Regional analysis of 5-HT1A and 5-HT2 receptors in the fawn-hooded rat.

The Fawn-Hooded strain of rats exhibits a hemorrhagic disorder, known as platelet storage pool deficiency. In addition to the platelet dysfunction, there is an altered response to certain serotonin drugs. To assess the characteristics of the binding to 5-HT1A and 5-HT2 receptors in this strain, regions of the brain from Fawn-Hooded, Sprague-Dawley and Wistar male rats were examined. The drug [3H]8-OH-DPAT was used to label 5-HT1A receptors and the Kd values for frontal cortex, hippocampus, striatum, hypothalamus and brainstem were similar in all three strains of rat. As with the 5-HT1A receptors, no differences were observed in the Kd values for 5-HT2 receptors, in any of the regions examined, among the three strains. However, the Bmax for the binding of [3H]8-OH-DPAT in the striatum and brainstem of Fawn-Hooded rats was less than in the Sprague-Dawley and Wistar animals. Furthermore, 5-HT2 receptors displayed a greater Bmax value in the striatum and in the frontal cortex of Fawn-Hooded animals, compared to Sprague-Dawley and Wistar rats. These differences in receptors are consistent with previous studies in which Fawn-Hooded rats were found to have altered serotonergic function, relative to Wistar and Sprague-Dawley animals.     

The anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor subtypes in rat brain: sensitivity to guanine nucleotides

Eltoprazine (DU 28853) inhibits offensive aggressive behaviour in several animal species. We characterized the binding of radiolabelled eltoprazine in rat brain by autoradiography. [3H]Eltoprazine displayed saturable and high-affinity binding to several brain areas, including the basal ganglia, hippocampal formation and cerebral cortex (Kd values ranging from 4.2 to 9.5 nM). The maximal binding capacities (Bmax) for [3H]eltoprazine were similar to those for [3H]5-HT and were highest in the substantia nigra and subiculum. Competition with eltoprazine for [3H]ligand binding to the various 5-HT1 receptor subtypes revealed preferential binding to 5-HT1A (IC50 values ranging from 42 to 50 nM) and 5-HT1B (IC50 values ranging from 25 to 38 nM) recognition sites. The drug had moderate affinity for 5-HT1C sites (IC50 = 282 nM). Addition of GTP or its stable analogue Gpp(NH)p to the radioligand assay caused a marked reduction (50-90%) in both [3H]eltoprazine and [3H]5-HT binding. These effects were substantially less in the choroid plexus. The binding of the antagonist (-)[125I]Iodocyanopindolol ([125I]ICYP) to 5-HT1B recognition sites, as quantified in the subiculum and substantia nigra, was either unaltered or slightly enhanced by the addition of 10(-3) M GTP. Furthermore, GTP did not affect the competition for [125I]ICYP binding by the 5-HT1-antagonist methiothepin, whereas it did significantly reduce the displacement by eltoprazine, resulting in an almost twofold increase in IC50 values. The data indicate that the anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor sites and that this interaction is modulated by guanine nucleotides.     

5-HT4 receptor mediated stimulation of gastric emptying in rats

It is well documented that certain substituted benzamides, such as cisapride, and benzimidazolones, such as BIMU 8, enhance gastric emptying in rats. As these compounds possess 5-HT₃ antagonistic and 5-HT₄ agonistic properties, the precise mechanisms (5-HT₃ or 5-HT₄) underlying their gastroprokinesic effects is still unclear. In the present study, we used SC 49518 (a benzamide and selective 5-HT₄ receptor agonist) and two selective 5-HT₄ receptor antagonists (RS 23597-190 and SB 204070) to elucidate the role of 5-HT₄ receptors in gastroprokinesis. SC 49518 (1–316 g/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED₅₀ = 2.3 g/kg; ip). SC 49518 also produced dose-dependent inhibition of bradycardia induced by 2-methyl 5-HT (von Bezold-Jarisch reflex) but with a 156 fold lower potency (ID₅₀ = 0.36 mg/kg; ip). The gastroprokinetic effects of SC 49518 (3–316 g/kg; ip) were significantly antagonized by the selective 5-HT₄ receptor antagonist RS 23597-190 (0.1 mg/kg/min; iv). SB 204070 (0.003-1 mg/kg; ip), another selective 5-HT₄ receptor antagonist, produced dose-dependent inhibition of the gastroprokinesic effects of SC 49518 (10 g/kg; ip), the inhibition attaining statistical significance at the dose of 0.1 mg/kg; ip. RS 23597-190 had no effects on gastric emptying per se whereas SB 204070 significantly increased gastric emptying by itself at 1 mg/kg; ip but not at 0.1 mg/kg; ip. These findings show, for the first time, that SC 49518, a selective 5-HT₄ receptor agonist, produces potent stimulation of gastric emptying in rats via a mechanism involving activation of 5-HT₄ receptors. It is suggested that a similar mechanism may account for the gastroprokinetic effects of other non-selective benzamides and benzimidazolones.     

