The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by “atypical” antipsychotics. In contrast, some findings indicate that not all of the “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI.

In our study, we evaluated the effect of four different “atypical” antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT_2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT_1A,2A/2C receptors and muscarinic receptors.

Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment.

In summary, the four “atypical” antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.     

Combined administration of an mGlu2/3 receptor agonist and a 5-HT2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants

Rationale

It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale.

Objectives

In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT_2A receptor antagonism.

Materials and methods

Specifically, we characterized the effects of coadministering submaximally effective doses of the 5-HT_2A receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of coadministering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc).

Results

At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity.

Conclusions

Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT_2A receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone.     

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Rationale

Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective

To further delineate the relationship between 5-HT_1A receptors and glutamate, the current study examined the effects of the 5-HT_1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.

Materials and methods

Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results

Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.

Conclusions

The current results indicate a functional interaction between 5-HT_1AR and NMDAR that may improve pharmacological treatment of PD patients.     

Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats

Background

Attentional deficits that accompany schizophrenia are not effectively treated by available antipsychotic medications. Disruption of NMDA receptor function is often used to model aspects of this disorder in rodents. We used the 5-choice serial reaction time task (5CSRTT) to characterize attentional deficits caused by acute administration or withdrawal from chronic administration of the NMDA receptor antagonist MK-801, and determine if they are ameliorated by haloperidol or clozapine.

Methods

Acute studies involved tests in the presence of MK-801: rats were administered haloperidol (0.008-0.125 mg/kg, SC) or clozapine (0.16-2.5 mg/kg, SC) in combination with MK-801 (0.25 mg/kg, IP) prior to daily test sessions. Chronic studies involved tests in the absence of MK-801: following daily tests, rats were administered MK-801 (0.5 mg/kg, IP) and tested 24 h later in the absence or presence of haloperidol or clozapine.

Results

Acute MK-801 disrupted performance: it decreased accuracy while increasing omissions, premature responses, and magazine entries. Haloperidol reduced disruptive effects associated with increased activation, whereas it exacerbated other deficits. Clozapine dose-dependently attenuated several of the MK-801-induced performance deficits. Withdrawal from chronic MK-801 progressively increased omissions and response latencies and decreased premature responding, suggesting an amotivational state. Neither haloperidol nor clozapine ameliorated these performance deficits.

Discussion

Acute administration and withdrawal from chronic MK-801 administration produced distinct behavioral profiles in the 5CSRTT. Acute MK-801 impaired attention and impulse control whereas chronic MK-801 withdrawal caused signs consistent with amotivation. Haloperidol and clozapine were more effective at attenuating deficits caused by acute MK-801 administration.     

5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB.

The hyperlocomotion induced by the noncompetitive NMDA antagonist MK-801 (0.3 mg/kg SC) in mice was attenuated by the nonselective 5-HT2 antagonist ritanserin (0.12 and 0.25 mg/kg SC) and by the 5-HT2A selective antagonist MDL100907 (0.05 and 0.1 mg/kg SC). SB242084 (0.25-1.0 mg/kg), a selective 5-HT(2C) antagonist, had no effect on MK-801-induced hyperactivity. These same doses of ritanserin and MDL100907 reduced the hyperactivity induced by cocaine (10 mg/ kg). Amphetamine (2.5 mg/kg SC) induced hyperlocomotion that was also attenuated by ritanserin (0.064).25 mg/kg SC). The hyperlocomotion induced by the D1 agonist C-APB (1.0 mg/kg) is not altered by pretreatment with ritanserin or MDL100907. This suggests that compounds that increase locomotor activity via indirectly increasing dopaminergic activity (either by increased release or blockade of reuptake) require the activation of a 5-HT2A receptor. Activity of compounds that act directly at the postsynaptic dopamine receptors such as C-APB is not dependent on such a mechanism. This suggests a selective involvement of 5-HT2A receptors but not 5-HT2c receptors in the mediation of the behavioral effects of compounds that increase synaptic concentration of dopamine but not directly acting agonists. This implies that the 5-HT2A receptors modulate elevation of extracellular dopamine, not the postsynaptic sensitivity of dopamine neurons.     

