The effects of the GABA-mimetic drugs, progabide and baclofen, on the biochemistry and function of 5-hydroxytryptamine and noradrenaline

Administration to mice of a single dose of (+/-)-baclofen (5 mg/kg) or progabide (100 mg/kg) significantly inhibited the head-twitch response mediated by 5-hydroxytryptamine (5-HT2) receptors 30 min (but not 3 hr) later, when the response was produced by injection of carbidopa (25 mg/kg) plus 5-hydroxytryptophan (5-HTP; 100 mg/kg). No change was seen in the head-twitch response when induced at this time by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg). Inhibition of the head-twitch response after injection of 5-HTP was produced by pretreatment with (-)-baclofen, but not (+)-baclofen; injection of (+)-baclofen with the (-)-baclofen did not alter the attenuation of the behaviour produced by the active isomer. Twenty-four hours after the last injection of progabide, given repeatedly (100 mg/kg injected 5 times over 10 days) specific binding of [3H]ketanserin in the frontal cortex was enhanced and the head-twitch response to both 5-HTP and 5-MeODMT was markedly increased. The sedation response mediated by alpha 2-adrenoceptors, which followed the injection of clonidine (0.25 mg/kg) was attenuated. Repeated administration of baclofen (10 mg/kg per day in drinking water) also increased the number of 5-HT2 receptors in the frontal cortex (16%) and enhanced the head-twitch behaviour after injection 5-HTP or 5-MeODMT. Clonidine-induced sedation, number of beta-adrenoceptors in the cortex and apomorphine-induced locomotor activity were all unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour following antidepressant treatment to mice.

The effects of repeated administration of antidepressant drugs or electroconvulsive shock on the binding of [3H]-spiperone to the 5-hydroxytryptamine 2 (5-HT2) receptor in mouse frontal cortex and the 5-HT-mediated head-twitch response have been examined. Repeated electroconvulsive shock increased both the head-twitch response and the number of 5-HT2 binding sites (Bmax). After 35 d but not 24 h or 14 d oral tranylcypromine (5.6 mg kg-1 per day) there was a marked decrease in both the behavioural response and the number of 5-HT2 receptors. Repeated oral doses of zimeldine (20 mg kg-1 per day, 14 days) also decreased the head-twitch response and the number of 5-HT2 binding sites and these effects persisted after 48 h withdrawal. Oral mianserin (2.1 mg kg-1 per day, 14 days) decreased both the behaviour and the number of 5-HT2 binding sites, but this change was also seen after acute (1 day) administration. After 48 h withdrawal from chronic treatment the head-twitch response was still decreased but the Bmax had returned to control values. Desipramine given orally (27 mg kg-1 per day, 14 days) decreased both the behaviour and number of 5-HT2 binding sites. After 48 h withdrawal, binding was still decreased but the head-twitch response was enhanced above control values. In contrast to repeated electroconvulsive shock (ECS), all drugs decreased both 5-HT2 binding and the head-twitch response, while the mice were still on treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Some anticonvulsant drugs alter monoamine-mediated behaviour in mice in ways similar to electroconvulsive shock; implications for antidepressant therapy.

The effects in mice of administration of the anticonvulsants, progabide, sodium valproate, diazepam, carbamazepine and phenytoin on 5-hydroxytryptophan (5-HTP)-induced head-twitch, apomorphine-induced locomotion, clonidine-induced sedation, and beta-adrenoceptor and 5-HT2 receptor number have been examined. Repeated progabide administration (400 mg kg-1, i.p. twice daily for 14 days) enhanced the head-twitch response the effect lasting for over 8 days after the last dose, and also increased 5-HT2 receptor number in frontal cortex. Progabide (400 mg kg-1, i.p.) enhanced the head-twitch response when given once daily for 10 days and when given intermittently (5 times over 10 days) but not after 1 day of administration. Repeated Na valproate (400 mg kg-1, i.p.) also increased the 5-HTP-induced head-twitch response and 5-HT2 receptor number in the frontal cortex when given twice daily for 14 days, but no behavioural enhancement was seen after 10 days' treatment. Diazepam (1.25 mg kg-1, i.p.) twice daily for 14 days increased the head-twitch response and 5-HT2 receptor number. Repeated progabide and valproate (but not diazepam) administration attenuated the sedation response to the alpha 2-adrenoceptor agonist, clonidine (0.15 mg kg-1) but neither drug altered beta-adrenoceptor number in the cerebral cortex. No changes in apomorphine-induced locomotor behaviour were seen after progabide, valproate or diazepam. Repeated carbamazepine (20 mg kg-1) or phenytoin (40 mg kg-1) administration failed to alter any of the biochemical or behavioural parameters listed above. Like repeated electroconvulsive shock (ECS), progabide altered the head-twitch response, clonidine-induced sedation response and 5-HT2 receptor number. Unlike repeated ECS, it did not alter beta-adrenoceptor number or the apomorphine-induced locomotor response. These data suggest that ECS may produce some changes in monoamine function by altering GABA metabolism as has previously been postulated.     

