Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A(1) receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of dizocilpine. Pretreatment with adenosine A(1) receptor agonists, 2-chloro-N(6)-cyclopentyladenosine (CCPA) (0.1, 0.3, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N(6)-cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p.), attenuated neurotoxicity by dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the dizocilpine-induced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 microM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A(1) receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.     

The effects of subchronic haloperidol on intact and dizocilpine-disrupted sensorimotor gating

Rationale: Reversal of deficits in prepulse inhibition (PPI) of the startle reflex in rats is considered a preclinical screen for potential antipsychotics. Whereas acutely administered antipsychotics consistently reverse apomorphine-induced deficits in PPI, some antipsychotics, including haloperidol, are unable to reverse deficits in PPI produced by non-competitive NMDA antagonists such as phencyclidine or dizocilpine (MK-801). Acute administration of antipsychotics tends to facilitate baseline PPI. However, the effect is generally not large enough in magnitude nor reliable enough to be considered a useful preclinical screen for antipsychotic activity. Objective: Because the clinical effects of antipsychotics typically require subchronic administration, this study tested the hypothesis that reversal of NMDA antagonist-induced deficits in PPI by antipsychotics require subchronic administration. A second aim of this study was to determine if subchronic administration of an antipsychotic produces a more potent facilitation of baseline PPI than acute administration. Methods: Rats received a subcutaneous injection of 0, 0.025, 0.1 or 0.5 mg/kg haloperidol for 16 consecutive days. On day 16, half the rats in each haloperidol dose group received a second subcutaneous injection consisting of either dizocilpine (0.1 mg/kg) or saline. Results: None of the haloperidol doses tested had a significant effect on baseline PPI. The 0.1 mg/kg dose of haloperidol diminished but did not completely reverse dizocilpine-induced disruption of PPI. The other doses had no significant effect. Conclusions: These results suggest that time course factors may partially modify the effects of haloperidol on dizocilpine-induced disruption of PPI but not its effect on baseline PPI. Received: 4 December 1998 / Final version: 19 April 1999     

Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine (MK-801), but not methamphetamine

Rationale Our group has recently shown that methamphetamine (METH) (2.5 mg/kg) induced delayed increases in glutamate (Glu) levels in the rat nucleus accumbens (NAC), and that its repeated administration leads to behavioral cross-sensitization to a selective uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801).Objectives The present study aims to examine whether valproate (VPA) would inhibit the delayed increases in Glu levels and prevent METH (2.5 mg/kg)-induced behavioral cross-sensitization to MK-801 (0.2 mg/kg).Materials and methods We examined the effects of post-treated VPA (50 mg/kg) on METH (2.5 mg/kg)-induced delayed increases in Glu levels. We injected VPA (50 mg/kg) at 120 min after each METH (2.5 mg/kg, once every other day, total of five times) administration and measured locomotor activity induced by challenge with MK-801 (0.2 mg/kg) or METH (0.15 mg/kg) after sufficient withdrawal period. Finally, we measured locomotion induced by MK-801 (0.2 mg/kg) after pretreatment of a competitive NMDA receptor antagonist, CPP (30 mg/kg). Effects of VPA on extracellular Glu levels were examined by using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor.Results VPA administered 120 min after METH injection had no effect on METH-induced hyperlocomotion, and inhibited METH-induced delayed increases in Glu levels. Repeated VPA administration prevented METH-induced behavioral cross-sensitization to MK-801, but not sensitization to METH. MK-801-induced hyperlocomotion was enhanced when pretreated with the competitive NMDA receptor antagonist, CPP.Conclusions These results suggest that VPA inhibits high-dose METH-induced delayed increases in Glu levels to prevent development of behavioral cross-sensitization to an NMDA antagonist, but not sensitization to METH.     

The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice

Repeated use of methamphetamine (METH) causes dependence in humans, and to date, there are no effective medication treatments for METH addiction. We previously reported that the antibiotic minocycline attenuated behavioral abnormalities (hyperactivity and behavioral sensitization) and dopaminergic neurotoxicity in mice and monkeys, after the administration of METH. In this study, we examined the effect of minocycline on METH-induced rewarding effects in mice using the conditioned place preference (CPP) paradigm. Minocycline (40 mg/kg, IP) significantly attenuated METH (1.0 mg/kg, SC)-induced place preference in mice. In vivo microdialysis experiments using free-moving mice, showed that minocycline (40 mg/kg, IP) significantly attenuated the increased extracellular dopamine (DA) levels within the nucleus accumbens, typically seen after the administration of METH (1.0 mg/kg, SC). These findings suggest that minocycline may block METH-induced rewarding effects by down regulating extracellular DA levels in the nucleus accumbens of mice. This would make minocycline a potential therapeutic drug for the treatment of METH induced disorders.     