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 5-HT1A receptor full agonist, 8-OH-DPAT inhibits ACTH-induced 5-HT2A receptor hyperfunction in rats: involvement of 5-HT1A receptors in the DOI-induced wet-dog shakes in ACTH-treated rats

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.     

Lithium and 5-HT1A receptor sensitivity: a neuroendocrine study in healthy volunteers

The effect of lithium administration (800 mg daily for 7 days) on the neuroendocrine and temperature responses to the 5-HT_1A receptor agonist, gepirone, was studied in eight healthy male volunteers. Gepirone (20 mg orally) significantly increased plasma levels of prolactin, growth hormone, corticotropin and cortisol, and lowered oral temperature. None of these responses was significantly altered by lithium treatment. The results suggest that the ability of short-term lithium treatment to increase 5-HT-mediated neuroendocrine responses in humans is unlikely to be related to changes in the sensitivity of pre- or post-synaptic 5-HT_1A receptors.     

Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity

Animal experimental studies suggest that the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) may involve neuroadaptive changes in pre- and post-synaptic serotonin_1A (5-HT_1A) receptors. We used the endocrine and hypothermic responses to the 5-HT_1A receptor agonist, gepirone (20 mg orally), to assess 5-HT_1A receptor sensitivity in 37 healthy male volunteers who were studied before and following random double-blind, allocation to treatment with paroxetine, nefazodone or placebo for 17 days. Following antidepressant drug treatment, hypothermic responses to gepirone were markedly decreased by paroxetine but only slightly diminished by nefazodone. Paroxetine also lowered the growth hormone and cortisol responses to gepirone. There was no change in either hypothermic or endocrine response following placebo treatment. Our results suggest that paroxetine treatment produces a striking attenuation of measures of both pre- and post-synaptic 5-HT_1A receptor function. Nefazodone appears to decrease the sensitivity of 5-HT_1A autoreceptors to some extent and this effect may contribute to its antidepressant activity. Received: 9 December 1996 /Final version: 17 February 1997     

5-HT(1A) receptor sensitivity in 5-HT(1B) receptor KO mice is unaffected by chronic fluvoxamine treatment

The 5-HT(1B) receptor has been implicated in disorders such as depression, anxiety and obsessive-compulsive disorder. In mice lacking the 5-HT(1B) receptor (5-HT(1B) knockout mice), important changes in physiology and behavior exist. In the absence of presynaptic 5-HT(1B) receptor inhibition, chronic SSRI treatment may differentially affect 5-HT(1A) receptor functionality. The present studies tested the hypothesis that chronically reducing 5-HT transporter (5-HTT) function with selective serotonin reuptake inhibitor (SSRI) treatment would accelerate 5-HT(1A) receptor desensitization in 5-HT(1B) knockout mice. Moreover, as 5-HT(1B) knockout mice have been found to display exaggerated autonomic and locomotor responses to environmental stressors, the effects of chronic SSRI treatment on the hyperreactive phenotype of 5-HT(1B) knockout mice were investigated. The stress-reducing effect of the 5-HT(1A) receptor agonist flesinoxan on increases in body temperature, heart rate and locomotor activity was similar in wild type and 5-HT(1B) knockout mice before and after chronic 21-day treatment with the SSRI fluvoxamine, indicating no apparent alteration of 5-HT(1A) receptor sensitivity in 5-HT(1B) knockout mice. Also, chronic SSRI treatment did not alter the increased stress reactivity to mild environmental stressors in 5-HT(1B) knockout mice. We demonstrate that no apparent differences in 5-HT(1A) receptor sensitivity occur between 5-HT(1B) knockout and wild type mice after chronic fluvoxamine treatment. Also, the hyperreactive phenotype of 5-HT(1B) knockout mice is unresponsive to chronic SSRI treatment. Taken together, these results indicate that constitutive absence of 5-HT(1B) receptors does not result in adaptive changes in 5-HT(1A) receptor functionality and that chronic SSRI treatment does not modify stress reactivity in 5-HT(1B) knockout mice.     