Circadian variation in behavioural responses to central 5-HT receptor stimulation in the mouse

The intensity of the head-twitch response and the 5-hydroxytryptamine (5-HT) syndrome (tremor, fore-paw treading, head-weaving and hind-limb abduction) was measured in male CFLP mice following IP injection of 5 mg/kg 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The results of separate experiments carried out at 1.5-h intervals throughout the light-dark cycle showed a clear circadian variation in head-twitch, with highest scores mid-light. No circadian variation in the 5-HT syndrome, or in any individual element of it, was observed. Dose-response curves constructed for 5-MeODMT mid-light and mid-dark over the range 2–64 mg/kg IP confirmed the difference in head-twitch response, showing a parallel shift to the right for mid-dark compared to mid-light up to 32 mg/kg. Again, no difference was seen between the two curves for the 5-HT syndrome. Measurement of the time course of behavioural activity following 5-MeODMT failed to show any differences between mid-light and mid-dark, making it unlikely that pharmacokinetic differences account for the observed circadian variation. It is suggested that the demonstration of a circadian rhythm in the head-twitch response and the failure to show any comparable rhythm in the 5-HT syndrome provides further evidence that these behaviours are mediated by different 5-HT-receptor subtypes.     

Antidepressant treatments: effects in rodents on dose-response curves of 5-hydroxytryptamine- and dopamine-mediated behaviours and 5-HT2 receptor number in frontal cortex.

The effects of repeated electroconvulsive shock (ECS) administration, repeated desmethylimipramine injection (5 mg kg-1, twice daily for 14 days) and acute administration of the beta-adrenoceptor, clenbuterol, on 5-hydroxytryptamine (5-HT)- and dopamine-mediated behaviours in mice have been examined. All three treatments enhanced the carbidopa/5-hydroxytryptophan (5-HTP)-induced head-twitch response at all doses of 5-HTP examined, producing a parallel shift in the dose-response curve. A single ECS administration or single dose of desmethylimipramine had no effect. Only repeated ECS enhanced the locomotor response to injection of apomorphine. The dose-response curve shift was not parallel. A single ECS had no effect. A 6-hydroxydopamine lesion of brain dopamine terminals also enhanced the apomorphine response, but again did not produce a parallel shift in the dose-response curve. Both repeated ECS and repeated desmethylimipramine administration to rats increased the number of 5-HT2 receptor sites in rat brain. Clenbuterol had no effect. The enhancing effects of repeated ECS and clenbuterol administration on the 5-HTP-induced head-twitch response were additive. Enhanced 5-HT-mediated behavioural responses are seen in both mice and rats after these treatments. If it is assumed, therefore, that similar receptor changes occur in both species it appears that there is no relationship in either behavioural system between the ability of the treatment to alter receptor number and the change in the dose-response curve (parallel or non-parallel). All three antidepressant treatments (ECS, a tricyclic and a beta-adrenoceptor agonist) increase 5-HT-mediated behavioural responses although clenbuterol did not increase 5-HT2 receptor number. Only ECS increased dopamine-mediated responses.     

The effect of benzodiazepines on the 5-HT agonist-induced head-twitch response in mice

The effects of four benzodiazepines (diazepam, clonazepam, oxazepam and clobazam) were studied on the head-twitch response induced in mice by several 5-HT receptor agonists. All the benzodiazepines tested potentiated the effects of the directly acting agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine and mescaline, without themselves inducing head-twitches. In contrast, none of them potentiated head-twitches induced by the indirectly acting agonist 5-hydroxytryptophan (5-HTP; with carbidopa 25 mg/kg), and in some experiments a clear inhibition was seen. The clonazepam (10 mg/kg) potentiation of 5-MeODMT-induced head-twitches was not antagonised by flumazenil, (+)-bicuculline, or by pretreatment with p-chlorophenylalanine. Neither was it mimicked by muscimol, which inhibited head-twitches. These results indicate that the observed potentiation is not mediated by benzodiazepine receptors and that it occurs postsynaptically to the initiating 5-HT receptors. The inability of the benzodiapines to potentiate 5-HTP-induced head-twitches probably reflects a reduction in 5-HT neuronal activity mediated by benzodiazepine receptors, as co-administration of flumazenil and clonazepam potentiated the effects of 5-HTP whereas each compound alone had no effect.     

