Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy (original) (raw)
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Neuroscience, 2013
Not only is the inferior colliculus (IC) a highly important center of integration within the central auditory pathway, but it may also play a modulatory role in sensorymotor circuitry. Previous evidence from our laboratory relating the IC to motor behavior shows that glutamate-mediated mechanisms within the IC modulate haloperidol-induced catalepsy. The high density of GABAergic receptors in the IC led to this study of a possible link between these receptors, haloperidol-induced catalepsy, and a possible involvement of the blockade of dopaminergic receptors. Catalepsy was evaluated by positioning both forepaws of rats on an elevated horizontal wooden bar and recording the time that the animal maintained this position. The present study shows that haloperidol-induced catalepsy was enhanced by local microinjection into the IC of midazolam (20 nmol/0.5 ll), a benzodiazepine receptor agonist, whereas animals receiving a microinjection of bicuculline (40 or 80 ng/0.5 ll), a GABAergic antagonist, showed a reduction in the time of catalepsy. However, the microinjection of haloperidol (2.5 or 5.0 lg/0.5 ll) bilaterally into the IC did not induce catalepsy. Therefore, our results suggest the involvement of the IC in the modulation of catalepsy induced by haloperidol, even though the dopaminergic mechanisms of the IC are unable to induce catalepsy when blocked by the direct microinjection of haloperidol. It is thus possible that the IC plays a role in sensorimotor gating and that GABA-mediated mechanisms are involved.
Haloperidol-induced morphological changes in striatum are associated with glutamate synapses
Brain Research, 1994
Sub-chronic treatment with the typical neuroleptic, haloperidol (0.5 mg/kg/d, s.c.), but not the atypical neuroleptic, clozapine (35 mg/kg/day, s.c.), causes an increase in synapses containing a perforated postsynaptic density (referred to as 'perforated' synapses) and in dopamine (DA) D 2 receptors within the caudate nucleus [46]. To determine if these perforated synapses are glutamatergic, we systemically co-administered MK-801 (0.3 mg/kg/day for 2 weeks), a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor-associated ion channel, and haloperidol. MK-801 blocked the haloperidol-induced increase in striatal perforated synapses, but not the haloperidol-induced increase in DA D 2 receptors. Injection of MK-801 into the striatum also attenuated the haloperidol-induced increase in perforated synapses. Post-embedding immuno-gold electron microscopy using antibodies to glutamate indicated that the gold particles were localized within striatal presynaptic nerve terminals that make contact with perforated postsynaptic densities. These findings support the hypothesis that the haloperidol-induced increase in perforated synapses is regulated by the NMDA subtype of excitatory glutamate receptor. The increase in perforated synapses following administration of haloperidol, which is associated with a high incidence of extrapyramidal side effects (EPS), and the lack of a synaptic change following administration of clozapine, known to have a low frequency of EPS, suggests that glutamate synapses play a role in the motoric side effects that are observed with typical neuroleptic drug treatment.
Pharmacology Biochemistry and Behavior, 1992
IWATA, S., K. IZUMI AND M. NOMOTO. Upregulation of postsynaptic dopamine receptors in the striatum does not influence haloperidol-induced catalepsy in mice. PHARMACOL BIOCHEM BEHAV 42(4) 803-808, 1992.-The incidence of haloperidol-induced catalepsy was investigated in mice whose postsynaptic dopamine (DA) receptors in the striatum had been upregulated by denervation with 6-hydroxydopamine (6-OHDA). In nonupregulated mice, which were injected with 6-OHDA 4 days before, DA in the striatum fell to 21% of the level found in vehicle-injected mice but [3H]spiperone binding to the membrane of the striatum did not increase. In upregulated mice, which were injected with 6-OHDA 28 days before, DA was at 240/0 and [3H]spiperone binding increased by 15e70. The EDw values (with 95ยข/0 confidence limits) for haloperidol-induced catalepsy in nonupregulated mice and that in upregulated mice was 0.40 mg/kg (0.25-0.65 mg/kg) and 0.29 mg/kg (0.16-0.51 mg/kg), respectively. There was no significant difference in the incidence of catalepsy between the two groups of mice. This suggests that the intensity of catalepsy produced by the DA receptor blockade may be unaltered even when the density of receptors increases.
