Modulation of dopamine release by striatal 5-HT2C receptors

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.     

Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT(2A) relative to weak D(2) antagonism, and 5-HT(1A) agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT(1A) agonism, 5-HT(2A) and D(2) antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT(1A) agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT(1A) antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT(2A/2C) agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT(2A) antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT(1A) agonism and 5-HT(2A) antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.     

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.     

An evaluation of the role of 5-HT(2) receptor antagonism during subchronic antipsychotic drug administration in rats

A widely postulated mechanism of action for the atypical profile of many novel antipsychotic drugs (APDs) is their relatively high affinity for 5-HT(2) receptors. The present study investigated motor function and striatal dopamine (DA) efflux and metabolism in rats given 21 daily injections of drugs that differed in 5-HT(2) affinity. These drugs included: risperidone (high 5-HT(2A/2C)/high D(2)), clozapine (high 5-HT(2A/2C)/low D(2)), haloperidol (low 5-HT(2A/2C)/high D(2)), haloperidol+ritanserin (selective 5-HT(2A/2C)), or vehicle. Rats injected with haloperidol (0.5 mg/kg) or haloperidol+ritanserin (0.5 mg/kg and 1.0 mg/kg, respectively) showed extreme catalepsy on day 1, but significantly decreased catalepsy when tested again on days 7 and 21. Acute or subchronic risperidone (0.05 or 0.5 mg/kg), clozapine (20 mg/kg), or vehicle did not induce significant catalepsy. Microdialysis performed 24 h after the last injection demonstrated that rats treated with risperidone, clozapine, or vehicle showed similar increases in DA efflux and metabolism following an acute injection of a selective DA D(2/3) antagonist (raclopride, 0.5 mg/kg). DA efflux showed an attenuated response to raclopride in the haloperidol alone group; this effect was less apparent in the haloperidol+ritanserin group. However, both of these groups showed a similar tolerance effect to the raclopride-induced increase in DA metabolites. These results suggest that the profile seen after subchronic risperidone more closely resembles clozapine than haloperidol. While ritanserin reduced the tolerance-like effects of haloperidol on striatal DA efflux, the overall results demonstrate that potent 5-HT(2) blockade alone may not entirely account for the distinctive profile of novel APDs.     

Atypical antipsychotic drugs,quetiapine, iloperidone,and melperone,preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism

Preferential increases in both cortical dopamine (DA) and acetylcholine (ACh) release have been proposed to distinguish the atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone and ziprasidone from typical APDs such as haloperidol. Although only clozapine and ziprasidone are directly acting 5-HT(1A) agonists, WAY100635, a selective 5-HT(1A) antagonist, partially attenuates these atypical APD-induced increases in cortical DA release that may be due to combined 5-HT(2A) and D(2) blockade. However, WAY100635 does not attenuate clozapine-induced cortical ACh release. The present study determined whether quetiapine, iloperidone and melperone, 5-HT(2A)/D(2) antagonist atypical APDs, also increase cortical DA and ACh release, and whether these effects are related to 5-HT(1A) agonism. Quetiapine (30 mg/kg), iloperidone (1-10 mg/kg), and melperone (3-10 mg/kg) increased DA and ACh release in the medial prefrontal cortex (mPFC). Iloperidone (10 mg/kg) and melperone (10 mg/kg), but not quetiapine (30 mg/kg), produced an equivalent or a smaller increase in DA release in the nucleus accumbens (NAC), respectively, compared to the mPFC, whereas none of them increased ACh release in the NAC. WAY100635 (0.2 mg/kg), which alone did not affect DA or ACh release, partially attenuated quetiapine (30 mg/kg)-, iloperidone (10 mg/kg)- and melperone (10 mg/kg)-induced DA release in the mPFC. WAY100635 also partially attenuated quetiapine (30 mg/kg)-induced ACh release in the mPFC, but not that induced by iloperidone (10 mg/kg) or melperone (10 mg/kg). These results indicate that quetiapine, iloperidone and melperone preferentially increase DA release in the mPFC, compared to the NAC via a 5-HT(1A)-related mechanism. However, 5-HT(1A) agonism may be important only for quetiapine-induced ACh release.     