Rapid changes in functional responsiveness of the 5-HT system after single-dose and multiple-dose treatment with antidepressants: effects of maprotiline and oxaprotiline and its enantiomers

Functional responsiveness to 5-HTP (L-5-hydroxytryptophan) and quipazine 24 h after one single dose and 24 h and 72 h after repeated administration (2.5 and 10 mg/kg twice daily for 7 days) of maprotiline, oxaprotiline and its (+) and (-) enantiomers was tested in the rat. All compounds markedly increased the behavioural effects of 5-HTP 24 h after one single injection. This effect was further enhanced after repeated treatment. The response to quipazine was less consistently affected than the response to 5-HTP. Neither drug increased the response to quipazine 24 h after the last injection. However, maprotiline and oxaprotiline enhanced the quipazine-induced head-twitch 72 h after the withdrawal of subchronic treat ment, enantiomers failed to do so. This differential effect of drugs in respect to the interactions with 5-HTP and quipazine is, however, not understood at present. The results of this study indicate that only one single dose of antidepressants may change the functional respon siveness of the 5-HT system and that such changes occur rapidly. The results also provide a possible rationale for the suggested antidepressant activity of levoprotiline, the (-) enantiomer of oxaprotiline and otherwise biochemically inactive compound.     

Selective cross-tolerance to 5-HT1A and 5-HT2 receptor-mediated temperature and corticosterone responses

The repeated administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 3 mg/kg, twice daily for 14 days) significantly diminished hypothermia and corticosterone secretion induced by an acute challenge with the 5-HT1A agonist 8-OH-DPAT (0.1 mg/kg) when compared to the responses in animals treated chronically with the solvent vehicle. In contrast, the chronic administration of 5-MeODMT did not alter the magnitude of hyperthermia or corticosterone secretion induced by the acute administration of MK-212 (1.0 mg/kg). The repeated administration of the 5-HT2 agonist DOI (1.0 mg/kg, daily for 7 days) significantly reduced the increase in corticosterone, but not body temperature, produced by MK-212. Chronic treatment with DOI did not alter the hypothermia or increase in corticosterone secretion elicited by 8-OH-DPAT. These data are consistent with other evidence that these physiological effects of 8-OH-DPAT and MK-212 are mediated by 5-HT1A and 5-HT2 receptors, respectively. Thus, data presented in these studies are suggestive that the chronic administration of 5-MeODMT diminishes the responsiveness of 5-HT1A receptor-mediated changes in body temperature and corticosterone secretion without altering the responses mediated by 5-HT2 receptors. In contrast, the chronic administration of DOI selectively diminishes the magnitude of 5-HT2 receptor-mediated changes in corticosterone secretion without affecting the responsiveness of those receptors involved in thermoregulatory responses. These selective changes in receptor responsiveness following the chronic administration of these 5-HT agonists further establishes the independence of 5-HT1A and 5-HT2 receptor-mediated pharmacological effects.     

Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors

The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated. The administration of the serotonin (5-HT) agonist 6-chloro-2(1-piperazinyl)-pyrazine (MK-212) produced a dose-related increase in body temperature. A maximal increase in body temperature of approx. 1.1°C was observed 30min after the administration of 3 mg/kg of MK-212. In contrast, administration of the putative 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) resulted in marked, dose-related hypothermic responses. Body temperatures were decreased approx. 3°C 30 min after an injection of 0.3 mg/kg of 8-OH-DPAT. Body temperatures were affected differentially by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). Large doses (3–10 mg/kg) of 5-MeODMT elicited hyperthermic responses, whereas small doses (0.5–1.0 mg/kg) produced hypothermie responses. Treatment of rats with ketanserin (3 mg/kg) completely prevented the hyperthermic effects of 5-MeODMT, and, in fact, converted a hyperthermic response to 5-MeODMT into a marked hypothermie response. Ketanserin (0.1–1.0 mg/kg) selectively antagonized the hyperthermic response to MK-212 but did not alter the hypothermic effect of 8-OH-DPAT. Mianserin (10 mg/kg) and pirenperone (0.03 mg/kg) also selectively antagonized hyperthermia induced by MK-212. In contrast, pindolol (0.03–0.1 mg/kg) and methiothepin (10 mg/kg) selectively antagonized hypothermia induced by 8-OH-DPAT but did not alter hyperthermia induced by MK-212. Spiperone (0.1–3 mg/kg) and pizotifen (10 mg/kg) attenuated the effects of both 8-OH-DPAT and MK-212. Xylamidine, a peripheral 5-HT antagonist, had no significant effect on hyperthermia induced by MK-212 or hypothermia induced by 8-OH-DPAT. It also was found that treatment of rats with the 5-HT₂ antagonists ketanserin or pirenperone alone resulted in a decrease in body temperature, whereas the administration of pindolol produced an increase in body temperature. On the basis of the present findings, it is concluded that the hyperthermic responses following the administration of MK-212 are mediated by central 5-HT₂ receptors and that the hypothermic responses to 8-OH-DPAT involve the activation of central 5-HT_1A receptors. The differential effects of 5-MeODMT on body temperature suggest that this indoleamine can activate both subtypes of 5-HT receptor.     