Effects of the 5-HT(3) receptor antagonist ondansetron on the ketamine- and dizocilpine-induced place preferences in mice

The effects of the 5-HT(3) receptor antagonist ondansetron on the ketamine- and dizocilpine-induced place preferences in mice were examined. The non-competitive NMDA receptor antagonists ketamine (1. 0-10 mg/kg, i.p.) and dizocilpine (0.1 and 0.2 mg/kg, i.p.) each produced a place preference in a dose-dependent manner. The ketamine (10 mg/kg)- and dizocilpine (0.2 mg/kg)-induced place preferences were dose-dependently blocked by pretreatment with ondansetron (0. 03-0.1 mg/kg, s.c.). These results suggest that 5-HT(3) receptor may be involved in the development of the place preferences produced by ketamine and dizocilpine.     

Differential effects of the antidepressant mirtazapine on amphetamine- and dizocilpine-induced PPI deficits

Prepulse inhibition (PPI) refers to the decrease in motor startle response to salient sensory stimuli (pulses) when they are closely preceded in time by another more modest sensory stimulus (prepulse). PPI deficits can be induced by stimulation of dopamine receptors (e.g., amphetamine or apomorphine) or blockade of NMDA glutamate receptors (e.g., dizocilpine or PCP). Previously we found that antagonists of α₂-noradrenergic and H₁-histaminergic receptors significantly attenuate PPI impairments caused by amphetamine or dizocilpine. In the current study we assessed the effects of the antidepressant mirtazapine, which has combined antagonist effects at α₂-noradrenergic, H₁-histaminergic and 5-HT serotonergic receptors, on amphetamine- and dizocilpine-induced PPI deficits. In Experiment 1, rats were tested for PPI of the startle response to a tactile air-puff stimulus after auditory prepulses of three different intensities. Drug treatments consisted of combinations of amphetamine (0 and 1 mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5 mg/kg), with all rats receiving all drug doses and combinations with different counterbalanced orders. In Experiment 2, a different group of rats was tested with drug treatments consisting of combinations of dizocilpine (0 and 0.05 mg/kg) and mirtazapine (0, 0.5, 1, 2, and 5 mg/kg). In Experiment 1 amphetamine (1 mg/kg) significantly reduced PPI whereas mirtazapine caused the opposite effect, with the highest dose of mirtazapine (5 mg/kg) effectively reversing the amphetamine-induced PPI deficit. In Experiment 2 dizocilpine (0.05 mg/kg) significantly reduced PPI, but mirtazapine did not have a significant effect on the inhibition of the startle response. These results indicate that the potential beneficial effects of combined α-adrenergic, 5-HT, and H₁ receptor blockade in counteracting PPI deficits may be associated to cases of sensorimotor gating disorders mediated by dopamine, but not necessarily to NMDA glutamate-induced PPI impairments.     

The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism

In the present series of studies, we have investigated the effects of antagonists selective for the 5-HT_2A, 5-HT_2B and 5-HT_2C receptors on motor and 'impulsive'-type behaviours elicited by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine. The selective 5-HT_2A receptor antagonist M100,907 (0.5 mg/kg) attenuated the hyperlocomotion and stereotypy produced by dizocilpine (0.1–0.3 mg/kg). The selective 5-HT_2B receptor antagonist SB215,505 (3 mg/kg) and the selective 5-HT_2C receptor antagonist SB242,084 (0.5 mg/kg) had no effect against either measure, except that SB242,084 produced a small potentiation of the hyperactivity response. Dizocilpine (0.03 mg/kg) increased premature responding in rats performing the 5-choice serial reaction time task (5-CSRTT), and increased response frequency consequently reducing the mean inter-response time (IRT) and efficiency of responding in a DRL24 task. M100,907 (0.5 mg/kg) attenuated each of these effects, as well as the increased premature responding produced by the NMDA NR2B selective antagonist Ro 63–1908 (1 mg/kg) in the 5-CSRTT. In contrast SB242,084 (0.5 mg/kg) did not attenuate the dizocilpine-induced premature responding or increased responding in the DRL24 task. Rather, SB242,084 (0.05–0.5 mg/kg) produced qualitatively similar effects to dizocilpine, increasing premature responding and reducing IRT. The results suggest that 5-HT_2A receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction. The 5-HT_2C receptor antagonist SB242,084 failed to exert equivalent effects, rather a trend toward exacerbation of the behavioural changes produced by dizocilpine was apparent.     

Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice

 Current data indicate that dopaminergic and glutamatergic neurotransmitter systems interact. The role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission, however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5–40 mg/kg) and LY300164 (1–6 mg/ kg), and the competitive AMPA antagonists, LY326325 (5–80 mg/kg) and NBQX (10–80 mg/kg), were compared to the dopamine antagonist, haloperidol (0.03– 1.0 mg/kg), for their ability to inhibit dopamine-mediated behaviors after IP administration in mice. The behavioral paradigms included amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing. All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine-induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI 52466 were more potent against amphetamine than against dizocilpine. In contrast, LY326325 was more potent against dizocilpine than against amphetamine. The hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific effects on motor behavior. The AMPA antagonists and haloperidol also attenuated amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466, LY300164, and NBQX failed to attenuate apomorphine-induced climbing and stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced stereotypy, but not climbing. These results indicate that AMPA receptor antagonists can attenuate the behavioral effects of drugs, such as amphetamine and dizocilpine, that increase dopamine neurotransmission. However, the behavioral effects of the direct dopamine agonist apomorphine are not consistently attenuated by AMPA antagonists. The competitive AMPA receptor antagonist LY326325 appears to have a profile distinct from both haloperidol and the other AMPA antagonists tested. Received: 23 December 1996/Final version: 8 September 1997     

Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling sensory stimulus is inhibited by a preceding sensory stimulus of a lower intensity. The current experiment used tactile startle rather than acoustic startle to determine the generality of PPI across sensory modalities. PPI is easily modeled in experimental animals and serves as a useful method for determining the neural bases for sensorimotor plasticity, which can be disturbed in sensory modulation disorders. In the current study, female Sprague-Dawley rats were tested for tactile startle PPI after an auditory pre-pulse. The glutamate NMDA receptor antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly total blockade of the PPI effect (p<0.0005). The antipsychotic drug clozapine (1.25 mg/kg, p<0.001 and 2.5 mg/kg p<0.05) significantly attenuated the dizocilpine-induced PPI impairment. Interestingly, the lower clozapine dose did not by self enhance PPI and the higher clozapine dose when given alone caused a significant (p<0.05) PPI impairment relative to control. Nicotine (0.2 and 0.4 mg/kg) did not significantly interact with the other treatments, though the higher nicotine dose did show a trend toward attenuating the PPI impairment caused by the high clozapine dose. These effects were replicated in a second experiment of clozapine-dizocilpine interactions without nicotine treatment. This study shows that PPI of tactile startle is dramatically impaired by blocking NMDA activation and that the prototypic atypical antipsychotic drug clozapine can correct this deficit. This may be relevant to the action of clozapine in attenuating sensory gating deficits in schizophrenia and may point to new avenues of treatment for sensory modulation disorders in which there is excessive tactile response.     

Glycine and <Emphasis Type="SmallCaps">d</Emphasis>-serine,but not <Emphasis Type="SmallCaps">d</Emphasis>-cycloserine,attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

RATIONALE: Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. OBJECTIVES: We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. RESULTS: High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex. CONCLUSIONS: The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.     

Effects of topiramate on the prepulse inhibition of the acoustic startle in rats.

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.     

Pharmacological and genetic evidence indicates that combined inhibition of NR2A and NR2B subunit containing NMDA receptors is required to disrupt prepulse inhibition

Rationale Glutamate signalling through the N-methyl-d-aspartate (NMDA) receptor is of critical importance for normal central nervous system (CNS) function, as indicated by the marked behavioural disturbances produced by non-subtype selective NMDA antagonists such as dizocilpine (MK-801).Objective The present studies were designed to investigate the involvement of the two major NMDA receptor subunits in the central nervous system, i.e. NR2A and NR2B, on sensorimotor gating in mice.Methods These experiments utilised the non-subtype-selective NMDA antagonist dizocilpine, a line of NR2A-KO mice and the selective NR2B antagonist Ro 63–1908, in the study of pre-pulse inhibition of the startle response (PPI).Results The non-selective NMDA receptor antagonist dizocilpine (0.1–1 mg/kg, IP) robustly disrupted PPI in wild-type mice. Conversely, selective genetic or pharmacological inhibition of either the NMDA NR2A or NR2B receptor subunit containing receptors, respectively, had no effect on PPI. Thus, NR2A KO mice showed normal PPI compared with wild-type littermate controls, and administration of Ro 63-1908 (1–10 mg/kg IP) to wild-type mice did not affect PPI. However, selective inhibition of NR2A and NR2B by administration of Ro 63–1908 to NR2A KO mice significantly disrupted PPI.Conclusions These data imply that concomitant inhibition of both NR2A and NR2B subunit-containing NMDA receptors is necessary to disrupt PPI, suggesting that inhibition of NR2A and NR2B-containing NMDA receptors is required to elicit behaviours suggestive of psychomimetic effects in man.     

