5-HT1A receptor function in depression: effect of chronic amitriptyline treatment

Summary Hypothermic responses to 5-HT_1A receptor activation by the selective ligand ipsapirone (IPS) were attenuated in depressed patients as compared to controls. Chronic treatment with amitriptyline (AMI) further impaired 5-HT_1Amediated hypothermia. The results indicate a subsensitive (presynaptic) 5-HT_1A receptor and/or a defective post-receptor signalling pathway in depression and are consistent with the hypothesis that 5-HT_1A receptors are down-regulted during AMI treatment.     

DOI, a 5-HT2A/2C receptor agonist, attenuates clozapine-induced cortical dopamine release

(±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 1.25, 2.5 and 5 mg/kg), a serotonin (5-HT)_2A/2C agonist, produced an inverted U-shaped increase in DA release in rat medial prefrontal cortex (mPFC) with a significant effect only at 2.5 mg/kg. This effect was completely abolished by M100907 (0.1 mg/kg), a 5-HT_2A antagonist, and WAY100635 (0.2 mg/kg), a 5-HT_1A antagonist, neither of which when given alone affected dopamine release. DOI (2.5 mg/kg), but not the 5-HT_2C agonist Ro 60-0175 (3 mg/kg), attenuated clozapine (20 mg/kg)-induced mPFC dopamine release. These results suggest that 5-HT_2A receptor stimulation increases basal cortical dopamine release via 5-HT_1A receptor stimulation, and inhibits clozapine-induced cortical dopamine release by diminishing 5-HT_2A receptor blockade.     

Increased midbrain 5-HT1A receptor number and responsiveness in cholestatic rats

Midbrain somatodendritic 5-HT_1A autoreceptors play a central inhibitory role in the regulation of serotonergic neurotransmission. Given that serotonergic neurotransmission appears to be altered in experimental cholestatic liver disease we examined alterations in midbrain 5-HT_1A autoreceptor binding and physiological responses in rats with experimental cholestatic liver disease in comparison to non-cholestatic controls. Using a standard receptor binding assay cholestatic rats exhibited an increase in midbrain 5-HT_1A receptor number but no change in receptor affinity compared to controls. Midbrain 5-HT_1A receptor mRNA expression as determined by semiquantitative RT–PCR was similar in cholestatic and non-cholestatic animals. In addition, cholestatic rats exhibited enhanced 5-HT_1A autoreceptor-mediated hypothermic and hyperphagic responses compared to non-cholestatic controls after the administration of the highly specific 5-HT_1A receptor agonist LY293284. These findings indicate that experimental cholestatic liver injury is associated with enhanced 5-HT_1A autoreceptor-mediated physiological responsiveness in the setting of increased midbrain 5-HT_1A receptor number but not affinity.     

Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

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Changes in rat cerebral blood volume due to modulation of the 5-HT1A receptor measured with susceptibility enhanced contrast MRI

Brain blood volume changes in the rat in response to 5-HT_1A agonist and antagonist administration were measured using susceptibility contrast enhanced magnetic resonance imaging (MRI). Administration of the 5-HT_1A agonist 8-OH-DPAT resulted in decreases in fractional brain blood volumes. Administration of the 5-HT_1A antagonist WAY-100635 following a dose of 8-OH-DPAT resulted in increases in fractional blood volumes greatest in hippocampus and cortex and smallest in thalamus and caudate-putamen. The magnitude of the regional increases in blood volumes paralleled the distribution of 5-HT_1A receptors in the rat brain. Administration of WAY-100635 alone resulted in decreases in cortical blood volume and increases in cerebellar blood volume.     

Sleep/waking effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT alone and in combination with the putative 5-HT1A antagonist NAN-190 in rats

Sleep, waking, and EEG power spectra were investigated in rats after intrathecal (IT) administration of a 5-HT_1A agonist and a 5-HT_1A antagonist. Total slow wave sleep (TSWS) was increased and waking was decreased over the 8-h recording period after the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol). Within TSWS, SWS1 was unchanged while SWS-2 tended to be increased. The 5-HT_1A antagonist 1-[2-Methoxyphenyl)-4-(4-(2-phthalimido)-butyl]piperazine hydrobomide (NAN-190) did not change and sleep/waking stages. Combined treatment with 8-OH-DPAT and NAN-190 increased variance. Following the combination, sleep and waking were not significantly different from control. SWS-2 tended to be reduced compared to the effect of 8-OH-DPAT alone. There were no systematic changes in neither waking nor TSWS fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments, indicating that sleep quality was not changed. The results confirm earlier data suggesting that in the spinal cord, stimulation of 5-HT1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased sleep tendency. The reason why the 8-OH-DPAT effect was not clearly antagonized by the putative 5-HT1A antagonist NAN-190, may be due to the generally weak antagonistic and also partial agonistic effect of NAN-190 as reported in the literature.     