5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT(1A) receptor stimulation on contextual learning in mice

The principal 5-HT(1A) receptor agonist 8-Hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) impairs several different types of learning. Besides 5-HT(1A) receptors, 8-OH-DPAT stimulates 5-HT(7) receptors, but it is not known whether 5-HT(7) receptors contribute to the impairments. The 5-HT(7) receptor antagonist (2R)-1-[(3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl] pyrrolidine (SB-269970) was combined with 8-OH-DPAT to dissociate 5-HT(1A) from 5-HT(7) receptor-mediated effects, in the passive avoidance task for emotional learning. SB-269970 intensified impairments caused by 8-OH-DPAT. SB-269970 alone had no effect on memory performance, but moderately decreased retention under suboptimal learning conditions. These findings indicate that 5-HT(7) receptor stimulation by 8-OH-DPAT counteracts 5-HT(1A) receptor-mediated impairments in hippocampal-dependent contextual learning.     

5-HT1A receptor activity disrupts spontaneous alternation behavior in rats

Agonists selective for three different serotonin (5-HT) receptor subtypes were tested for the ability to disrupt spontaneous alternation behavior (SAB) in the CD strain of rats. Rats were scored for alternation or repetition in their choice of arms of a T-maze equally baited with chocolate milk. Compared with vehicle controls, the 5-HT(1A) agonist 8-hydroxy-dipropylaminotetraline (8-OH-DPAT; 2 mg/kg) significantly (P<.0001) increased repetitive choices (disrupted SAB). In contrast, intraperitoneal injections with the 5-HT(2) agonist R-(-)-dimethoxyiodophenylaminoethane (DOI; 1 mg/kg) or the 5-HT(3) agonist N-methyl quipazine (NMQ; 3 mg/kg) had no significant effect on SAB in CD rats. Onset of vicarious trial and error (VTE) behavior prolonged the time required for each rat to select an arm of the T-maze when injected with either 8-OH-DPAT (P<.0001) or buspirone (1-2 mg/kg), a 5-HT(1A) partial agonist. The disruption of SAB and the induction of VTE behavior were reversible with behavioral scores returning to preinjection levels within 48 h after injections. The disruption of SAB by 8-OH-DPAT was also seen with the Long-Evans rat strain. The results extend the use of the SAB model and point to a specific role of 5-HT(1A) receptors in the induction of repetitive behavioral patterns.     

8-OH-DPAT-induced effects on prepulse inhibition: pre- vs. post-synaptic 5-HT1A receptor activation

Prepulse inhibition (PPI) is a measure of sensorimotor gating that is deficient in schizophrenia. In rats, administration of the serotonin-1A (5-HT1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), causes a disruption of PPI. It is unclear whether this effect is due to the activation of pre- or post-synaptic 5-HT1A receptors, however pre-synaptic receptors located in the dorsal raphe nucleus (DRN) may play a role. Our previous research showed that castrated rats have a reduced sensitivity to 8-OH-DPAT-induced disruptions of PPI. Therefore, in , male Sprague-Dawley rats were sham-operated or castrated and micro-injected with 8-OH-DPAT directly into the DRN. In , male rats were sham-operated or received a selective serotonergic, 5,7-dihydroxytryptamine lesion of the DRN. 8-OH-DPAT was injected subcutaneously in these rats. In both sham-operated and castrated rats, a micro-injection of 8-OH-DPAT into the DRN did not disrupt PPI. Instead, in castrated rats, 8-OH-DPAT treatment tended to increase PPI. A DRN lesion caused a significant reduction in 5-HT content in the frontal cortex (70% reduction), striatum (69%) and ventral hippocampus (76%). In both sham-operated and DRN-lesioned rats, systemic 8-OH-DPAT significantly disrupted PPI. Taken together, these data suggest that the disruption of PPI observed in rats with systemic 8-OH-DPAT treatment is predominantly due to an activation of post-synaptic, rather than pre-synaptic, 5-HT1A receptors.     

