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PubMed2006

Differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus.

Compared to first-generation antipsychotics (FGAs) such as haloperidol, second-generation antipsychotics (SGAs) such as olanzapine are found superior to improve cognitive performance and reduce negative symptoms with no extrapyramidal symptoms (EPS). These clinical effects of SGAs have been reported to be associated with the most replicated phenomenon, favorable changes in brain regional blood flow and volume. The changes in brain regional blood flow are shown to parallel changes in angiogenesis, which is primarily mediated by vascular endothelial growth factor (VEGF) through its receptor, Flk-1, on endothelial cells. Therefore, we studied the differential effects of time-dependent treatment (14 and 45 days) with haloperidol and olanzapine (2 and 10 mg/kg/day, respectively, in drinking water) on hippocampal levels of VEGF, its receptor Flk-1, and angiogenesis in adult rat. The levels of VEGF were determined by both Western blot analysis and ELISA, and Flk-1 levels were determined by Western blot analysis. Immunohistochemical analysis of rat endothelial cell antigen-1 (RECA-1) and laminin were used to evaluate the changes in angiogenesis. After 14 days of treatment with both haloperidol and olanzapine, the levels of VEGF and angiogenesis were significantly increased (p<0.001 vs vehicle for both), but 45 days of treatment with haloperidol reduced their levels back to levels in vehicle-treated rats. However, olanzapine treatment further increased VEGF levels (p<0.05 vs levels after 14 days of treatment). Changes in the levels of Flk-1 paralleled the changes in VEGF levels. Thus, the data indicate that haloperidol and olanzapine have distinct time-dependent patterns of regulation of VEGF and angiogenesis. These changes probably provide a new molecular mechanism to better explain their differential effects on the patterns of regional blood flow and associated changes in regional volume/neuroplasticity and psychopathology.

Animals↗
PubMed1999

Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia.

BACKGROUND: There is relatively little information regarding the efficacy of newer atypical antipsychotic drugs for patients with schizophrenia who are treatment-resistant to neuroleptic agents. Several lines of evidence suggest that a clinical trial of olanzapine in this population is warranted. METHODS: A subpopulation of patients (n = 526) meeting treatment-resistant criteria selected from a large, prospective, double-blind, 6-week study assessing the efficacy and safety of olanzapine and haloperidol were examined. Both last-observation-carried-forward (LOCF) and completers (observed cases) analyses were conducted. RESULTS: Olanzapine demonstrated significantly greater mean improvement from baseline in Positive and Negative Syndrome Scale (PANSS) negative symptoms, comorbid depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale, akathisia as measured by Barnes Akathisia Scale, and extrapyramidal symptoms as measured by Simpson-Angus Extrapyramidal Rating Scale with both LOCF and completers analyses. In addition, olanzapine was significantly superior to haloperidol for Brief Psychiatric Rating Scale total (p = .006), PANSS total (p = .005), and PANSS positive symptoms (p = .017) in completers of the 6-week study. Significantly greater response rates were observed in olanzapine-treated (47%) than haloperidol-treated (35%) patients in the LOCF analysis (p = .008), but significance was not reached in the completers analysis (p = .093). Mean doses (+/- SD) of olanzapine and haloperidol were 11.1 +/- 3.4 mg/day and 10.0 +/- 3.6 mg/day, respectively. CONCLUSIONS: Olanzapine was superior to haloperidol for key symptom domains and parkinsonian side effects. Implications of these data for the therapeutics of this severely ill subgroup are discussed.

Adult↗
PubMed1997

Differential effects of acute administration of clozapine or haloperidol on local cerebral glucose utilization in the rat.

We employed the [14C]2-deoxyglucose method in order to map local brain metabolic activity of rats administered 1, 5, or 20 mg/kg of clozapine, or 0.5 mg/kg of haloperidol, as compared to saline. Clozapine produced a dose-dependent reduction of glucose utilization. At the dose of 1 mg/kg, the effects were limited to limbic areas. An additional number of structures were significantly affected following administration of 5 mg/kg (the whole hippocampal formation and septal area, and cortical limbic areas). The dose of 20 mg/kg markedly reduced glucose utilization in most of the areas examined. Haloperidol (0.5 mg/kg) reduced glucose utilization of the orbital cortex, hippocampal formation and septal area, globus pallidus, amygdala, ventral thalamus, and substantia nigra reticulata. The results show that acute administration of clozapine or haloperidol are associated with different distribution patterns of altered cerebral energy metabolism. Clozapine differently from haloperidol, reduces energy metabolism of the nucleus accumbens and other limbic areas. Haloperidol, but not clozapine (1 or 5 mg/kg), affects the substantia nigra reticulata.

