to the hyperphagic effect of 8-OH-DPAT on wet mash intake was substantially increased, so that the minimally effective dose was reduced to 3 micrograms/kg. Similarly, 8-OH-DPAT was more efficacious in increasing milk intake in satiated rats. Thus, 30 and 40 micrograms/kg 8-OH-DPAT produced a 4-fold increase of milk intake in completely satiated rats compared to a 2-fold increase in partially satiated animals at a dose of 30 micrograms/kg. The increased intake of liquid and wet mash diets observed after treatment with low doses of 8-OH-DPAT argues against the involvement of non-specific gnawing in the increased consumption of solid food produced by the drug. Rather, the data suggest that 8-OH-DPAT may specifically stimulate appetite by counteracting a tonic serotonergic inhibition of feeding. The present experiments also showed that 8-OH-DPAT attenuates fenfluramine-induced anorexia which is thought to depend on increased serotonergic neurotransmission.
Various putative agonists of the 5-HT1A receptor subtype induce feeding in rats, probably by activating raphé somatodendritic 5-HT autoreceptors. These drugs also produce a marked increase in plasma concentrations of corticotropin (ACTH). In the present experiment we attempted to localize the site of action of 5-HT1A agonists on the secretion of ACTH and examined the relationship between 5-HT1A agonist-induced feeding and ACTH secretion. Rats were injected with either the high affinity 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.016-1.0 mg/kg, s.c.) or the novel anxiolytics buspirone, gepirone or ipsapirone (2.0-16.0 mg/kg, s.c.), and either had their food intake measured 2 hr post injection or were sacrificed 30-40 min post injection for measurement of plasma ACTH. Plasma ACTH also was measured in rats pretreated with the serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) for three days (150 mg/kg, i.p. per day) and subsequently injected with 8-OH-DPAT (0.3 mg/kg, s.c.). As previously reported, the 5-HT1A agonists increased both food agonists increased both food intake and plasma ACTH concentrations. After 8-OH-DPAT, ipsapirone and gepirone the amount of food consumed was positively correlated with the concentration of plasma ACTH. No such correlation was evident following buspirone. PCPA pretreatment resulted in near total depletion of brain 5-HT content but had no effect on the ACTH rise induced by 8-OH-DPAT. Therefore, in contrast to the presynaptic site previously proposed for 5-HT1A agonist-induced feeding, the present results suggest a agonist-induced feeding, the present results suggest a postsynaptic location for the 5-HT1A receptor mediating ACTH release.
The behavioural effects of the selective NK-3 tachykinin receptor agonist senktide were studied following intracisternal and subcutaneous administration in rodents. Behavioural manifestations of 5-hydroxytryptaminergic stimulation, including head twitches (mice), wet dog shakes (rats), forepaw treading, flat body posture, hindlimb splaying and Straub tail, were seen following the intracisternal (0.01-1.2 nmol) or subcutaneous (0.1-2.4 mumol kg-1) administration of senktide in both species. We conclude that stimulation of NK-3 receptors stimulates 5-hydroxytryptaminergic pathways in rodent brain, and that senktide may cross the blood-brain barrier in biologically significant amounts.
Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (5-HT) syndrome, while substance P, neurokinin A and eledoisin failed to elicit any such behaviours. Senktide-induced head twitches were prevented by pretreatment with the 5-HT2 antagonists ketanserin and ritanserin, while forepaw treading was attenuated by the 5-HT1 antagonists (-)-pindolol and methysergide. These data suggest that NK-3 agonists interact with central 5-HT mechanisms.
Ru 24969 and two other putative 5-HT1B agonists 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl) phenyl]piperazine (TFMPP) and RU 24969 dose-dependently decreased food intake over 4 h (and in the case of RU 24969 also over 24 h) in free-feeding male Sprague-Dawley rats. Decreasing the doses of the agonists below the range eliciting anorexia did not cause hyperphagia. The anorexic effect of RU 24969 over 4 h was antagonised by metergoline, (-)pindolol and (+/-)cyanopindolol, but not by ketanserin, spiperone or haloperidol. Metergoline and (+/-)cyanopindolol also antagonised the anorexic effect of RU 24969 over 24 h. This data is consistent with an action mediated by 5-HT1B receptors. Locomotor activity induced by RU 24969 was markedly antagonised by haloperidol despite its lack of effect on the anorexic response. Persistence of the anorexic effect of RU 24969 after p-chlorophenylalanine (pCPA) pretreatment suggests that 5-HT1B agonists induce anorexia at a postsynaptic 5-HT receptor.