5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D₁ receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K⁺-evoked [³H]ACh release while SCH 23390, a dopamine D₁ receptor antagonist, had no effect. [³H]ACh release was decreased by the dopamine D₂ receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D₂ receptor antagonist haloperidol. The selective neurokinin NK₁ receptor agonist [Sar⁹, met(O₂)¹¹]SP also potentiated K⁺-evoked release of [³H]ACh. GR 82334, a NK₁ receptor antagonist, blocked not only the effect of [Sar⁹, met(O₂)¹¹]SP but also the release of ACh induced by the D₁ receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT_2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D₁ receptor stimulation. Mesulergine, a more selective 5-HT_2C antagonist, showed an intrinsic releasing effect but did not affect K⁺-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT_1/2 antagonists, as well as ondansetron, a 5-HT₃ receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT₂ receptor agonists were ineffective. However, the 5-HT₂ agonist DOI was able to prevent the antagonism by ketanserin of the increased [³H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT_2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK₁ agonist. The results suggest that 5-HT₂ receptors, probably of the 5-HT_2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D₁ receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK₁ receptors located on cholinergic interneurons.     

Antagonism of muscarinic receptors in the rabbit iris-ciliary body by 8-OH-DPAT and other 5-HT1A receptor agonists

Summary Physiological studies have shown that serotonin and 5-HT_1A agonists can influence muscarinic function in the rabbit iris-ciliary body (ICB). The purpose of this study was to examine whether a direct interaction exists between muscarinic and 5-HT_1A receptors in the ICB. At high concentrations, the 5-HT_1A agonist 8-OH-DPAT attenuated the carbachol-induced stimulation of inositol phosphates (InsPs) production, but this was not blocked by the presence of 5-HT_1A antagonists. In contrast, serotonin failed to influence carbachol-induced InsPs formation. Moreover, 8-OH-DPAT but not serotonin displayed affinity for [³H]QNB binding sites in the ICB. The combined data suggest that activation of 5-HT_1A receptors in the ICB does not cause a modulation of muscarinic receptor-stimulated phosphoinositide turnover. The data instead suggest that, at high concentrations, 8-OH-DPAT acts as an antagonist at muscarinic receptors and in this way influences muscarinic receptor function. The mechanism of 5-HT-induced modulation of muscarinic function in the ICB therefore remains to be elucidated.     

Crucial role of the 5-HT2C receptor, but not of the 5-HT2A receptor, in the down regulation of stimulated dopamine release produced by pressure exposure in freely moving rats

Helium pressure of more than 2 MPa is a well known factor underlying pressure-dependent central neuroexcitatory disorders, referred to as the high-pressure neurological syndrome. This includes an increase in both serotonin (5-HT) and dopamine (DA) release. The relationship between the increase in 5-HT transmission produced by helium pressure and its effect on DA release has been clarified in a recent study, which have first demonstrated that the helium pressure-induced increase in DA release was dependent on some 5-HT receptor activation. In the present study, we examined in freely moving rats the role of 5-HT_2A and 5-HT_2C receptors in the increase in DA release induced by 8 MPa helium pressure. We used the 5-HT_2A receptor antagonist ketanserin and the 5-HT_2C receptor agonist m-CPP which have been demonstrated to reduce DA function. Because neither ketanserin is an ideal 5-HT_2A receptor antagonist nor m-CPP an ideal 5-HT_2C receptor agonist, additional experiments were made at normal pressure to check up on the selectivity of ketanserin and m-CPP for 5-HT_2A and 5-HT_2C receptors, respectively. Administration of m-CPP reduced both DA basal level and the helium pressure-induced increase in DA release, whereas administration of ketanserin only showed a little effect on the increase in DA release produced by high helium pressure. These results suggest that the 5-HT_2C receptor, but not the 5-HT_2A receptor, would play a crucial role in the helium pressure-induced increase in DA release. This further suggests that helium pressure may simultaneously induce an increase in 5-HT transmission at the level of 5-HT_2A receptors and a decrease in 5-HT transmission at the level of 5-HT_2C receptors.     

