Activation of central 5HT1B receptors increases locomotor activity in mice

The effects of 5-HT1B/D receptor agonists anpirtoline, S-CM-GTNH2 and CP93129 were examined in locomotor activity tests in mice. Anpirtoline and S-CM-GTNH2 both significantly increased locomotor activity (ambulation) (minimum affective doses; 3 and 30 mg/kg respectively). CP 93129 injected subcutaneously was without effect, but increased locomotor activity when given i.c.v. Thus activation of central 5-HT1B receptors results in increased locomotor activity. The effects of anpirtoline and S-CM-GTNH2 were blocked by the antagonist GR 127935 suggesting that GR 127935 is an effective antagonist of 5-HT1B receptors in vivo. © 1997 John Wiley & Sons, Ltd.     

Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice

RATIONALE: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D receptors. It penetrates into the central nervous system and, like other 5-HT1B/D agonists, its pharmacotherapeutic profile may include significant anti-aggressive effects. OBJECTIVES: To examine whether zolmitriptan has potential anti-aggressive effects by studying two kinds of aggressive behavior in mice--species-typical and aggression under the influence of alcohol. A second objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. METHODS: Initially, the anti-aggressive effects of zolmitriptan were studied in male CFW mice during 5-min resident-intruder confrontations. To confirm the 5-HT1B receptor as a critical site of action for the anti-aggressive effects, the zolmitriptan dose-effect determinations were repeated after pretreatment with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.) in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Finally, mice were infused with the neurotoxin 5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17 mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. RESULTS: Zolmitriptan exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60-80%. CONCLUSIONS: Zolmitriptan proved to be an effective and behaviorally specific anti-aggressive agent in situations that engender moderate and alcohol-heightened levels of aggression. These effects are potentially due to activation of post-synaptic 5-HT1BD receptors.     

Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice

Rationale In rodents, serotonin 1B (5-HT_1B) agonists specifically reduce aggressive behaviors, including several forms of escalated aggression. One form of escalated aggression is seen in mice that seek the opportunity to attack another mouse by accelerating their responding during a fixed interval (FI) schedule. Responses preceding the opportunity to attack may reflect aggressive motivation. Objective This study investigated the effects of two 5-HT_1B receptor agonists on the motivation to fight and the performance of heightened aggression. Materials and methods Male mice were housed as “residents” and performed nose-poke responses on an FI 10-min schedule with the opportunity to briefly attack an “intruder” serving as the reinforcer. In the first experiment, the 5-HT_1B receptor agonist, CP-94,253 (0–10 mg/kg, IP), was given 30 min before the FI 10 schedule. To confirm that CP-94,253 achieved its effects via 5-HT_1B receptors, the 5HT_1B/1D receptor antagonist, GR 127935 (10 mg/kg, IP) was administrated before the agonist injection. In the second experiment, the 5-HT_1B agonist CP-93,129 (0–1.0 μg) was microinjected into the dorsal raphe 10 min before the FI 10 schedule. Results The agonists had similar effects on all behaviors. CP-94,253 and CP-93,129 significantly reduced the escalated aggression towards the intruder at doses lower than those required to affect operant responding. The highest doses of CP-94,253 (10 mg/kg) and CP-93,129 (1.0 μg) decreased the rate and accelerating pattern of responding during the FI 10 schedule; lower doses were less effective. GR 127935 antagonized CP-94,253’s effects on all other behaviors, except response rate. Conclusions These data extend the anti-aggressive effects of 5-HT_1B agonists to a type of escalated aggression that is rewarding and further suggest that these effects are associated with actions at 5-HT_1B receptors in the dorsal raphe.     

Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253

Rationale: Models of heightened aggression may be particularly relevant in exploring pharmacological options for the clinical treatment of aggressive and impulsive disorders. Objectives: To investigate and compare the effects of a 5-HT_1B selective agonist, CP-94,253, on aggression that was heightened as a result of 1) social instigation or 2) alcohol treatment. Methods: Male CFW mice were administered 1.0 g/kg EtOH and were subsequently confronted by an intruder in their home cage. In a separate experimental procedure, resident male mice were instigated to aggressive behavior by brief exposure to a provocative stimulus male. To test the hypothesis that activation of the 5-HT_1B receptor subtype would preferentially attenuate heightened aggression, in comparison to the moderate levels of species-typical aggressive behaviors, the selective agonist, CP-94,253 (1.0–30 mg/kg, IP), and antagonists to the 5-HT_1B (GR 127935; 10 mg/kg, IP) and the 5-HT_1A receptor (WAY 100,635; 0.1 mg/kg IP) were used. Results: CP-94,253 suppressed non-heightened aggressive behavior (ED₅₀=7.2 mg/kg ). GR 127935, but not WAY 100,635 shifted the ED₅₀ for CP-94,253 to 14.5 mg/kg. Importantly, the anti-aggressive effects of CP-94,253 were not accompanied by locomotor sedation. Alcohol-heightened and instigation-heightened aggression were suppressed at lower doses than those necessary to suppress non-heightened aggression (ED₅₀=3.8 and 2.7 mg/kg, respectively). Conclusions: The current results support the hypothesis that activation of 5-HT_1B receptors modulates very high levels of aggressive behavior in a pharmacologically and behaviorally specific manner. Received: 5 January 1999 / Final version: 16 April 1999     