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 and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: an in vivo extracellular single cell study

In this study, we examined the effect of the acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB-243213 (0.025-3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle-treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB-243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle-treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB-243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle-treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB-243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle-treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)-apomorphine (50 microg/kg). The repeated administration of either 1 or 3 mg/kg of SB-243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB-243213. Overall, our results indicate that antagonism of the 5-HT2C receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration.     

Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism

Atypical antipsychotic drugs (APDs) such as clozapine, but not the typical APD haloperidol, improve some aspects of cognition in schizophrenia. This advantage has been attributed, in part, to the ability of the atypical APDs to markedly increase acetylcholine (ACh) and dopamine (DA) release in rat medial prefrontal cortex (mPFC), while producing a minimal effect in the nucleus accumbens (NAC) or striatum. The atypical APD-induced preferential release of DA, but not ACh, in the mPFC is partially inhibited by the selective 5-HT(1A) antagonist WAY100635. However, little is known about these effects of atypical APDs in the ventral hippocampus (vHIP), another possible site of action of atypical APDs with regard to cognitive enhancement. The present study demonstrates that clozapine (10 mg/kg) comparably increases both ACh and DA release in the vHIP and mPFC. The increases in DA, but not ACh, release in both regions were partially attenuated by WAY100635 (0.2 mg/kg), which had no effect by itself on the release of either neurotransmitter in either region. Tetrodotoxin (TTX; 1 microM), a Na(+) channel blocker, in the perfusion medium, eliminated the clozapine (10 mg/kg)-induced ACh and DA release in the vHIP, indicating their neuronal origin. Haloperidol produced a slight increase in ACh release in the vHIP at 1 mg/kg, and DA release in the mPFC at 0.1 mg/kg. In conclusion, clozapine increases ACh and DA release in the vHIP and mPFC, whereas haloperidol has minimal effects on the release of these two neurotransmitters in either region. These differences may contribute, at least in part, to the superior ability of clozapine, compared to haloperidol, to improve cognition in schizophrenia. 5-HT(1A) agonism is important to the ability of clozapine and perhaps other atypical APDs to increase DA, but not ACh, release in the vHIP, as well as the mPFC. The role of hippocampus in the cognitive effects of atypical APDs warrants more intensive study.     

5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex.

BACKGROUND: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT(1A) receptors. 5-HT(1A) receptor agonism may be an important feature in ziprasidone's clinical actions because 5-HT(1A) agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D(2) antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT(1A) agonist activity of ziprasidone by measuring the contribution of 5-HT(1A) receptor activation to the ziprasidone-induced cortical dopamine release in rats. METHODS: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT(1A) receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT(1A) antagonist, WAY-100635. For comparison, the D(2)/5-HT(2A) antagonists clozapine and olanzapine, the D(2) antagonist haloperidol, the 5-HT(2A) antagonist MDL 100,907 and the 5-HT(1A) agonist 8-OHDPAT were included. RESULTS: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (> or =3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT(1A) agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D(2) antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT(2A) antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. CONCLUSIONS: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT(1A) receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT(1A) receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.     

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.     

Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors

In vivo microdialysis and electrophysiological techniques were used to elucidate the role of the 5-HT₂ 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 μg/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 μg/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.     

Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B)) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320 microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK 212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT(2C) antagonist SB 242084 ?6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline? (200 microg/kg), given intravenously 10 min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C) receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.     

Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Many studies suggest that the 5-HT6 receptors are involved, along with other 5-HT receptors, in the pathophysiology and pharmacotherapy of schizophrenia. It is a putative therapeutic target of atypical antipsychotic drugs, notably clozapine, as well as some other psychotropic agents. Preferential potentiation of dopamine (DA) efflux in the medial prefrontal cortex (mPFC) and hippocampus (HIP) has been suggested to contribute to the ability of atypical antipsychotic drugs (APDs), e.g. clozapine, risperidone, olanzapine and ziprasidone, to improve cognitive function in schizophrenia. The present study demonstrated that SB-399885, a selective 5-HT6 receptor antagonist, at doses of 3 and 10 mg/kg, had no effect on cortical DA release in freely moving rats. However, both doses of SB-399885 slightly but significantly increased DA release in the HIP. Of particular interest, SB-399885, 3 mg/kg, significantly potentiated the ability of a typical antipsychotic drug haloperidol, a D2 receptor antagonist, at a dose of 0.1 mg/kg, to increase DA release in the HIP but not the mPFC. The atypical antipsychotic drug risperidone, a multireceptor antagonist, which lacks 5-HT6 receptor antagonist properties, at doses of 0.1, 0.3 and 1.0 mg/kg, produced a bell-shaped dose response effect on DA efflux in the mPFC and HIP. SB-399885 potentiated risperidone (1.0 mg/kg)-induced DA efflux in both regions. The increase in the HIP, but not the mPFC, DA efflux by 0.3 mg/kg risperidone was also potentiated by SB-399885, 3 mg/kg. These results suggest that the combined blockade of 5-HT6 and D2 receptors may contribute to the potentiation of haloperidol- and risperidone-induced DA efflux in the mPFC or HIP. The present data provides additional evidence in support of a possible therapeutic role for 5-HT6 receptor antagonism, as an addition on therapy, to enhance cognitive function in schizophrenia.     

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.     

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.     

An evaluation of the role of 5-HT2 receptor antagonism during subchronic antipsychotic drug administration in rats

A widely postulated mechanism of action for the atypical profile of many novel antipsychotic drugs (APDs) is their relatively high affinity for 5-HT₂ receptors. The present study investigated motor function and striatal dopamine (DA) efflux and metabolism in rats given 21 daily injections of drugs that differed in 5-HT₂ affinity. These drugs included: risperidone (high 5-HT_2A/2C/high D₂), clozapine (high 5-HT_2A/2C/low D₂), haloperidol (low 5-HT_2A/2C/high D₂), haloperidol+ritanserin (selective 5-HT_2A/2C), or vehicle. Rats injected with haloperidol (0.5 mg/kg) or haloperidol+ritanserin (0.5 mg/kg and 1.0 mg/kg, respectively) showed extreme catalepsy on day 1, but significantly decreased catalepsy when tested again on days 7 and 21. Acute or subchronic risperidone (0.05 or 0.5 mg/kg), clozapine (20 mg/kg), or vehicle did not induce significant catalepsy. Microdialysis performed 24 h after the last injection demonstrated that rats treated with risperidone, clozapine, or vehicle showed similar increases in DA efflux and metabolism following an acute injection of a selective DA D_2/3 antagonist (raclopride, 0.5 mg/kg). DA efflux showed an attenuated response to raclopride in the haloperidol alone group; this effect was less apparent in the haloperidol+ritanserin group. However, both of these groups showed a similar tolerance effect to the raclopride-induced increase in DA metabolites. These results suggest that the profile seen after subchronic risperidone more closely resembles clozapine than haloperidol. While ritanserin reduced the tolerance-like effects of haloperidol on striatal DA efflux, the overall results demonstrate that potent 5-HT₂ blockade alone may not entirely account for the distinctive profile of novel APDs.     

Conditional involvement of striatal serotonin3 receptors in the control of in vivo dopamine outflow in the rat striatum