Brain Research, 1988
BicucuUine (0.5-50 ng), injected bilaterally into the zona incerta-lateral hypothalamus (ZI-LH) of the rat, inhibited catalepsy evoked by haloperidol (1 mg/kg s.c.) in a dose-dependent manner. The same effect was obtained by injections of bicuculline directed towards the ventromedial thalamic nucleus (Vm), but then higher doses of the drug were necessary (10-50 ng). Muscimol (10-50 ng), injected into the ZI-LH, evoked a state of catalepsy almost identical to that of haloperidol. Bicuculline (50 rig) abolished the catalepsy evoked by muscimol (25 ng). Bicuculline injected into ZI-LH in doses of 0.5-2.5 ng did not change locomotor activity of rats as measured in photoresistor actometers, whereas it had a slightly stimulating effect at a dose of 5 ng. A comparison between the doses of bicuculline injected into the ZI-LH and Vm suggests that, irrespective of Vm synapses, GABA synapses of this region are involved in the mediation of haloperidol-induced catalepsy. A similar conclusion regarding the catalepsy and rigidity induced by morphine was drawn previously. It seems, therefore, that the catalepsy antagonism of bicuculline is independent of the action of the drug which promotes the locomotor stimulation.
Brain Research Bulletin, 1994
TUCCI, S., R. FERNANDEZ, T. BAPTISTA, E. MURZI AND L. HERNANDEZ. Dopamine increase in rhe prefrontal cortex correlates with reversal of haloperidol-induced catalepsy in rats. BRAIN RES BULL 35(2) 125-133, 1994.-The mechanism by which forced swimming reverses haloperidol-induced catalepsy was examined by measuring dopamine (DA) turnover in the nucleus accumbens-ventromedial caudate (NAC-C) and the prefrontal cortex (PFC) in rats. DA and its metabolites 3,4-dihydroxiphenylacetic acid (DOPAC) and homovanillic acid (HVA) were assessed by microdialysis and high pressure liquid chromatography with electrochemical detection (HPLC-ED) after systemic administration of a cataleptic dose of haloperidol (5 mg/kg) or saline. Haloperidol-induced catalepsy was temporarily suppressed by forced swimming. Haloperidol-treated rats showed an increase of DA, DOPAC, and HVA overflow in the PFC and the NAC-C. This increase was greater in the PFC of rats that were forced to swim. Rats that were not treated with haloperidol but were forced to swim (control group) showed an increase of DA, DOPAC, and HVA in the PFC but not in the NAC-C. Zero micrograms, 5 pg, 10 pg. and 20 pg of DA was bilaterally injected in the PFC of cataleptic rats to evaluate the hypothesis that DA in the PFC reverses catalepsy. Haloperidol-induced catalepsy was diminished by bilateral microinjections of IO pg and 20 pg but not by 5 pg of DA in the PFC. The higher the dose of DA, the longer the decrease of catalepsy. These results suggest that an increase of DA turnover in the PFC might mediate temporal suppression of haloperidol-induced catalepsy. The mechanism by which the mesocortical DA system reduces catalepsy is discussed.
Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats
European Journal of Pharmacology, 2008
Typical antipsychotics such as the dopamine D 2 receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D 2 receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D 2 receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D 2 receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D 2 receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D 2 receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D 2 receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-Methyl-D-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D 1 receptors as well as a blockade of dopamine D 2 receptors.
