Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.     

Anxiolytic-like effects of DOI microinjections into the hippocampus (but not the amygdala nor the PAG) in the mice four plates test

Anxiolytic-like effects of DOI, a 5-HT(2A/2C) agonist have been observed in the four plates test (FPT) after intra-peritoneal administrations. In the present study, DOI (1 microg, 2 microg or 5 microg per mice) was directly injected to three brain structures, the hippocampus, the amygdala and the periaqueductal gray matter (PAG). Tests were carried out immediately after injections. In amygdala and PAG, DOI exerted an anxiogenic-like effect. In the hippocampus, a strong anxiolytic-like effect was found only when injecting 5 microg DOI/mice in the FPT, with a size effect comparable to the anxiolytic-like effect of diazepam 1mg/kg injected intra-peritoneally. DOI or vehicle injections did not affect locomotor activity. These results help us to understand mechanisms of action of DOI in animal models of anxiety, probably through an interaction with other neurotransmitter system, which may take place in the hippocampus.     

Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety

The behavioural effects of 5-HT₂ receptor agonists, 5-HT_2A and 5-HT_2C receptor antagonists were investigated in the mouse four plates test (FPT), light/dark paradigm (L/D) and the elevated plus maze (EPM), in order to elucidate the role of the 5-HT₂ receptor subtypes in these models and to address the inconclusive results previously reported using rat psychopharmacological models. All compounds were administered intraperitoneally 30 min before each test. DOI, a preferential 5-HT_2A agonist (0.5–8 mg/kg) and BW 723C86, a 5-HT_2B agonist (8 and 16 mg/kg) provoked an anxiolytic-like response in the FPT. In the EPM, an anxiolytic-like effect was observed for DOI (0.5, 1 and 2 mg/kg), BW 723C86 (0.5, 4, 8 and 16 mg/kg), RO 60-0175 a 5-HT_2C agonist (4 mg/kg) and the non-selective 5-HT₂ receptor agonist mCPP (0.25 mg/kg.). Ketanserin, a 5-HT_2A/2C non-selective receptor antagonist (0.015 and 0.03 mg/kg), induced an anxiogenic-like effect in the L/D paradigm. The 5-HT_2C antagonists (RS 10-2221, SDZ SER082 and SB 206553) were without effect in all three tests. These behavioural results are indicative of an anxiolytic-like action of 5-HT₂ receptor agonists, an anxiogenic-like effect of 5-HT_2A receptor antagonism, whereas the blockade of 5-HT_2C receptors are without effect in the mouse models studied.     

Anxiolytic-like effect of 5-HT(2) ligands and benzodiazepines co-administration: comparison of two animal models of anxiety (the four-plate test and the elevated plus maze)

Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT(2A/2C) agonist DOI and the 5-HT(2B) agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT(2) ligands in the FPT and the EPM. Indeed, close distribution of GABA(A) and 5-HT(2) receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT(2A) ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.     

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-HT2A antagonist, and WAY100635 (0.2 mg/kg), a 5-HT1A antagonist, neither of which when given alone affected dopamine release. DOI (2.5 mg/kg), but not the 5-HT2C agonist Ro 60-0175 (3 mg/kg), attenuated clozapine (20 mg/kg)-induced mPFC dopamine release. These results suggest that 5-HT2A receptor stimulation increases basal cortical dopamine release via 5-HT1A receptor stimulation, and inhibits clozapine-induced cortical dopamine release by diminishing 5-HT2A receptor blockade.     

Studies on the involvement of the dopaminergic system in the 5-HT2 agonist (DOI)-induced premature responding in a five-choice serial reaction time task

The present experiments investigated whether the enhanced premature (impulsive) responding induced by DOI, [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride], a 5-HT2A/2C receptor agonist, is mediated by activation of the dopaminergic system and if this effect of DOI occurs in the nucleus accumbens. Therefore, the effects of a dopamine (D1/2) receptor antagonist given alone or combined with DOI were examined on the performance of rats in a five-choice serial reaction time (5-CSRT) task. Secondly, the effects of DOI in nucleus accumbens core and shell were studied, in order to find the target brain area for DOI-induced premature responding. The results indicate that DOI (0.1 mg/kg, subcutaneously) increases the number of premature responses, as found previously. alpha-Flupenthixol (0.03 mg/kg), a D1/2 dopamine receptor antagonist, and raclopride (0.015 mg/kg), a D2 receptor antagonist, attenuated the DOI-induced enhancement in premature responding. SCH 23390 (0.005 mg/kg), a selective D1 receptor antagonist with little affinity to 5-HT2 receptors totally blocked the effect of DOI. Those doses of DA antagonists did not significantly decrease premature responding when given alone. On the other hand, higher doses of all of these dopamine antagonists increased the number of omissions and decreased the number of ITI hole responses. In contrast to subcutaneous administration, direct injections of DOI (1, 3, and 10 microg bilaterally) to the nucleus accumbens shell or core had no effect on premature responding. These results suggest that the activation of the dopamine system mediates, at least in part, the effect of a 5-HT2 agonist on premature responding, but the nucleus accumbens is not the primary site for this action.     