Effects of sertraline and citalopram given repeatedly on the responsiveness of 5-HT receptor subpopulations

Summary The effect of repeated treatment (5 and 10 mg/kg,po, twice daily, 14 days) with sertraline and citalopram (antidepressants which selectively inhibit the reuptake of 5-hydroxytryptamine (5-HT)) on the responsiveness of different 5-HT receptors to their agonists, was examined in rats and mice. Sertraline and citalopram (both at a dose 5 and 10 mg/kg) antagonized (the first one more potently) the hypothermia induced in mice by 8-OH-DPAT (a 5-HT_1A agonist), but not the behavioural syndrome induced in rats by this substance. The m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT_1B effect) was increased by sertraline and citalopram (only in a dose of 10 mg/kg). Both antidepressants, given repeatedly (as well acutely) attenuated exploratory hypoactivity induced in rats by m-chlorophenylpiperazine (a 5-HT_1C effect). L-5-HTP-induced head twitches in mice (5-HT₂ effect) were antagonized dose-dependently by both repeated sertraline and citalopram. Both antidepressants (citalopram only in higher dose) reduced the fenfluramine-induced hyperthermia in rats (5-HT₂ effect).The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT_1A (presynaptic) and 5-HT₂ receptors but increase the responsiveness of 5-HT_1B receptors to respective agonists.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

Serotonin 5-HT1A and 5-HT2/1C receptors in the midbrain periaqueductal gray differentially modulate defensive rage behavior elicited from the medial hypothalamus of the cat

Recent studies have established that the expression of defensive rage behavior in the cat is mediated over a descending pathway from the medial hypothalamus to the dorsolateral quadrant of the midbrain periaqueductal gray matter (PAG). The present study was designed to determine the roles played by 5-HT_1A and 5-HT_2/1C receptors in this region of PAG in modulating defensive rage behavior elicited from the cat's medial hypothalamus. Monopolar stimulating electrodes were implanted into the medial hypothalamus from which defensive rage behavior could be elicited by electrical stimulation. During the course of the study, the `hissing' component of the defensive rage response was used as a measure of defensive rage behavior. Cannula-electrodes were implanted into sites within the PAG from which defensive rage could also be elicited by electrical stimulation in order that 5-HT compounds could be microinjected into behaviorally identifiable regions of the PAG at a later time. Microinjections of the selective 5-HT_1A agonist, (+)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OHDPAT) (50 pmol, 2.0 and 3.0 nmol), into the PAG suppressed the hissing response in a dose-dependent manner. Administration of the selective 5-HT_1A antagonist, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) (1.5 and 3.0 nmol), blocked the suppressive effects of 8-OHDPAT upon hissing. In contrast, microinjections of the 5-HT_2/1C receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+)-DOI hydrochloride) (0.01, 1.0 and 1.5 nmol) facilitated the occurrence of hissing elicited from the medial hypothalamus in a dose-dependent manner. Immunohistochemical analysis revealed the presence of 5-HT axons and preterminals throughout the PAG, and in particular, in its dorsolateral aspect which receives major inputs from the medial hypothalamus in association with defensive rage behavior. The overall findings of the study provide evidence that activation of 5-HT_1A and 5-HT_2/1C receptors within the midbrain PAG differentially modulate the expression of defensive rage behavior elicited from the medial hypothalamus of the cat.     

Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

[¹¹C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT_2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [¹¹C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT_2A receptors with [¹¹C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [¹¹C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [¹¹C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT_2A receptor antagonist ketanserin before a second PET scan significantly decreased [¹¹C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [¹¹C]Cimbi-36 binding is selective for 5-HT_2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT_2A receptors in the human brain. Thus, we here describe [¹¹C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT_2A receptors in the human brain.     

Implication of the 5-HT2A and 5-HT2C (but not 5HT1A) receptors located within the periaqueductal gray in the elevated plus-maze test–retest paradigm in mice