Regulation of sensitivity to 5-hydroxytryptamine in pulmonary supernumerary but not conventional arteries by a 5-HT(1D)-like receptor

Bovine pulmonary supernumerary arteries are more sensitive to 5-hydroxtryptamine (5-HT) (pD(2) 6.43+/-0.25) than conventional arteries (pD(2) 5.32+/-0.16). This study investigated receptors for 5-HT in ring segments of these arteries. The 5-HT(2) receptor agonist, 2,5 dimethoxy-4-iodoamphetamine hydrobromide (DOI) constricts both arteries. The selective 5-HT(2) receptor antagonist ritanserin produced insurmountable antagonism of 5-HT concentration-response curves in both arteries, whereas the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'(5-methyl- 1,2,4-oxadiazol-3-yl[1,1,-biphenyl]-4-carboxamide hydrochloride (GR127935) produced much greater antagonism in supernumerary arteries. In rings preconstricted with 9,11-dideoxy-9, 11-methanoepoxy prostalagdin F(2alpha) (U46619) and relaxed with the adenylyl cyclase activator forskolin, the selective 5-HT(ID) receptor agonist 2-[5-[3-(4-methylsulphonylamino) benzyl-1,2, 4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine (L694247) reversed the relaxation. Concentration-response curves for L694247-induced reversal of forskolin-relaxation were antagonised by GR127935 in supernumerary (pK(B) 8.6) and conventional (pK(B) 8.4) arteries, whereas concentration-response curves to 5-HT-were less sensitive to antagonism by GR127935T and this was more obvious in conventional (pK(B) 7.6) than supernumerary (pK(B) 8.1) arteries. Neither the selective 5-HT(1D) receptor antagonist (1-(3-chlorophenyl)-4-[3, 3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride (BRL15572) nor the 5-HT(1B) receptor antagonist (2,3,6, 7-tetrahydro-1'-methyl-5-[2'methyl-4'5-(methyl-1,2,4-oxadiazol-3-y l) biphenyl-4-carbonyl]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride (SB224289) antagonised concentration-response curves induced by 5-HT or 5-HT(1)-receptor-selective agonists. In addition to the 5-HT(2A) receptor, 5-HT activates a GR127935-sensitive and a GR127935-insensitive receptor in these arteries. Supernumerary arteries have a greater proportion of GR127935-sensitive receptors, which display only some of the pharmacological characteristics of the cloned 5-HT(ID) receptor. It is possible that the GR127935-sensitive receptor could be a species homologue of the human 5-HT(1B) receptor that is insensitive to SB224289.     

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline

RATIONALE: In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. OBJECTIVES: To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. METHODS: Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. RESULTS: After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. CONCLUSIONS: Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.     

Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram

The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect.     

GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig.

5-HT(1B/D) receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)-H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide ) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT(1B/D) receptor agonists in the guinea pig. Previous studies have shown that 5-HT1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT(1B/D) receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT1A and 5-HT(1B/D) receptor stimulation on locomotor activity in that species. The full agonist at 5-HT1A receptors, 8-OH-DPAT (R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3-1.25 mg kg(-1) s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5 ]decane-7,9-dione HCl) (5.0-20.0 mg kg(-1) s.c.). The 5-HT(1B/D) receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg(-1) s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT1A receptor antagonist WAY100635 (N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg(-1), but not by the 5-HT(1B/D) receptor antagonist GR127935 (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) (0.25-1.0 mg kg(-1)). GR46611, at doses that were without effect given alone (0.5-2.5 mg kg(-1)), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg(-1)) and buspirone (10 mg kg(-1)). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT(1B/D) receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT1A receptor stimulation in guinea pigs.     

Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists

Serotonergic transmission has been suggested to modulate the effects of cocaine. However, the specific receptors underlying this phenomenon have not been identified. To evaluate the role of the 5-HT1B receptor in mediating the actions of cocaine, we used two model systems: knockout (KO) mice lacking the 5-HT1B receptor and an acute treatment with the 5-HT1B/1D antagonist GR127935. GR127935 attenuated the ability of cocaine to stimulate locomotion and induce c-fos expression in the striatum. However, GR127935 had no apparent effect on the rewarding or sensitizing effects of cocaine. In contrast, as demonstrated previously, the 5-HT1B receptor KO mice showed a heightened locomotor response to cocaine, as well as an increased propensity to self-administer cocaine. Thus, an acute pharmacological blockade of the 5-HT1B receptor decreases some effects of cocaine, while a constitutive genetic KO of the same receptor has opposite effects. These results suggest that compensatory changes have taken place during the development of the 5-HT1B KO mice, which may have rendered these mice more vulnerable to cocaine. The 5-HT1B KO mice should therefore be considered as a genetic model of vulnerability to drug abuse rather than a classic pharmacological tool.     

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.     

Evidence for 5-HT(1B/1D) and 5-HT(2A) receptors mediating constriction of the canine internal carotid circulation

The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1 - 10 microg min(-1)), sumatriptan (0.3 - 10 microg min(-1); 5-HT(1B/1D)), 5-methoxytryptamine (1 - 100 microg min(-1); 5-HT(1), 5-HT(2), 5-HT(4), 5-ht(6) and 5-HT(7)) or DOI (0.31 - 10 microg min(-1); 5-HT(2)), but not 5-carboxamidotryptamine (0.01 - 0.3 microg min(-1); 5-HT(1), 5-ht(5A) and 5-HT(7)), 1-(m-chlorophenyl)-biguanide (mCPBG; 1 - 1000 microg min(-1); 5-HT(3)) or cisapride (1 - 1000 microg min(-1); 5-HT(4)), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 microg kg(-1); 5-HT(2A/2B/2C)) in combination with tropisetron (3000 microg kg(-1); 5-HT(3/4)) or the cyclo-oxygenase inhibitor, indomethacin (5000 microg kg(-1)), but were abolished by the 5-HT(1B/1D) receptor antagonist, GR127935 (30 microg kg(-1)). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 microg kg(-1)) or ketanserin (100 microg kg(-1); 5-HT(2A)), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT(1B/1D) and 5-HT(2A) receptors.     

Stimulation of 5-HT1B receptors decreases cocaine- and sucrose-seeking behavior

Serotonin systems have been implicated in incentive motivation for cocaine, yet little is known about the role of 5-HT(1B) receptors in these processes. We used the extinction/reinstatement model to examine the effects of the 5-HT(1B/1A) receptor agonist, RU24969, on reinstatement of extinguished cocaine-seeking behavior. Rats trained to self-administer cocaine subsequently underwent extinction. They were then tested twice for cue and cocaine-primed reinstatement of extinguished cocaine-seeking behavior, receiving saline pretreatment 1 day and their assigned dose of RU24969 (0.3, 1.0, 3.0 mg/kg) the other day. Rats were later trained on a schedule of sucrose reinforcement in novel chambers and then tested for effects of RU24969 on cue reinstatement of sucrose-seeking behavior and locomotion. RU24969 decreased cue and cocaine reinstatement of cocaine-seeking behavior and cue reinstatement of sucrose-seeking behavior. Locomotion was increased only at the highest RU24969 dose (3 mg/kg). A subsequent experiment demonstrated that the effects of RU24969 (1 mg/kg) on extinguished cocaine-seeking behavior were reversed by the 5-HT(1B) antagonist GR127935 (3 mg/kg). These findings suggest that the effects of RU24969 on cue and cocaine reinstatement of cocaine-seeking behavior are 5-HT(1B) receptor-mediated. Overall, the results suggest that stimulation of 5-HT(1B) receptors may produce a general decrease in motivation.     