Synapse, 1996
Treatment with haloperidol, a dopamine receptor D-2 antagonist, for one month resulted in an increase in the mean percentage of asymmetric synapses containing a discontinuous, or perforated, postsynaptic density (PSD) [Meshul et al. (1994) Brain Res., 648:181-1951 and a change in the density of striatal glutamate immunoreactivity within those presynaptic terminals [Meshul and Tan (1994) Synapse, 18:205-2171. We speculated that this haloperidol-induced change in glutamate density might be due to an activation of the corticostriatal pathway. To determine if activation of this pathway leads to similar morphological changes previously described following haloperidol treatment, GABA (lo+ M, 0.5 1.1) was injected into the thalamic motor (W VM) nuclei daily for 3 weeks. This treatment resulted in an increase in the mean percentage of striatal asymmetric synapses containing a perforated PSD and an increase in the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated or non-perforated PSD. Subchronic injections of GABA into the thalamic somatosensory nuclei (VPMNPL) had no effect on the mean percentage of synapses with perforated PSDs but resulted in a small, but significant, increase in density of glutamate immunoreactivity. Using in vivo microdialysis, an acute injection of GABA M, 15 pl) into VLNM resulted in a prolonged rise in the extracellular level of striatal glutamate. The increase in asymmetric synapses with perforated PSDs and in glutamate immunoreactivity within nerve terminals of the striatum following either subchronic haloperidol treatment or GABA injections into VLNM suggest that an increase in glutamate release may be a common factor in these two experiments. It is possible that the extrapyramidal side effects associated with haloperidol treatment may be due, in part, to an increase in release of glutamate within the corticostriatal pathway. o 1996 Wiley-Liss, Inc.
2007
Aim: Catalepsy occurs following high dopamine D2 receptor blockade by the typical antipsychotic drug haloperidol. The present study investigated the effect of different drugs affecting monoamine neurotransmission in this animal model of Parkinson's disease in mice. Materials and Methods: Drugs were intraperitoneally administered with haloperidol 30 min prior to testing. Catalepsy was measured using the bar test. Results: Catalepsy duration was reduced by the non-selective noradrenaline and serotonin reuptake inhibitors imipramine and amitriptyline (21.1% and 22.3% reduction by 20 mg/kg imipramine and amitriptyline, respectively). Catalepsy duration was increased by the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine, and citalopram and by the serotonin receptor antagonist and reuptake inhibitor nefazodone (maximal increases of 112.4%, 38.5%, 30.8% and 112.4%, respectively). In contrast, the duration of catalepsy was decreased by the serotonin and dopamine reuptake inhibitor
Effects of Subchronic Clozapine and Haloperidol on Striatal Glutamatergic Synapses
Journal of Neurochemistry, 2002
Subchronic treatment with haloperidol increases the number of asymmetric glutamate synapses associated with a perforated postsynaptic density in the striatum. To characterize these synaptic changes further, the effects of subchronic (28 days) administration of an atypical antipsychotic, clozapine (30 mg/kg, s.c.), or a typical antipsychotic, haloperidol (0.5 mg/kg, s.c.), on the binding of [ 3H]MK-801to the NMDA receptor-linked ion channel complex and on the in situ hybridization of riboprobes for NMDAR2A and 2B subunits and splice variants of the NMDAR1 subunit were examined in striatal preparations from rats. The density of striatal glutamate immunogold labeling associated with nerve terminals of all asymmetric synapses and the immunoreactivity of those asymmetric synapses associated with a perforated postsynaptic density were also examined by electron microscopy. Subchronic neuroleptic administration had no effect on [3H]MK-801 binding to striatal membrane preparations. Both drugs increased glutamate immunogold labeling in nerve terminals of all asymmetric synapses, but only haloperidol increased the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated postsynaptic density. Whereas subchronic administration of clozapine, but not haloperidol, resulted in a significant increase in the hybridization of a riboprobe that labels all splice variants of the NMDAR1 subunit, both drugs significantly decreased the abundance of NMDAR1 subunit mRNA containing a 63-base insert. Neither drug altered mRNA for the 2A subunit, but clozapine significantly increased hybridization of a probe for the 2B subunit. The data suggest that some neuroleptic effects may be mediated by glutamatergic systems and that typical and atypical antipsychotics can have varying effects on the density of glutamate in presynaptic terminals and on the expression of specific NMDA receptor splice variant mRNAs. Alternatively, NMDAR1 subunit splice variants may differentially respond to interactions with glutamate.