Single footshock attenuates c-Fos expression induced by 5-HT2A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rat brain

Administration of 3 mg/kg 5-hydroxytryptamine2A/2C (5-HT2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced c-Fos expression in all areas of the rat neocortex. The single footshock 24 h before DOI administration significantly attenuated DOI-induced c-Fos expression in layer IV of the primary somatosensory cortex. These changes in c-Fos expression suggest an adaptational change in the somatosensory cortex by acute stress.     

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.     

In vivo evidence for serotonin 5-HT2C receptor-mediated long-lasting excitability of lumbar spinal reflex and its functional interaction with 5-HT1A receptor in the mammalian spinal cord

The purpose of the present study was to investigate the 5-HT(2C) receptor-mediated effects on the spinal monosynaptic mass reflex activities and also its functional interactions with 5-HT(1A) receptors in anesthetized, acutely spinalized mammalian adult spinal cord in vivo. Intravenous administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) (0.1 mg/kg), an agonist of 5-HT(2A/2C) receptors, significantly increased the excitability of spinal motoneurons as reflected by an increase in the spinal monosynaptic mass reflex amplitude to 150-200% of the control. 5-HT(2A/2C) receptor-induced motoneuron excitability was slow, persistent and long-lasting for more than 2h that was significantly inhibited by 5-HT(2C) receptor specific antagonist SB 242084 administered 10 min prior to DOI. Simultaneous administration of DOI (0.1 mg/kg, i.v.) along with (+/-)-8-hydroxy dipropylaminotetraline hydrobromide (8-OH-DPAT) (0.1 mg/kg, i.v.) completely inhibited DOI-induced spinal monosynaptic mass reflex facilitation. In another separate study, administration of 8-OH-DPAT (0.1 mg/kg, i.v.) at the maximum response of DOI also inhibited the motoneuron's excitability; however, the inhibition lasted only for a period of 40-60 min after administration of 8-OH-DPAT, after which the spinal monosynaptic mass reflex amplitude reached its maximum level. These findings suggest that the 5-HT(2C) receptor is primarily involved in the mediation of the long-lasting excitability of spinal motoneurons and possibly interacts with its functional counterpart, 5-HT(1A) receptors in the mammalian adult spinal cord.     

Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors

In vivo microdialysis and electrophysiological techniques were used to elucidate the role of the 5-HT(2) receptor family on the control of mesolimbic dopaminergic system exerted by serotonin (5-HT). Administration of RO 60-0175 (1 mg/kg, i.p.), a selective 5-HT(2C) receptor agonist, significantly decreased dopamine (DA) release by 26+/-4% (below baseline) 60 min after injection. Moreover, RO 60-0175 (80-320 microg/kg, i.v.) dose-dependently decreased the basal firing rate of DA neurons in the ventral tegmental area (VTA), reaching its maximal inhibitory effect (53.9+/-15%, below baseline) after the dose of 320 microg/kg. The selective 5-HT(2C) receptor antagonist SB 242084 completely blocked the inhibitory action of RO 60-0175 on accumbal DA release and on the firing rate of VTA DA cells. On the contrary, both (+/-)-DOI, a mixed 5-HT(2A/2C) receptor agonist, and the selective 5-HT(2B) agonist BW 723C86, did not affect either DA release in the nucleus accumbens or the firing rate of VTA DA cells. Taken together, these data confirm that central 5-HT system exerts an inhibitory control on the mesolimbic DA system and that 5-HT(2C) receptors are involved in this effect.     