SR146131, a cholecystokinin-A receptor agonist,antagonizes prepulse inhibition deficits produced by dizocilpine and DOI

Abstract Rationale. Converging evidence has demonstrated that cholecystokinin (CCK) inhibits mesolimbic brain dopamine (DA) function via activation of CCK-A (CCK-1) receptors. These effects of CCK have stimulated interest in the potential use of CCK agonists as antipsychotic drugs. Most research on the antipsychotic-like drug effects of CCK has used CCK or CCK analogues that nonselectively activate both CCK-A and CCK-B (CCK-2) receptors, which may produce opposite effects. SR146131, a CCK-A selective nonpeptide agonist, has recently been developed (Sanofi-Synthelabo). Objective. To determine whether SR146131 exhibits antipsychotic-like qualities in the prepulse inhibition (PPI) paradigm. Methods. We performed experiments to determine whether SR146131 (vehicle, 0.01, 0.1, 1.0 mg/kg) would attenuate PPI deficits induced by amphetamine (2.0 mg/kg), an indirect dopamine agonist, and dizocilpine (0.1 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Since SR146131 demonstrated significant effects on PPI disrupted by the noncompetitive NMDA antagonist, an effect associated with drugs that inhibit serotonin (5HT)2A transmission, we also tested the effects of SR146131 on PPI disruption produced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5 mg/kg), a direct 5HT2A agonist. Results. SR146131 did not significantly affect startle magnitude, baseline PPI, or amphetamine-induced PPI deficits. However, it dose-dependently antagonized dizocilpine and DOI-induced PPI deficits. Conclusions. The lack of an effect of SR146131 on amphetamine-induced disruption of PPI suggests that a selective nonpeptide CCK-A agonist may not produce antipsychotic-like effects on dopamine transmission. However, the unexpected effects of SR146131 on dizocilpine and DOI-induced PPI deficits are consistent with the effects of drugs that inhibit transmission in the 5HT2A receptor system, including atypical antipsychotic drugs. Possible mechanisms underlying these findings are discussed. Electronic Publication     

Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors

Rationale Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear.Objective We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801).Methods In adult, male CFW mice, sensitization was induced by either ten daily injections of d-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined.Results The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization.Conclusions These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.     

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.     

Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.     

Risperidone attenuates MK-801-induced hyperlocomotion in mice via the blockade of serotonin 5-HT 2A/2C receptors

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, like phencyclidine (PCP), elicit schizophrenia-like symptoms in humans and behavioral abnormalities in animals, such as hyperactivity. We investigated the effect of the atypical antipsychotic risperidone on hyperlocomotion produced in mice by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801), an NMDA receptor antagonist. MK-801 (0.125, 0.25, 0.50 mg/kg) dose-dependently increased the total distance traveled in an open field during a 90 min period in mice. The increase in MK-801 (0.25 mg/kg)-induced total distance traveled was attenuated by pretreatment with risperidone at doses that alone had no effect on spontaneous locomotor activity. Furthermore, (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a serotonin 5-HT(2A/2C) receptor agonist, at the doses that failed to change spontaneous locomotor activity or hyperlocomotion induced by MK-801, reversed the attenuation by risperidone. The serotonin 5-HT(2A/2C) receptor antagonist, ritanserin, enhanced the inhibitory effect of risperidone. These findings indicate that risperidone attenuates MK-801-induced hyperlocomotion in mice by blocking serotonin 5-HT(2A/2C) receptors.     

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.     

Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats

RATIONALE: Tetracycline antibiotics share some neuroprotective and CNS effects with N-methyl- D-aspartate (NMDA) receptor antagonists. OBJECTIVES: The acute effects of two tetracycline antibiotics were compared to those of the prototypic NMDA antagonist phencyclidine (PCP). METHODS: The effects of minocycline (10-56 mg/kg) and doxycycline (10-56 mg/kg) were evaluated in Sprague-Dawley rats trained to discriminate 2.0 mg/kg IP of PCP from saline under a fixed ratio schedule of food presentation. RESULTS: Even though minocycline and doxycycline did not substitute for PCP, pretreatment with 32 mg/kg of either drug produced leftward shifts in the PCP dose-response curve. The 32 mg/kg dose of minocycline also produced a leftward shift in the dose-response curve for dizocilpine (MK-801), another NMDA channel blocker, in the same subjects. CONCLUSIONS: Tetracycline antibiotics may interact either directly or indirectly with NMDA receptors. This suggests that they might be utilized in treatment of brain disorders in which NMDA receptor over-activation has been implicated.     

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.