Nicotine withdrawal leads to increased sensitivity of serotonergic neurons to the 5-HT1A agonist 8-OH-DPAT

In order to explore the neurophysiology of nicotine withdrawal, we examined the activity of serotonergic neurons in the dorsal raphe nucleus in rats undergoing withdrawal from chronic exposure to nicotine. Animals were exposed to nicotine (6 mg/kg per day base) via SC implanted osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal. Rats were anesthetized on various days of the procedure and the effect of the 5-hydroxytryptamine (5-HT)-1A agonist 8-OH-DPAT on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus was examined. The sensitivity of serotonergic neurons to 8-OH-DPAT was not changed by the chronic administration of nicotine or saline; slightly increased on day 2 of withdrawal; significantly increased on days 3 and 4 of withdrawal; and no longer significantly increased by day 7 of withdrawal. These results indicate that serotonergic neurons in the dorsal raphe nucleus have an increased sensitivity to systemically administered 8-OH-DPAT in rats undergoing nicotine withdrawal and that the serotonergic system may play a role in the symptoms of nicotine withdrawal. Received: 13 September 1996/Final version: 29 April 1997     

Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists,antagonists or antidepressants

The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT_1A receptor mediated lower lip retraction (LLR), 5-HT_1C receptor mediated penile erections (PE) or 5-HT₂ receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT_1A and 5-HT₂ receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT_1C receptor mediated behaviour remained unchanged. The ED₅₀ for the 5-HT_1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1mg/kg/day) pretreated rats. The number of 5-HT₂ receptor mediated (±)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT_1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED₅₀ for 8-OH-DPAT induced LLR (ED₅₀ values were 0.06 and 0.14 mg/kg, respectively, in placebo — and tranylcypromine — pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT_1C and 5-HT₂ receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT_1A and 5-HT₂ but not 5-HT_1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT_1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed.     

Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats.

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats

Rationale

Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.

Objective

We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.

Results

MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25–1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.

Conclusion

The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.     

Corticosterone responses in 5-HT1B receptor knockout mice to stress or 5-HT1A receptor activation are normal

RATIONALE: Previous research found no adaptations in presynaptic 5-HT1A receptors in mice lacking 5-HT1B receptors (5-HT1B KO). Stress and 5-HT1A receptor agonists induce corticosterone release in mice via hypothalamus-pituitary-adrenal (HPA) axis activation. 5-HT1B KO mice are hyperreactive to mild stressors and this might be reflected in altered postsynaptic 5-HT1A receptor sensitivity. OBJECTIVES: Our aim was to determine whether the activity of the HPA axis was increased in 5-HT1B KO mice in response to mild stress and pharmacological activation of 5-HT1A receptors as an indication of putative adaptive changes in postsynaptic 5-HT1A receptor function. METHODS: The effect of mild stress [i.e., the stress-induced hyperthermia (SIH) paradigm], induced by rectal temperature measurement, was determined on temperature and corticosterone over time (0, 5, 10, 20, 30, 60, and 90 min) in 5-HT1B KO and wildtype mice. In addition, corticosterone was measured 60 min after 5-HT1A receptor activation by flesinoxan (0, 0.03, 0.1, 0.3, 1, and 3 mg/kg s.c.). Blood was collected and plasma corticosterone levels were determined by radioimmunoassay. RESULTS: Both genotypes showed comparable time-dependent SIH responses, whereas basal temperature was higher in 5-HT1B KO mice. The effect of SIH on temperature was mirrored by mild increases in plasma corticosterone. Activation of 5-HT1A receptors caused a strong dose-dependent release of corticosterone in both genotypes. Neither response observed showed differences between both genotypes. CONCLUSIONS: Although 5-HT1B KO mice are hyperreactive to mild stress, this reactivity is not reflected by stronger corticosterone responses in the SIH paradigm. The lack of shift in dose-response curves for flesinoxan suggests that postsynaptic 5-HT1A receptor function is unaffected in 5-HT1B KO mice.     