Animals↗
PubMed2001

Effects of long-term haloperidol treatment on glutamate-evoked ascorbate release in rat striatum.

Repeated haloperidol injections increase extracellular striatal ascorbate. Because ascorbate release depends on glutamate uptake, we assessed this mechanism in the haloperidol effect. Linear staircase voltammetry was combined with intrastriatal infusions of L- or D-glutamate or saline in behaving rats after 7 or 21 days of haloperidol (0.5 mg/kg, s.c.). Control animals, receiving either vehicle or no treatment, responded to L-, but not D-glutamate or saline infusion with a 50% increase in ascorbate. In contrast, glutamate-evoked ascorbate release disappeared after 7 but reappeared after 21 days of haloperidol. Thus, increased striatal ascorbate release following chronic haloperidol cannot be explained by an enhanced response to glutamate.

Animals↗
PubMed2002

5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy.

Studies have shown that 5-HT1A receptor ligands modulate antipsychotic-induced catalepsy. Here, we further examined the role of intrinsic activity at 5-HT1A receptors in these effects. The anti-cataleptic effects of 5-HT(1A) receptor ligands with positive intrinsic activity [from high to low: 3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone fumaric acid salt (F 13714), eptapirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 2-[4-[4-(7-methoxy-1-naphtyl) piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione maleic acid salt (F 11461), buspirone, 2-[4-[4-(7-benzofuranyl)piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione (F 12826), ipsapirone, and (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride (WAY 100135)] and negative intrinsic activity [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide dihydrochloride (WAY 100635)] were examined. Catalepsy was induced by the classical antipsychotic haloperidol (0.63 mg/kg) and measured in the cross-legged position test and in the bar test. All 5-HT1A receptor agonists, except WAY 100135, significantly attenuated the effects of haloperidol in the cross-legged position test. All agonists had similar effects in the bar test, except ipsapirone, which failed to attenuate haloperidol-induced catalepsy. In contrast to the effects observed with the agonists, the inverse agonist WAY 100635 appeared to enhance haloperidol-induced catalepsy in both tests, in agreement with earlier findings. The maximal effects of the 5-HT1A receptor ligands to attenuate catalepsy correlated positively with the rank order of their intrinsic activity at 5-HT1A receptors (either catalepsy test: r(S)=0.92, P<0.001). F 13714, which had the highest intrinsic activity, maximally inhibited haloperidol-induced catalepsy in the cross-legged position and bar tests (100% and 99% inhibition, respectively). Because the magnitude of the anti-cataleptic effects of 5-HT1A receptor ligands correlates positively with their intrinsic activity, it is likely that F 13714 has marked anti-cataleptic effects because of its high intrinsic activity at 5-HT1A receptors.

Animals↗
PubMed2003

Possible antioxidant and neuroprotective mechanisms of FK506 in attenuating haloperidol-induced orofacial dyskinesia.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Chronic haloperidol (1 mg/kg for 21 days) treatment significantly induced vacuous chewing movements and tongue protrusions in rats, and FK506 (Tacrolimus) [[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate] dose dependently (0.5 and 1 mg/kg) reduced these haloperidol-induced movements. Biochemical analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the levels of glutathione and of the antioxidant defense enzymes, superoxide dismutase and catalase, in the brains of rats. Co-administration of FK506 dose dependently (0.5 and 1 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels induced by chronic haloperidol treatment. It also significantly reversed the haloperidol-induced decrease in brain superoxide dismutase and catalase levels. The major findings of the present study suggest that oxidative stress-induced neuronal death might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, FK506 could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.

Animals↗
PubMed1997

Effects of serotonergic agents on the up-regulation of dopamine D2 receptors induced by haloperidol in rat striatum.

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptors, while that with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D2 receptor up-regulation, Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT2A receptors are highly occupied compared with dopamine D2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.

Animals↗
PubMed1997

Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats.