The effects of corticosterone on 5-HT receptor function in rodents.

In the mouse, administration of corticosterone-21-acetate (30 mg/kg, s.c. daily) for 3 and 10 days produced an attenuation of the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), which was not present after administration for 1 day. A similar effect was observed in the rat after administration of corticosterone-21-acetate (30 mg/kg, s.c. daily) for 10 days. Mice which had been given corticosterone for 10 days displayed the serotonin syndrome when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg, s.c.), 15 min after injection of carbidopa (25 mg/kg, i.p.). This was not seen in control animals. The serotonin syndrome was also induced in mice using 8-OH-DPAT; this increased in a dose-dependent manner and could be significantly decreased by pre-treatment with 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, i.p., 30 min prior to administration of 8-OH-DPAT), a 5-HT1A receptor antagonist. Administration of corticosterone (30 mg/kg, s.c. daily) did not significantly alter the serotonin syndrome induced in treated mice, compared with controls. Mice pre-treated for 3 or 10 days with corticosterone did not differ from controls in the number of head-twitches induced by 5-HTP and carbidopa or 5-methoxy-N,N-dimethyltryptamine, nor did they differ from controls in their response to the putative 5-HT1B agonist 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl)1-H indole (RU 24969, 3 mg/kg, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis

Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB(1) receptors. Whether central and/or peripheral cannabinoid CB(1) receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the head-twitch response (a centrally mediated serotonin 5-HT(2A) receptor-induced behavior) and emesis (a serotonin 5-HT(3) receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both head-twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the head-twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced head-twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews. Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced head-twitch response in a dose-dependent manner with similar ID(50) values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID(50s), at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose-response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT(3) receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1-1 mg/kg) nearly completely prevented 2-methylserotonin-induced, centrally mediated, head-twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT(3) receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced head-twitch and emesis via cannabinoid CB(1) receptors since the CB(1) receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours.     

The influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice: Possible implications for the actions of antidepressant drugs

This study has investigated the influence of central noradrenergic function on 5-HT₂-mediated head-twitch responses in mice. Central injection of low doses of the α₁-adrenoceptor agonists phenylephrine or methoxamine, or peripheral administration of the antagonist prazosin had no effect on the head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). High doses of both α₁-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the α₂-adrenoceptor agonist clonidine, and potentiated by the antagonists idazoxan and yohimbine. Clonidine also potently inhibited this response when produced by 5-hydroxytryptophan (5-HTP) and carbidopa. The action of the β-adrenoceptor agonist clenbuterol on head-twitches was paradoxical, this drug enhancing the responses to precursor loading (5-HTP/carbidopa) but inhibiting those induced by direct agonists (5-MeODMT, quipazine). Lesioning noradrenergic neurons by central injection of 6-hydroxydopamine (6-OHDA) or peripheral administration of DSP-4 resulted in enhanced head-twitch behaviour. 6-Hydroxydopamine lesioning did not alter the inhibition of head-twitch responses by clonidine but prevented their enhancement following withdrawal from repeated desmethylimipramine (DMI) administration. It is therefore suggested that head-twitch behaviour may be under tonic control by a population of α₂-adrenoceptors which are not on presynaptic noradrenergic terminals, but are postsynaptic and located “down-stream” of the 5-HT₂ receptor. In addition, the enhancement of this behaviour produced by withdrawal from repeated DMI administration probably also resulted from alterations in central noradrenergic function.     