The anxiolytic-like effect of 5-HT1B receptor ligands in rats: a possible mechanism of action

We have examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg kg(-1)), and the influence of flumazenil (Ro 15-1788, 10 mg kg(-1)), a benzodiazepine receptor antagonist, on the anxiolytic-like activity of CP 94253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine), a 5-HT1B receptor agonist, SB 216641 (N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide), a 5-HT1B receptor antagonist, and GR 127935 (N-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-l, l'-biphenyl-4-carboxamide), a 5-HT1B/1D receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. CP 94253 (2.5 mg kg(-1)), SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test in vehicle- and p-CA-pretreated rats. Flumazenil did not change the anxiolytic-like effect of CP 94253 (2.5 mg kg(-1)), but wholly blocked the anxiolytic-like effects of SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)). p-CA and flumazenil alone were inactive in the conflict drinking test. The results suggested that the anxiolytic-like effect of the 5-HT1B receptor ligands CP 94253, SB 216641 and GR 127935 was possibly linked to the postsynaptic 5-HT1B receptors or/and 5-HT1B heteroreceptors. The results suggested also that benzodiazepine receptors were indirectly involved in the effects of SB 216641 and GR 127935 (but not of CP 94253), which might have been due to a possible interaction between the 5-HT and the GABA/benzodiazepine systems.     

Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT 1A/1B/2C receptors

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C), and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D(+)S(-), administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D(-)S(+) had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5-HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5-HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that blockade of any of its components produces a degradation of its discriminative effects.     

Activation of 5-HT(1B) receptors in the nucleus accumbens reduces self-administration of amphetamine on a progressive ratio schedule

Brain serotonin interacts with dopamine function in a complex fashion. Previous work from our laboratory showed that activation of 5-HT(1B) receptors within the nucleus accumbens attenuates the ability of amphetamine to increase responding for conditioned reinforcement. The primary purpose of these experiments was to determine the impact of 5-HT receptor stimulation, with particular focus on 5-HT(1B) receptors in the nucleus accumbens on the reinforcing effect of amphetamine. To this end several experiments determined the effects of injecting 5-HT, and various 5-HT agonists, into the nucleus accumbens on responding for intravenous infusions of amphetamine (60 microg/kg) delivered according to a progressive ratio schedule of reinforcement. Both 5-HT (2.5, 5 and 10 microg) and the selective 5-HT(1B) receptor agonist CP93,129 (0.625, 1.25 and 2.5 microg) dose-dependently reduced responding for amphetamine. Injections of 5-HT but not CP93,129 also reduced responding for food under a similar PR schedule. The 5-HT(1A) agonist 8-OH-DPAT (5 microg) and the nonselective 5-HT(2) agonist DOI (10 microg) failed to alter amphetamine self-administration. Pretreatment with the selective 5-HT(1B/1D) receptor antagonist GR127935 (3 mg/kg) attenuated the ability of 5-HT and CP93,129 to reduce amphetamine self-administration following their injection into the nucleus accumbens. These results extend our previous findings that increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT(1B) receptors is particularly important in this regard.     

Effect of serotonin (5-HT)1B receptor ligands on cocaine sensitization in rats

Recent studies have shown that antagonists of serotonin (5-HT)1B receptors attenuate cocaine-induced locomotor hyperactivity, whereas agonists enhance reinforcing and discriminative stimulus effects of the psychostimulant. The present study was designed to determine how 5-HT1B receptor ligands affected the development or the expression phase of sensitization to the cocaine-induced locomotor response in rats. In Experiment 1, rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either saline, GR 127935 (5-HT1B antagonist), CP 94,253 (5-HT1B agonist) or GR 127935 + CP 94,253. On day 10, they received a challenge dose of cocaine (10 mg/kg). In Experiment 2, animals received either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with saline, GR 127935, CP 94,253 or GR 127935 + CP 94,253, on day 10. In Experiment 3, rats received either saline, cocaine or CP 94,253 for 5 days; on day 10 they received challenge doses of CP 94,253 or cocaine. In rats treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was about twice as high as that observed after its first administration. The effect evoked by cocaine challenge was further increased in animals treated repeatedly with CP 94,253 + cocaine, but not with GR 127935 + CP 94,253 + cocaine. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine or GR 127935 + cocaine (Experiment 1). In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently increased when that drug was combined with CP 94,253, but not with GR 127935 + CP 94,253. No difference was observed in the locomotor response of rats challenged with cocaine or GR 127935 + cocaine (Experiment 2). When rats were treated repeatedly with cocaine, a challenge dose of CP 94,253 produced an about threefold increase in the locomotor effect compared to the animals treated likewise with saline (Experiment 3). Our results indicate that 5-HT1B receptors are involved in neither the development nor the expression of sensitization to cocaine-induced locomotor hyperactivity. On the other hand, they also show that pharmacological activation of 5-HT1B receptors enhances both phases of this phenomenon, and that repeated administration of cocaine leads to an increased functional reactivity of these receptors.     