A microdialysis study of ST1936, a novel 5-HT6 receptor agonist

The function of 5-HT6 receptors, one of the last additions to the large family of 5-HT receptors, is largely unknown due to the limited knowledge of their transduction mechanisms, lack of full centrally acting agonists and inconsistencies in the pharmacological and neurochemical effects of the antagonists. Recently, a new full agonist, ST1936, with nanomolar affinity for 5-HT6 receptors, has become available. Here we report the effect of ST1936 (5-10-20 mg/kg/ip) on dialysate DA, NA and 5-HT in the medial prefrontal cortex (PFCX) and in the shell and core of the nucleus accumbens (NAc). Systemic administration of ST1936 dose-dependently increased dialysate DA and NA in the NAc shell and PFCX and to a lesser extent in the NAc core; these effects were prevented by systemic administration of the two 5-HT6 receptor antagonists, SB271046 (10-20 mg/kg/ip) and SB399885 (5 mg/kg/ip).These properties of ST1936 suggest that 5-HT6 receptors control the activity of DA and NA neurons projecting to the NAc and to the PFCX.     

Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat

Background and purpose:

The beneficial effect of 5-HT₆ receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT₆ receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.

Experimental approach:

The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.

Key results:

Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.

Conclusions and implications:

These data suggest a potential therapeutic role of 5-HT₆ receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer''s disease and schizophrenia.     

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents

Rationale

As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF₁ receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.

Objectives

To determine the effects of CRF₁ receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.

Methods

CP154,526 (10–40 mg/kg), SSR125543 (3–30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by d-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of d-amphetamine (2.5–5 mg/kg) and MK801 (0.3–1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on d-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis.

Results

No CRF_1?antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not d-amphetamine. Further, d-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526.

Conclusion

The inability of CRF₁ receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.     

5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice

Rationale

Blockade of 5-HT6 receptors (5-HT6R) is known to improve cognitive performances in the rodent. This improvement has been hypothesized to be the result, at least in part, of a modulation of the cholinergic neurotransmission.

Objective

We assessed the effects of 5-HT6R blockade on selected types of memory relevant to functional deficits of ageing and neurodegenerative diseases, in mice that present a scopolamine-induced cholinergic disruption of memory.

Method

Following the selection of an adequate dose of scopolamine to induce cognitive deficits, we have studied the effects of the selective 5-HT6R antagonist SB-271046, alone or in combination with scopolamine, on working memory (spontaneous alternation task in the T-maze), recognition memory (place recognition) and aversive learning (passive avoidance).

Results

SB-271046 alone failed to affect working memory, recognition memory and aversive learning performances. In contrast, SB-271046 was able to reverse the scopolamine-induced deficits in working memory (only at 30?mg?kg^?1) and those of acquisition and retrieval of aversive learning (dose-dependent effect); scopolamine-induced deficits in episodic-like memory (acquisition and retrieval) were partially counteracted by 5-HT6R blockade.

Conclusion

The modulation between 5-HT6R and the cholinergic system appears to be predominant for working memory and aversive learning, but not for other types of memory (i.e. episodic-like memory). Interactions between 5-HT6R and alternative neurotransmission systems (i.e. glutamatergic system) should be further studied. The respective involvement of these interactions in the memory disorders related to ageing and neurodegenerative diseases is of pivotal importance regarding the possible use of 5-HT6R antagonists in the treatment of memory disorders in humans.     

Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.     

Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia

The 5-HT(6) receptor is targeted by several new antipsychotics such as clozapine, olanzapine, and sertindole. We studied the effect of SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], a specific 5-HT(6) receptor antagonist, in three models for the positive symptoms of schizophrenia---D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI). We also tested this compound in a model for the negative symptoms of schizophrenia, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility, and to induce catalepsy in rats. The effect of SB-271046 was compared to clozapine in all models tested. This study showed that SB-271046 had no beneficial effect in PCP-disrupted SIT. However, SB-271046 dose-dependently normalised D-amphetamine-disrupted PPI, but did not reverse PCP-disrupted PPI. In addition, SB-271046 did not antagonise D-amphetamine-induced hyperactivity. Thus, this specific 5-HT(6) receptor antagonist was associated with a clear positive outcome in only one model for the positive symptoms of schizophrenia, and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy.     

Differential influence of selective 5-HT5A vs 5-HT1A, 5-HT1B,or 5-HT2C receptor blockade upon light-induced phase shifts in circadian activity rhythms: Interaction studies with citalopram

Though serotonergic mechanisms modulate circadian rhythms, roles of individual serotonin (5-HT) receptors remain uncertain since data are lacking for antagonists. Herein, both the 5-HT_5A receptor antagonist, A843277 (10 mg/kg), and the 5-HT_1B antagonist, SB224289 (1 mg/kg), inhibited light-induced phase advances in hamster circadian wheel-running rhythms. Conversely, though 5-HT_1A and 5-HT₇ receptors are likewise implicated in circadian scheduling, their blockade by WAY100635 (0.5 mg/kg) and SB269970 (1 mg/kg), respectively, was ineffective. Since actions of 5-HT reuptake inhibitors are modified by antagonists, we evaluated their influence on suppression of phase advances by citalopram (10 mg/kg). Its action was potentiated by WAY100635 and the 5-HT_2C antagonist, SB242084 (1 mg/kg), but not by A842377, SB224289, SB269970, and antagonists at 5-HT_2A (MDL100907) and 5-HT₆ (SB399885) receptors. In conclusion, this is the first in vivo evidence for an influence of 5-HT_5A receptors upon circadian rhythms, but no single class of 5-HT receptor mediates their control by citalopram.     

Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding.

These studies investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B), or 5-HT(2C) receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT(2A) receptor antagonist M100907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT(2C) receptor antagonist SB242084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT(2B) antagonist SB215505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100907 and SB242084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100907 (0.5-2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242084 (0.5-1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242084. These results indicate distinct, and in some cases opposite, effects of a 5-HT(2A) compared with a 5-HT(2C) receptor antagonist on various cocaine-mediated behavioral effects.     

Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats

Rationale

Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy.

Objectives and methods

We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21.

Results

In the PPI task, GTS-21 (1–10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1–10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313–5 mg/kg).

Conclusions

The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders.     

The effects of an acute challenge with the NMDA receptor antagonists,MK-801, PEAQX,and ifenprodil,on social inhibition in adolescent and adult male rats

Rationale

NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown.

Objectives

The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny.

Methods

In separate experiments, adolescent and adult male Sprague–Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test.

Results

Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects.

Conclusions

Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist—age differences that may be related to different subunit expression patterns during development.     

Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward.

Previous studies have shown that effective antipsychotic medications attenuate reward, an effect that is generally attributed to their effectiveness at blocking the dopamine D2-like receptors. As blockade of the serotonin type 2a (5-HT2a) receptors is a common property of the newer antipsychotics, the present study compared the effect of haloperidol, clozapine, and M100907 (a selective 5-HT2a antagonist) and the combined effect of haloperidol and M100907 treatment on brain stimulation reward (BSR). Experiments were performed on male Sprague-Dawley rats trained to produce an operant response to obtain electrical stimulation in the lateral hypothalamus. Measures of reward threshold were determined in different groups of rats using the curve-shift method using fixed current intensity and variable frequency before and at different times after injection of haloperidol (0.01, 0.05, 0.1, and 0.25 mg/kg), clozapine (1, 7.5, 15, and 30 mg/kg), M100907 (0.033, 0.1, and 0.3 mg/kg), or their vehicle. The effect of M100907 (0.3 mg/kg) on the attenuation of BSR by a sub- and suprathreshold dose of haloperidol was studied in another group of rats. Clozapine produced a dose-orderly increase in reward threshold with a mean maximal increase of 50%; at high doses, clozapine induced cessation of responding in several animals at different time periods. Haloperidol induced a dose-dependent increase in reward threshold, with the mean maximal increase (75%) being observed at the highest dose; it also produced a dose-dependent reduction of maximum rates of responding. M100907 failed to alter reward at any of the doses tested and had no effect on the subthreshold dose (0.01 mg/kg) of haloperidol. But when combined with a suprathreshold dose of haloperidol, M100907 reduced the reward-attenuating effect of haloperidol. These results show that 5-HT2a receptors are unlikely to constitute a component of the reward-relevant pathway activated by lateral hypothalamic stimulation. However, blockade of 5-HT2a receptors may account for the relatively lower level of reward attenuation produced by clozapine, and predict that antipsychotic medications that have a high affinity for the 5-HT2a receptor may be less likely to induce dysphoria.     

The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Rationale

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.

Objectives

In the current study, the effects of partial nAChR agonist and 5-HT₃ receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.

Results

R3487/MEM3454, at doses of 0.1–10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose–response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT₃ receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.

Conclusions

These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT₃ receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.     

Modification of the behavioral effects of morphine in rats by serotonin (5-HT)1A and 5-HT2A receptor agonists: antinociception, drug discrimination, and locomotor activity

Rationale

Indirect-acting serotonin (5-HT) receptor agonists can enhance the antinociceptive effects of morphine; however, the specific 5-HT receptor subtype(s) mediating this enhancement is not established.

Objective

This study examined interactions between morphine and both 5-HT_1A and 5-HT_2A receptor agonists in rats using measures of antinociception (radiant heat tail flick and warm water tail withdrawal), drug discrimination (3.2 mg/kg morphine versus saline), and locomotion.