Effect of acute lipopolysaccharide administration on (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane-induced wet dog shake behavior in rats: comparison with body weight change and locomotor activity

1. Several reports have shown that serotonin (5-HT)2A receptor density and its function are altered after physiological or pharmacological stress. To examine whether an acute administration of lipopolysaccharide (LPS), a bacterial endotoxin, affected 5-HT2A receptor function, wet dog shakes of male Wistar rats were observed after a subcutaneous injection of DOI, a 5-HT2A receptor agonist following LPS treatment. Body weight change and locomotor activity were also observed. 2. DOI (1 mg/kg)-induced WDS significantly decreased after 400 or 1000 microg/kg LPS treatment compared with that of control rats 1 and 3 hr after injection, and WDS completely recovered 8 hr after LPS treatment. Treatment with 10 mg/kg indomethacin (IND) or 1 mg/kg naltrexone (NLTX) canceled the effect of 400 microg/kg LPS on DOI-induced WDS. 3. Body weight decrease was significantly greater in LPS-treated rats compared with control rats 3, 5 and 8 hr after treatment. Treatment with IND (10 mg/kg) significantly recovered the reduction in body weight induced by 400 microg/kg LPS. Treatment with NLTX (1 mg/kg) also prevented the LPS effect on body weight decrease. 4. Eight hr after treatment with LPS (400 microg/kg), the rats showed significant attenuation of locomotor activity. IND (10 mg/kg) treatment abolished the inhibitory effect of LPS on locomotor activity, and NLTX (1 mg/kg) also improved the decrease in locomotion 8 hr after LPS treatment. 5. Plasma tumor necrosis factor (TNF)-alpha concentration dramatically increased 1 hr after the injection of 400 microg/kg LPS, and returned almost to the basal level 3 hr later. Next, rats were injected with 50 microg/kg TNF-alpha intraperitoneally, and body weight change and DOI-induced WDS was determined 3 hr after TNF-alpha injection. Body weight loss was significantly greater in rats treated with TNF-alpha. On the other hand, DOI-induced WDS was not altered when rats were treated with TNF-alpha. 6. These results suggest that acute treatment with LPS inhibited 5-HT2A receptor-mediated behavior via cyclooxygenase and opioid receptor activation, but that the inhibition of the WDS by LPS appears to be independent of TNF-alpha production.     

Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats.

BACKGROUND: The dibenzoxazepine amoxapine was introduced as an antidepressant but has shown antipsychoticlike activity in a number of animal screening tests. A recent positron emission tomography study showed a 5-HT(2)/D(2) receptor occupancy profile of amoxapine that is very similar to that of established atypical antipsychotics. Schizophrenics display deficits in sensory gating mechanisms, such as prepulse inhibition (PPI) of the acoustic startle reflex. A similar deficit can be produced by dopamine (DA) and by 5-HT(2A/C) receptor agonists in rats. Antipsychotic compounds reverse this effect. METHODS: Effects of amoxapine on apomorphine- or 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced disruption of PPI were studied in adult male Sprague-Dawley rats. The extrapyramidal side effect (EPS) liability of amoxapine was assessed using the inclined grid catalepsy (CAT) test. Statistical analyses were performed by analysis of variance (ANOVA) for fully repeated measures (PPI) and by the Kruskal-Wallis one-way ANOVA by ranks (CAT). RESULTS: Apomorphine (0.5 mg/kg) produced a significant reduction in PPI compared with the case of rats in the saline control group. Pretreatment with amoxapine (10 mg/kg) significantly attenuated the apomorphine-induced disruption of PPI. DOI (0.5 mg/kg) significantly reduced PPI compared with saline controls. Pretreatment with amoxapine (5 or 10 mg/kg) produced a significant attenuation of the DOI-induced disruption of PPI. Amoxapine by itself did not alter PPI. Amoxapine (5 or 10 mg/kg) did not produce CAT. CONCLUSIONS: The DA D(2)/5-HT(2) receptor antagonist amoxapine produced an antipsychoticlike reversal of both apomorphine- and DOI-induced disruption of PPI. Furthermore, the same doses of amoxapine that reversed disruption of PPI did not produce CAT. The results confirm and lend further support to the results of previous studies on amoxapine, suggesting that amoxapine might possess antipsychotic activity with little propensity for producing EPS.     