5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms

Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. In this paper, studies focusing on anxiety using 5-HT1A receptor knockout (1AKO) and 5-HT1B receptor knockout (1BKO) mice are reviewed. 1AKO mice on different genetic background strains have initially been described as more anxious. In 1AKO mice on the 129/Sv background strain, the initial findings could not always be replicated, although under certain conditions, mild anxiety-like responses were observed in these 1AKO mice. In 1BKO mice, some indications of reduced anxiety have been found, but these observations may be confounded partly with increased motor impulsivity of these mutants. To study whether the putative effects of the null mutations on anxiety were reflected in the autonomic nervous system, basal heart rate and body temperature of 1AKO and 1BKO mice were measured, as well as their autonomic responses to novel cage exposure and to reversal of the light-dark rhythm. 1AKO mice did not differ from wild-type mice in any parameter, neither under non-stress conditions, nor following novel cage exposure. In 1BKO mice, basal heart rate was reduced and body temperature was increased. 1BKO mice showed exaggerated autonomic responses to novel cage stress. Adaptation to the reversal of the light-dark cycle was comparable in the three genotypes. The stress-induced hyperthermia procedure showed no differential responses of the three genotypes to the stressor. Pharmacological responses to various psychotropic drugs in the stress-induced hyperthermia test were also comparable in 1AKO, 1BKO and wild-type mice. The present data illustrate the complexity of studying the behavioural and physiological consequences of deletion of genes coding for important receptors in the CNS.     

Ligand-5-HT1A receptor interaction

In the present paper the general structure and pharmacophore of some 5-HT1A receptor ligands are described. For several compounds (approximately 15) the intrinsic activity in lower lip retraction (postsynaptic, rat) and hypothermia (presynaptic, mice) tests was determined. For the identified functional presynaptic agonists and antagonists the influence on the brain serotonin level was examined. No direct correlation between the functional intrinsic activity and the influence on the level was observed. Molecular modelling revealed the possibility of the existence of different binding sites for different examined compounds.     

Opposite effects of antidepressants and corticosterone on the sensitivity of hippocampal CA1 neurons to 5-HT1A and 5-HT4 receptor activation

Using extracellular and intracellular ex vivo recording techniques we studied changes in the reactivity of hippocampal pyramidal CA1 neurons to serotonin (5-HT) and to the 5-HT1A- and 5-HT4 receptor agonists (+/-)-2-dipropylamino-8-hydroxy- 1,2,3 ,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, evoked by repeated electroconvulsive shock (ECS), imipramine and corticosterone treatments. Rats were subjected to ECS for 1 or 10 days, treated with imipramine for 1, 7, 14 or 21 days (10 mg/kg p.o., twice daily) and with corticosterone for 7 days (10 mg/kg s.c., twice daily). Hippocampal slices were prepared 2 days after the last treatment. Activation of 5-HT1A receptors decreased the amplitude of population spikes evoked by stimulation of the Schaffer/collateral-commissural pathway and hyperpolarized CA1 cells. Activation of 5-HT4 receptors increased the population spike amplitude and decreased the amplitude of slow afterhyperpolarization. Both repeated ECS and imipramine enhanced the effects related to 5-HT1A receptor activation and attenuated the effects of 5-HT4 receptor activation. The action of imipramine was significant after a 7-day treatment and reached a maximum after 14 daily applications, remaining at the same level in a group of animals treated for 21 days. Repeated corticosterone attenuated the inhibitory effect of 5-HT and 8-OH-DPAT on the population spike amplitude and enhanced the increase in population spike amplitude induced by zacopride. These findings indicate that antidepressant treatments and repeated corticosterone have opposite effects on hippocampal responsiveness to 5-HT1A and 5-HT4 receptor activation. In consequence, antidepressants enhance, whereas corticosterone reduces the 5-HT-mediated inhibition of hippocampal CA1 cells, which may be relevant to the antidepressant and pro-depressant effects of either treatment, respectively.