Phencyclidine-induced head-weaving and head-twitch through interaction with 5-HT1 and 5-HT2 receptors in reserpinized rats

Phencyclidine mainly produced head-weaving and head-twitches at doses of 5-7.5 mg/kg and of 7.5-12.5 mg/kg, respectively. Phencyclidine-induced head-twitches and head-weaving were blocked by pretreatment with ritanserin (1 mg/kg), a selective serotonin (5-HT)2 receptor antagonist and with pindolol (20 mg/kg, s.c.), a 5-HT1 receptor antagonist, respectively. In reserpine-pretreated rats, the degree of utilization of 5-HT and the number of 5-HT1 ([3H]5-HT) and 5-HT2 ([3H]ketanserin) binding sites were significantly increased compared with the figures for the vehicle-pretreated rats. The intensity of phencyclidine-induced head-weaving (at the dose of 2.5 mg/kg) and head-twitch (at the doses of 2.5 and 5 mg/kg) was significantly increased in reserpine-pretreated rats compared with that of vehicle-pretreated rats. Furthermore, in the reserpine-pretreated rats, the intensity of phencyclidine (1.25 mg/kg)-induced head-weaving and head-twitches was increased in combination with imipramine, while the intensity of phencyclidine (2.5 mg/kg)-induced head-weaving and head-twitch was decreased by pretreatment with mianserin, a non-selective 5-HT receptor antagonist. These results indicate that phencyclidine induced head-weaving by interacting with 5-HT1 receptors, indirectly after the release of 5-HT and/or with some other mechanisms and induced head-twitch by interacting with 5-HT2 receptors directly and/or indirectly.     

In mice repeated administration of electroconvulsive shock or desmethylimipramine produces rapid alterations in 5-HT2-mediated head-twitch responses and cortical 5-HT2 receptor number

Mice treated with a single electroconvulsive shock (ECS) daily for up to 3 days showed progressively enhanced head-twitch to 5-methoxy-N,N'-dimethyltryptamine 24 h after 1,2 and 3 shocks. Injection of desmethylimipramine (DMI, 5 mg/kg) twice daily for up to 3.5 days progressively decreased head-twitch responses on days 2, 3 and 4. Cortical [3H]ketanserin binding was increased by ECS X 3 and decreased by 3.5 days DMI treatment. These data demonstrate that in mice antidepressant treatments produce rapid changes 5-HT2 function.     

5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil.

Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT1A/5-HT2 agonist 5-methoxy,N-N dimethyltryptamine (5-MeODMT) (0.5-8 mg/kg, SC), the specific 5-HT1A agonist 8-hydroxy(di-n-propylamino)tetralin (8-OH-DPAT) (0.125-16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100-250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT1A antagonist NAN-190 (0.25-8 mg/kg, SC) when dosed 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT1A agonists such as quipazine (2-16 mg/kg, SC) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT2 antagonist ritanserin (0.0125-0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreatment with the selective 5-HT1A agonist 8-OH-DPAT (0.005-0.04 mg/kg, SC), demonstrating a 5-HT1A/5-HT2 receptor subtype interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

5-Hydroxytryptamine agonistic action of methysergide and the absence of supersensitivity to 5-HT agonists in spinal flexor reflexes in rats

The intravenous administration of L-5-hydroxytryptophan (5-HTP), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), p-chloroamphetamine (PCA), LSD and methysergide to acute spinal rats, transected at C1, stimulated the flexor reflexes induced by electrical stimulation applied to the skin of the toe. The enhancement produced by 5-HTP, 5-MeODMT and PCA, was not antagonized by the prior administration of a dose of LSD or methysergide, although the enhancement produced by 5-MeODMT, LSD and methysergide, but not that produced by 5-HTP and PCA, was antagonized by cyproheptadine. In rats treated with 5,6-dihydroxytryptamine (intracisternal administration, 2 weeks previously) supersensitivity was observed to the effects of 5-HTP, a precursor of 5-HT, while subsensitivity was observed for the effects of PCA, a releaser of 5-HT. However, no supersensitivity was observed for the effects of 5-MeODMT, LSD and methysergide. These results suggest that methysergide may have an agonistic action on the 5-HT receptors in spinal cord and that supersensitivity to 5-HTP in rats treated with 5,6-dihydroxytryptamine was due to the lack of uptake of 5-HT into terminals of descending 5-HT fibres or to the change in 5-HT receptors which were not sensitive to 5-MeODMT, LSD, methysergide or cyproheptadine.     

Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists.

The effects of chronic (14 day) administration to mice of the 5-HT1 agonists 8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) IH indole (RU 24969) on the hypothermic response to 8-OH-DPAT and the locomotor response to RU 24969 have been examined. Chronic administration of 8-OH-DPAT (5 mg kg-1, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969. Chronic injection of RU 24969 (3 mg kg-1, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Chronic administration of the putative presynaptic 5-HT1 antagonist isapirone (10 mg kg-1, i.p.) decreased the hypothermic response following 8-OH-DPAT injection but did not alter RU 24969-induced locomotion. Chronic treatment with 8-OH-DPAT (5 mg kg-1, s.c.) produced a modest enhancement of the 5-HT2 receptor-mediated head-twitch behaviour initiated by 5-hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5-HT2 receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8-OH-DPAT. These data suggest that chronic administration of the 5-HT1 agonists induces tolerance in their respective responses but not cross-tolerance, while chronic isapirone may down-regulate the 5-HT1A site in a matter analogous to that seen by 5-HT2 receptors following 5-HT2 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Further evidence for an anomalous regulation of cortical 5-HT2 receptors: studies with 5-HT precursors

Rats pretreated with either phenelzine (50 mg/kg 18 h and 12 mg/kg 90 min previously) or carbidopa (25 mg/kg 30 min previously) then given tryptophan or 5-hydroxytryptophan (5-HTP), developed wet-dog shakes which were more intense after 5-HTP. Cortical 5-HT2 receptors were significantly reduced within 3 h of tryptophan (150 or 500 mg/kg) given to phenelzine-treated rats. 5-HTP either did not affect (150 mg/kg) or slightly increased (350 mg/kg) 5-HT2 receptor numbers in rats pretreated with carbidopa. The response to 5-HTP (350 mg/kg) was not altered by pretreatment with alpha-methyl-p-tyrosine, haloperidol, propranolol or yohimbine.     

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.     

Effects of a selective 5-HT reuptake blocker,citalopram, on the sensitivity of 5-HT autoreceptors: Electrophysiological studies in the rat brain

Summary Citalopram (CIT), is a selective serotonin (5-HT) reuptake blocker and a clinically effective antidepressant. The present electrophysiological studies were undertaken to investigate in vivo the acute and long-term effects of CIT administration on 5-HT neurotransmission. In a first series of experiments, a single dose of CIT (0.05–0.5 mg/kg) was administered intravenously to naive rats while recording the activity of a 5-HT-containing neuron in the nucleus raphe dorsalis. A dose-response relationship of the inhibitory effect of CIT on the firing activity of 5-HT neurons was obtained with an ED₅₀ of 0.23±0.03 mg/kg. In a second series of experiments, rats were treated with CIT (20 mg/kg/day, i.p.) for 2, 7 and 14 days. In rats treated for 2 days, there was a marked reduction in the firing activity of 5-HT neurons in the nucleus raphe dorsalis; there was a partial recovery after 7 days and a complete recovery after 14 days of treatment. The response of 5-HT neurons to intravenously administered LSD was decreased in rats treated for 14 days with CIT, indicating a desensitization of the somatodendritic 5-HT autoreceptor. In a third series of experiments, carried out in rats treated with CIT (20 mg/kg/day, i.p.) for 14 days, the suppression of firing activity of CA₃ hippocampal pyramidal neurons produced by microiontophoretically-applied 5-HT and by the electrical activation of the ascending 5-HT pathway was measured. Long-term treatment with CIT did not modify the responsiveness of these neurons to microiontophoretically-applied 5-HT; however, the effect of the electrical activation of the ascending 5-HT pathway on these same neurons was enhanced. To determine if 5-HT reuptake blockade could be responsible for this enhancement, CIT (1 mg/kg) was injected intravenously in naive rats while stimulating the ascending 5-HT pathway; it failed to modify the effectiveness of the stimulation. To assess the involvement of the 5-HT terminal autoreceptor, methiothepin, a 5-HT autoreceptor antagonist, was injected intravenously (1 mg/kg) in naive rats and in rats treated for 14 days with CIT while stimulating the ascending 5-HT pathway. Methiothepin enhanced the effect of the stimulation in naive rats but failed to do so in the CIT-treated rats. It is concluded that long-term CIT treatment enhances 5-HT neurotransmission by desensitizing both the somatodendritic and terminal 5-HT autoreceptors.