Serotonergic involvement in methamphetamine-induced locomotor activity: a detailed pharmacological study

The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT(2C) receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D(1) and D(2) receptor antagonists SCH23390 and haloperidol, D(2) partial agonists terguride, (-)3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT(1B) antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT(1A) antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED=0.125 mg/kg), WAY163909 (MED=3mg/kg), Ro 60-0175 (MED=3mg/kg), haloperidol (MED=0.1mg/kg), clozapine (MED=5mg/kg), aripiprazole (MED=1mg/kg), (-)3PPP (MED=3mg/kg), terguride (MED=0.2mg/kg) and SCH23390 (MED=0.001325 mg/kg) attenuated METH-induced locomotor activity. Administration of 20mg/kg fluvoxamine attenuated, while SB242084 (MED=0.25mg/kg) potentiated METH-induced activity. These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT(2A) and 5-HT(2C) receptors, but demonstrate that 5-HT(1B) receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated.     

Brain structures implicated in the four-plate test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI

Four-plate test-retest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to four-plate test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naïve and experienced mice: a benzodiazepine, diazepam that is only active in naïve mice; and a 5-HT_2A/2C agonist, DOI that exert its anxiolytic-like effect both in naïve and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naïve and experienced mice. Diazepam had an anxiolytic-like effect in naïve mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).     

c-Fos proteins, induced by the serotonin receptor agonist DOI, are not expressed in 5-HT2A positive cortical neurons.

In the present study, we tried to find out whether the expression of c-Fos proteins induced by DOI, an agonist of 5-HT2A/2C receptor subtypes is colocalized with 5-HT2A receptor protein in cortical neurons. 5-HT2A receptor protein was found in two major neuronal elements: dendritic processes (seen in layers II/III-V) and less abundantly in cell bodies (layer V). In our experiment, DOI (8 mg/kg) induced a robust appearance of c-Fos proteins mainly in neuronal nuclei of the upper part of layer V/IV, and a moderate amount of sparsely distributed nuclei in deep cortical layers (V and VI). It was found that c-Fos proteins never occurred in cortical neurons, which were immunopositive for the presence of 5-HT2A receptor protein. It is concluded that the induction of c-Fos proteins expression by DOI though initiated by activation of 5-HT2A receptors, requires the involvement of intermediate neurotransmitter(s). Additionally, our study indicates that the appearance of DOI-induced c-Fos proteins cannot be used as a simple and direct marker of localization and site of activation of 5-HT2A receptors.     

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.     

Regulation of striatal neuropeptide mRNAs: effects of the 5-HT(2) antagonist SR46349B in adult rats with a neonatal 6-hydroxydopamine lesion.

The intrastriatal injection of 6-hydroxydopamine (6-OHDA) in newborn rats produces a marked striatal dopamine (DA) depletion, accompanied by a serotonin (5-HT) hyperinnervation and an up-regulation of 5-HT receptors. The aim of the present study was to investigate whether the increase in 5-HT(2) receptors could compensate for some of the DA lesion-induced effects, such as the increase in striatal preproenkephalin (PPE) and the decrease in preprotachykinin A (PPT-A) mRNA levels. Three months after the DA lesion, the effect of the selective 5-HT(2) antagonist SR46349B was investigated by a subacute treatment (10 mg/kg, IP, twice per day for 3.5 days). In sham-operated rats, the blockade of 5-HT(2) receptors decreased PPE mRNA levels in the striatum and, by contrast, had no effect on PPT-A mRNA levels. In rats with a unilateral neonatal DA lesion, SR46349B had no more effect on PPE mRNA levels in the intact striatum and was unable to modify the lesion induced-increase in PPE mRNA. The decrease in PPT-A mRNA levels induced by the neonatal DA lesion was not changed after SR46349B treatment in the posterior part of the lesioned striatum. Our results suggest that SR46349B indirectly decreases PPE mRNA levels in striatopallidal neurons in intact animals through a desinhibition of DA neuron activity. This is further evidenced by the lack of PPE mRNA changes in the DA lesioned striatum despite the up-regulation of 5-HT(2) receptor transmission induced in this model. Finally, the absence of any effect of 5-HT(2) antagonist on the expression of PPT-A mRNA in intact animals is discussed. The precise role of 5-HT(2) receptor on PPT-A mRNA biosynthesis after a neonatal lesion should be clarified by further experiments using 5-HT(2) agonists.     

Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3alpha,5alpha-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT(1A) receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT3 agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3alpha,5alpha-THP. Furthermore, FGIN 1-27, an MDR agonist that increases endogenous content of 3alpha,5alpha-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT1A, 5-HT2A/1C or 5-HT3 receptor agonist on 3alpha,5alpha-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 microg/mouse, i.c.v.). However this effect of different serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3alpha,5alpha-THP.