A single exposure to the elevated plus-maze test (EPM) increases open arms avoidance and reduces or abolishes the anxiolytic-like effect of benzodiazepines assessed during a second trial, a phenomenon defined as “one-trial tolerance” (OTT). It has been emphasized that the dorsal portion of the midbrain periaqueductal gray (dPAG) plays a role on this enhanced aversion phenomenon in maze-experienced rodents. Given that intra-dPAG injections of a wide range of serotonergic 5-HT_1A, 5-HT_2A and 5-HT_2C receptor agonists produce anxiolytic-like effects in maze-naïve rodents, the present study examined the effects of the 5-HT_1A receptor agonist 8-OH-DPAT (5.6 and 10.0 nmol in 0.15 µl) the preferential 5-HT_2A receptor agonist DOI (2.0 and 8.0 nmol in 0.1 µl) and the preferential 5-HT_2C receptor agonist MK-212 (21.2 and 63.6 nmol in 0.1 µl) microinjected into the dPAG prior to Trial 1 and Trial 2 on the behaviour of mice in the EPM. Test sessions were recorded and subsequently scored for anxiety-like behaviour (percentage of open arms entries and time) as well as general locomotor activity (closed arm entries). The results showed a lack of 8-OH-DPAT (5.6 and 10.0 nmol) effect on the behaviour of maze-naïve and maze-experienced mice, while intra-dPAG microinfusions of DOI (8 nmol) reduced anxiety-like behaviour only in maze-experienced mice that had received a similar treatment prior to Trial 1. Furthermore, intra-dPAG MK-212 (63.6 nmol) showed an anxiolytic-like effect on both Trial 1 and Trial 2. Importantly, these effects were observed in the absence of any significant change in closed arm entries, the parameter considered to be a valid index of locomotor activity in the plus-maze. These results support the dPAG as a crucial structure involved in the neurobiology of the OTT phenomenon as well as accounting the role of the 5-HT_2A and 5-HT_2C receptors located within this midbrain structure on the emotional state induced by EPM test and retest paradigm mice.     

Cardiovascular effects of intrathecal administration of agents active at 5-hydroxytryptamine1-receptors in the rat: modulation by substance P and a substance P antagonist

Summary The intrathecal (i.th., T 8–10) administration in conscious rats of the 5-hydroxytryptamine (5-HT)_1A agonist 8-OH-DPAT (10 nmol), and to a lesser extent the 5-HT_1B agonist CGS 12066B (6 nmol), resulted in a blood pressure reduction and a bradycardia. These responses were prevented by the i.th. pretreatment with substance P (SP) (6.5 nmol) and enhanced following pretreatment with the non-peptide SP antagonist CP-96,345 (10 nmol). The partial 5-HT_1A agonist 8-MeO-CLEPAT (10 nmol) had by itself small cardiovascular effects. Following the pretreatment with SP, 8-MeO-CLEPAT caused a pressor response and a tachycardia whereas the opposite effects were observed following pretreatment with the SP antagonist. These results support the notion of a functional interaction between serotonergic and SP mechanisms at the level of the preganglionic sympathetic nerves in the spinal cord.     

The effect of ipsapirone and S(−)-pindolol on dopamine release in rat striatum and nucleus accumbens

Serotonin (5-hydroxytryptamine, 5-HT)_1A receptor agonism and 5-HT_2A receptor antagonism are components in the action of some of the recently developed antipsychotic drugs, e.g., clozapine and ziprasidone. However, studies of the role of 5-HT_1A receptor agonism in the ability of these drugs to modulate dopamine (DA) release in the nucleus accumbens (NAC), which may be relevant to antipsychotic action, are lacking. Thus, we examined the effect of clinically available agents, ipsapirone, a 5-HT_1A receptor partial agonist, and the mixed 5-HT_1A/1B/β receptor antagonist S(−)-pindolol, on DA release in the NAC compared to the striatum (STR). Ipsapirone produced a biphasic effect; low dose (0.1 mg/kg) decreased, high dose (3 mg/kg) increased and intermediate doses (0.1 and 1 mg/kg) did not change DA release in the NAC, respectively. However, ipsapirone, at all doses (0.3, 1, 3, but not 0.1 mg/kg) increased striatal DA release. S(−)-pindolol (3, 10, but not 1 mg/kg) produced a comparable increase in DA release in the NAC and STR. These results suggest that the ability of lower dose of ipsapirone to decrease DA release in the NAC is more likely to be due to 5-HT_1A receptor agonism. On the other hand, the effect of higher dose of ipsapirone on striatal DA release may be due to 5-HT_1A receptor antagonism, as is the case with S(−)-pindolol. The mechanism and clinical significance of these results for developing antipsychotic drugs is discussed.     

Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis

Serotonin type 2A (5-HT_2A) receptor-mediated neurotransmitter is known to activate hypothalamic–pituitary–adrenal (HPA) axis, regulate sleep–awake cycle, induce anorexia and hyperthermia. Interaction between melatonin and 5-HT_2A receptors in the regulation of the sleep–awake cycle and head-twitch response in rat have been reported. Previous studies have shown that melatonin has suppressant effect on HPA axis activation, decreases core body temperature and induces hyperphagia in animals. However, melatonin interaction with 5-HT_2A receptors in mediation of these actions is not yet reported. We have studied the acute effect of melatonin and its antagonist, luzindole on centrally administered (±)-1-(2,5-dimethoxy-4-iodophenyl) 2-amino propane (DOI; a 5-HT_2A/2C agonist)-induced activation of HPA axis, hypophagia and hyperthermia in 24-h food-deprived rats. Like ritanserin [(1 mg/kg, i.p.) 5-HT_2A/2C antagonist], peripherally administered melatonin (1.5 and 3 mg/kg, i.p.) did not affect the food intake, rectal temperature or basal adrenal ascorbic acid level. However, pretreatment of rats with it significantly reversed DOI (10 μg, intraventricular)-induced anorexia and activation of HPA axis. But the hyperthermia induced by DOI was not sensitive to reversal by melatonin. Mel₁ receptor subtype antagonist luzindole (5 μg, intraventricular) did not modulate the DOI effect but antagonized the melatonin (3 mg/kg, i.p.) reversal of 5-HT_2A agonist response. The present data suggest that melatonin reversal of DOI-induced hypophagia could be due to suppression of 5-HT_2A mediated activation of HPA axis.     

Effect of alcohols on G-protein coupling of serotonin1A receptors from bovine hippocampus

The serotonin_1A (5-hydroxytryptamine [5-HT]_1A) receptors are members of a superfamily of seven transmembrane domain receptors that couple to G-proteins. Serotonergic signalling has been shown to play an important role in alcohol intake, preference and dependence. G-protein coupling of the 5-HT_1A receptor serves as an important determinant for serotonergic signalling. We have studied the effect of alcohols on G-protein coupling of bovine hippocampal 5-HT_1A receptors in native membranes. This was done by monitoring the modulation of ligand (agonist and antagonist) binding in presence of alcohols by guanosine-5′-O-(3-thiotriphosphate) (GTP-γ-S), a non-hydrolyzable analogue of GTP. Our results show that alcohols inhibit the specific binding of the agonist 8-hydroxy-2-(di-N-propylamino)tetralin (except in case of ethanol) and the antagonist 4-(2′-methoxy)-phenyl-1-[2′-(N-2″-pyridinyl)-p-fluorobenzamido]ethyl-piperazine to 5-HT_1A receptors in a concentration-dependent manner. Further, we show here that the action of alcohols on the bovine hippocampal 5-HT_1A receptors could be modulated by guanine nucleotides and that the mode of action of ethanol on the 5-HT_1A receptor may be quite different than that of other alcohols. The effect of GTP-γ-S on the agonist and the antagonist binding is found to be markedly different. Our results could be significant in the overall context of the role of G-protein coupling in serotonergic neurotransmission and its role in alcohol tolerance and dependence.     

Chronic electroconvulsive shock and 5-HT autoreceptor activity in rat brain: an in vivo microdialysis study

Summary In vivo microdialysis was used to determine the effects of chronic electroconvulsive shock (ECS), given daily for 10 days, on basal 5-HT levels in rat frontal cortex and hippocampus and on the effect of systemic administration of the 5-HT-la receptor agonist, 8-OH-DPAT (0.2 mg/kg), to reduce 5-HT levels in these areas by activation of somatodendritic autoreceptors. Neither basal 5-HT levels nor the effects of 8-OH-DPAT on 5-HT levels were altered after chronic ECS. The effect of systemic administration of the 5-HT_1A and 5-HT_1B antagonist, (±)-pindolol (10mg/kg), to increase 5-HT levels in hippocampus, was also not affected by chronic ECS.     

Serotoninergic Mechanisms of Immunomodulation Under Different Psychoemotional States: I. A role of 5-HT1a Receptor Subtype

The present study demonstrates the involvement of serotonin (5-HT) receptors of the 5-HT_1A type in immunoinhibitory effect of 5-HTergic system of the brain. A selective agonist of 5-HT_1A receptors 8-OH-DPAT (1 mg/kg) induces the immunosuppression, whereas 5-HT_1A blockade with WAY-100635 (1 mg/kg) resulted in immunostimulation. It is also shown that immunomodulating effects of the drugs were dependent on psychoemotional status of animals acquired aggressive or submissive behavior under social conflict conditions. Activation of 5-HT_1A receptors produced a decrease of the immunity in aggressive mice, whereas 5-HT_1A receptor blockade caused immunostimulation in submissive animals.