Methods

Male Sprague–Dawley rats (n?=?7-8 per group) were used to examine the effects of morphine alone and in combination with DOM (5-HT_2A agonist) and 8-OH-DPAT (5-HT_1A agonist).

Results

DOM did not modify antinociceptive or discriminative stimulus effects while modestly attenuating locomotor-stimulating effects of morphine; the effect of DOM (0.32 mg/kg) on morphine-induced locomotion was prevented by the 5-HT_2A receptor-selective antagonist MDL 100907. In contrast, 8-OH-DPAT (0.032–0.32 mg/kg) fully attenuated the antinociceptive effects (both procedures), did not modify the discriminative stimulus effects, and enhanced (0.32 mg/kg) the locomotor-stimulating effects of morphine. These effects of 8-OH-DPAT were prevented by the 5-HT_1A receptor-selective antagonist WAY100635.

Conclusion

Agonists acting at 5-HT_1A or 5-HT_2A receptors do not modify all effects of mu opioid receptor agonists in a similar manner. Moreover, interactions between 5-HT and opioid receptor agonists vary significantly between rats and nonhuman primates, underscoring the value of comparing drug interactions across a broad range of conditions and in multiple species.     

Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy

An in vivo binding assay is characterized for [(3)H]M100907 binding to rat brain, as a measure of 5-HT(2A) receptor occupancy. Dose-response analyses were performed for various 5-HT(2A) antagonist reference agents, providing receptor occupancy ED(50) values in conjunction with plasma and brain concentration levels. Ketanserin and M100907 yielded dose-dependent increases in 5-HT(2A) receptor occupancy with ED(50)s of 0.316 mg/kg and 0.100 mg/kg, respectively. The atypical antipsychotics risperidone, olanzapine, and clozapine dose-dependently inhibited in vivo [(3)H]M100907 binding with ED(50) values of 0.051, 0.144, and 1.17 mg/kg, respectively. In contrast, the typical antipsychotic haloperidol exhibited only 20.1% receptor occupancy at 10 mg/kg despite producing dose-dependent increases in plasma and brain exposure levels. The novel psychopharmacologic agent asenapine dose-dependently occupied 5-HT(2A) receptors in rat brain with an ED(50) of 0.011 mg/kg, demonstrating higher 5-HT(2A) receptor potency compared with the other atypical antipsychotics tested. This enhanced potency was supported by a lower plasma exposure EC(50) of 0.477 ng/ml, compared with risperidone (1.57 ng/ml) and olanzapine (7.81 ng/ml) and was confirmed in time course studies. The validated [(3)H]M100907 rat in vivo binding assay allows for preclinical measurement of 5-HT(2A) receptor occupancy, providing essential data for understanding the pharmacological profile of novel antipsychotic agents. Additionally, the corresponding plasma and brain drug exposure data analyses provides a valuable data set for 5-HT(2A) reference agents by enabling direct comparison with any complementary studies performed in rats, thus providing a foundation for predictive pharmacokinetic/pharmacodynamic models and, importantly, allowing for translation to human receptor occupancy studies using [(11)C]M100907 positron emission tomography.     

Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task

In this work we aimed to re-examine the 5-HT6 receptor role, by testing the selective antagonists SB-357134 (1-30 mg/kg p.o.) and SB-399885 (1-30 mg/kg p.o.) during memory consolidation of conditioned responses (CR%), in an autoshaping Pavlovian/instrumental learning task. Bioavailability, half-life and minimum effective dose to induce inappetence for SB-357134 were 65%, 3.4 h, and 30 mg/kg p.o., and for SB-399885 were 52%, 2.2 h, and 50 mg/kg p.o., respectively. Oral acute and chronic administration of either SB-357134 or SB-399885 improved memory consolidation compared to control groups. Acute administration of SB-357134, at 1, 3, 10 and 30 mg/kg, produced a CR% inverted-U curve, eliciting the latter dose a 7-fold increase relative to saline group. Acute injection of SB-399885 produced significant CR% increments, being 1 mg/kg the most effective dose. Repeated administration (7 days) of either SB-357134 (10 mg/kg) or SB-399885 (1 mg/kg) elicited the most significant CR% increments. Moreover, modeling the potential therapeutic benefits of 5-HT6 receptor blockade, acute or repeated administration of SB-399885, at 10 mg/kg reversed memory deficits produced by scopolamine or dizocilpine, and SB-357134 (3 and 10 mg/kg) prevented amnesia and even improved performance. These data support the notion that endogenously 5-HT acting, via 5-HT6 receptor, improves memory consolidation.