Effects of a selective 5-HT1B receptor agonist and antagonists in animal models of anxiety and depression

The purpose of the present study was to investigate the effects of the selective 5-HT1B receptor agonist CP 94253, the selective 5-HT1B receptor antagonist SB 216641, and the 5-HT1B/1D receptor antagonist GR 127935 in behavioral tests commonly used to predict anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as reference drugs. In the Vogel conflict drinking test, CP 94253 (1.25-5 mg/kg), SB 216641 (2.5-5 mg/kg) and GR 127935 (5-10 mg/kg) showed anxiolytic-like effects comparable to that of diazepam (2.5-5 mg/kg). In the elevated plus-maze test, antianxiety-like activity of all the compounds tested was also observed: the effects of CP 94253 (2.5 mg/kg) and SB 216641 (5 mg/kg) were similar to that of diazepam (5 mg/kg), while GR 127935 (up to 40 mg/kg) was less active. In the four-plate test, the compounds tested (5-10 mg/kg) produced anxiolytic-like effects which were weaker than that of diazepam (2.5-5 mg/kg). In the forced swimming test, CP 94253 (5-10 mg/kg), like imipramine (30 mg/kg), showed anti-immobility action, whereas SB 216641 (2.5-10 mg/kg) and GR 127935 (20-40 mg/kg) did not affect the immobility time in mice. The results indicate that the selective agonist (CP 94253) and antagonists (SB 216641 and GR 127935) of 5-HT1B receptors produce effects that are characteristic of anxiolytics, in the preclinical models used; however, CP 94253 also behaves like an antidepressant drug.     

An evaluation of the effect of NAS-181, a new selective 5-HT<Subscript>1B</Subscript> receptor antagonist,on extracellular 5-HT levels in rat frontal cortex

In the mammalian brain 5-HT(1B) receptors are present as autoreceptors regulating the release of serotonin (5-HT) by inhibitory feedback. The antagonistic properties of NAS-181 ((R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl] morpholine methane sulfonate), a new selective antagonist for the rodent 5-HT(1B) receptor, were determined by using an agonist-induced decrease of extracellular 5-HT. The 5-HT(1B) receptor agonist CP93129 (0.030.3 microM) applied by reversed microdialysis, dose-dependently reduced 5-HT levels in rat frontal cortex. The suppressant effect of CP93129 (0.1 microM) was smaller in the presence of fluvoxamine (3-10 microM), a 5-HT reuptake inhibitor. The effects of NAS-181 on CP93129 were compared with GR127935, a mixed 5-HT (1B/1D) receptor antagonist, and SB224289, a 5-HT(1B) receptor antagonist. Both in the presence and absence of fluvoxamine, the suppressant effect of CP93129 on extracellular 5-HT was attenuated by NAS-181 (1 microM) and GR127935 (10 microM), but not by SB224289 (1 microM). In the absence of fluvoxamine, GR127935, SB224289 and NAS-181 all reduced 5-HT levels, suggesting partial agonistic properties of these compounds. In conclusion, the results show that NAS-181 is a potent 5-HT(1B) receptor antagonist.     

Functional characterization of the 5-HT terminal autoreceptor in the guinea-pig brain cortex.

1 In guinea-pig cerebral cortical slices in vitro we have shown that the rank order of potency of 5-hydroxytrptamine (5-HT), 5-carboxamidotryptamine and sumatriptan for inhibition of electrically stimulated [3H]-5-HT release correlates well with published data on their 5-HT1D receptor binding affinities. 2 Both the non-selective 5-HT1D receptor antagonist, methiothepin and the selective 5-HT1D receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl]phenyl]-2'-methyl-4'- (5-methyl-1,2,4-oxadiazole-3-yl) [1,1-biphenyl]4-carboxamide (GR127935) increased stimulated [3H]-5-HT release per se and also attenuated agonist-induced inhibition of [3H]-5-HT release. GR127935 (10 nM-100 nM) produced a pA2 of 9.0 against 5-HT, which is consistent with its 5-HT1D receptor binding affinity. 3 From these findings we conclude that, in guinea-pig cerebral cortex, the 5-HT terminal autoreceptor is of the 5-HT1D receptor subtype. However, three observations suggest the presence of multiple terminal autoreceptors: shallow inhibition curves to the agonists; a shallow Schild slope of GR127935 antagonism and differences in the maximal responses to 5-HT between whole cortex and frontal cortex.