Serotonin3 (5-HT3) receptors can affect motor control through an interaction with the nigrostriatal dopamine (DA) neurons, but the neurochemical basis for this interaction remains controversial. In this study, using in vivo microdialysis, we assessed the hypothesis that 5-HT3 receptor-dependent control of striatal DA release is conditioned by the degree of DA and/or 5-HT neuron activity and the means of DA release (impulse-dependent vs. impulse-independent). The different DA-releasing effects of morphine (1 and 10 mg/kg), haloperidol (0.01 mg/kg), amphetamine (1 and 2.5 mg/kg), and cocaine (10 and 20 mg/kg) were studied in the striatum of freely moving rats administered selective 5-HT3 antagonists ondansetron (0.1 mg/kg) or MDL 72222 (0.03 mg/kg). Neither of the 5-HT3 antagonists modified basal DA release by itself. Pretreatment with ondansetron or MDL 72222 reduced the increase in striatal DA release induced by 10 mg/kg morphine but not by 1 mg/kg morphine, haloperidol, amphetamine or cocaine. The effect of 10 mg/kg morphine was also prevented by intrastriatal ondansetron (1 microm) administration. Reverse dialysis with ondansetron also reduced the increase in DA release induced by the combination of haloperidol and the 5-HT reuptake inhibitor citalopram (1 mg/kg). Considering the different DA and 5-HT-releasing properties of the drugs used, our results demonstrate that striatal 5-HT3 receptors control selectively the depolarization-dependent exocytosis of DA only when central DA and 5-HT tones are increased concomitantly.     

Differential effects of 5-HT(2A) and 5-HT(2C) receptor blockade on strategy-switching

Recent experiments indicate that blockade of serotonin (5-HT) 2A and 2C receptors have differential effects on reversal learning. The present experiments investigated the effects of the 5-HT(2A) receptor antagonist, ketanserin and 5-HT(2C) receptor antagonist, SB242084 on acquisition and strategy-switching in a visual cue-response paradigm. Long-Evans rats were trained in a cross-maze to enter an arm based on color (visual cue version) or a specific turn response (response version). Systemic treatment with ketanserin did not affect initial learning of a visual cue or response discrimination, but ketanserin at 0.5 mg/kg significantly enhanced a switch between visual cue and response strategies. Ketanserin facilitated strategy-switching by inhibiting responses to a previously relevant strategy without affecting choices to never-reinforced strategies. Treatment with SB242084 (0.5, 1.0 or 2.0 mg/kg) did not affect acquisition of a visual cue or response discrimination. SB242084 treatment also did not affect strategy-switching. The present findings suggest that blockade of 5-HT(2A), but not 5-HT(2C), receptors enhance strategy switching.     

Valproic acid potentiates both typical and atypical antipsychotic-induced prefrontal cortical dopamine release

Antipsychotic drugs (APD)s and anticonvulsant mood-stabilizers are now frequently used in combination with one another in treating both schizophrenia and bipolar disorder. We have recently reported that the atypical APDs, e.g. clozapine and risperidone, as well as the anticonvulsant mood-stabilizers, valproic acid (VPA), zonisamide, and carbamazepine, but not the typical APD haloperidol, increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). The increased DA release was partially (atypical APDs) or completely (mood-stabilizers) blocked by the serotonin (5-HT)1A receptor antagonist WAY100635. Diminished prefrontal cortical DA activity may contribute to cognitive impairment in virtually all the patients with schizophrenia and, perhaps, bipolar disorder. Thus, the enhanced release of cortical DA by these agents may be beneficial in this regard. It is, therefore, of considerable interest to determine whether combined administration of these agents augments prefrontal cortical DA release, and if so, whether the increase is dependent upon 5-HT1A receptor activation. VPA (50 mg/kg), which was insufficient by itself to increase prefrontal cortical DA release, potentiated the ability of clozapine (20 mg/kg) and risperidone (1 mg/kg) to increase DA release in the mPFC, but not in the nucleus accumbens (NAC). VPA (50 mg/kg) also potentiated haloperidol (0.5 mg/kg)-induced DA release in the mPFC; this increase was completely abolished by WAY100635 (0.2 mg/kg). These results suggest that, in combination with VPA, both typical and atypical APDs produce greater increases in prefrontal cortical DA release than either type of drug alone via a mechanism dependent upon 5-HT(1A) receptor activation. Furthermore, they provide a strong rationale for testing for possible clinical synergism of an APD and anticonvulsant mood-stabilizer in improving the cognitive deficits present in patients with schizophrenia and bipolar disorder.     

Serotonin receptors: their key role in drugs to treat schizophrenia

Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.