The effect of adenosine A1 and A2 receptor agonists and antagonists was investigated on haloperidol-induced catalepsy in rats. Pretreatment (i.p.) with the non-selective adenosine receptor antagonist, theophylline, or the selective adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), significantly reversed haloperidol-induced catalepsy, whereas the selective adenosine A1 receptor antagonists, 8-phenyltheophylline and 8-cyclopentyl-1,3-dipropylxanthine produced no effect. Similar administration of the adenosine A2 receptor agonists, 5'-(N-cyclopropyl)-carboxamidoadenosine and 5'-N-ethylcarboxamidoadenosine (NECA), and the mixed agonists with predominantly A1 site of action, N6-(2-phenylisopropyl) adenosine or 2-chloroadenosine, potentiated haloperidol-induced catalepsy. Higher doses of the adenosine agonists produced catalepsy when given alone. However, N6-cyclopentyladenosine, a highly selective adenosine A1 receptor agonist, was ineffective in these respects. The per se cataleptic effect of adenosine agonists was blocked by DMPX and the centrally acting anticholinergic agent, scopolamine. Scopolamine also attenuated the potentiation of haloperidol-induced catalepsy by adenosine agonists. Further, i.c.v. administration of NECA and DMPX produced a similar effect as that produced after their systemic administration. These findings demonstrate the differential influence of adenosine A1 and A2 receptors on haloperidol-induced catalepsy and support the hypothesis that the functional interaction between adenosine and dopamine mechanisms might occur through adenosine A2 receptors at the level of cholinergic neurons. The results suggest that adenosine A2, but not A1, receptor antagonists may be of potential use in the treatment of Parkinson's disease.

2-Chloroadenosine↗
PubMed1998

Olanzapine-induced Fos expression in the rat forebrain; cross-tolerance with haloperidol and clozapine.

Acute administration of the atypical antipsychotic drug olanzapine (5 mg kg(-1 i.p.) increased the number of Fos-positive cells moderately in the prefrontal cortex and the striatum; more pronounced were the effects in the nucleus accumbens, the lateral septum, the hypothalamic paraventricular nucleus and the amygdala. The acutely-induced Fos responses of olanzapine were significantly reduced in all brain areas investigated after a 3-week treatment period, indicating the development of tolerance. Through evaluation of cross-tolerance we investigated whether the effects of olanzapine, haloperidol and clozapine on Fos expression and on plasma corticosterone are mediated by the same or by different mechanisms. Cross-tolerance between olanzapine and either haloperidol or clozapine was assessed by the administration of a challenge dose of olanzapine to rats, that were pretreated for 3 weeks with either the same drug, with saline (1 ml kg(-1) day(-1), haloperidol (1 mg kg(-1) day(-1) or clozapine (20 mg kg(-1) day(-1). A competitive dose of olanzapine in long-term haloperidol-treated rats showed cross-tolerance in the rostral part of the cingulate cortex, the dorsomedial and the dorsolateral striatum, the nucleus accumbens and the lateral septum. Cross-tolerance between olanzapine and clozapine, however, was limited to limbic nuclei, including the prefrontal cortex, the lateral septum, the hypothalamic paraventricular nucleus and the amygdala, with minor effects in the mid- and caudal parts of the cingulate cortex. Interesting are the common effects in the lateral septum, possibly an important target for antipsychotic efficacy. Olanzapine administration induced elevated levels of plasma corticosterone and cross-tolerance was seen in haloperidol- and clozapine-pretreated rats.

Animals↗
PubMed1999

Enhanced striatal dopamine D(2) receptor-induced [35S]GTPgammaS binding after haloperidol treatment.

Dopamine receptor-G protein coupling and dopamine D(2) receptor density were assessed in rats treated for 3 weeks with either haloperidol (2 mg/kg; i.p.) or vehicle. After 3 days of withdrawal, agonist-induced guanosine 5'-O-(gamma-[35S]thio)triphosphate ([35S]GTPgammaS) and [3H]spiperone binding were determined in striatal homogenates. Maximal [3H]spiperone binding was increased (24.8%, P<0.01) following haloperidol treatment. The efficacy of dopamine and the dopamine D(2) receptor agonist R(-)-10, 11-dihydroxy-N-n-propylnorapomorphine (NPA) to induce [35S]GTPgammaS binding were found to be increased by 24.1% (P<0.01) and 44.6% (P<0. 001), respectively. When measured in the presence of a saturating concentration of a dopamine D(2) receptor antagonist, the response to dopamine was not significantly affected by haloperidol treatment. In addition, the measurement of haloperidol-induced catalepsy confirmed that the efficient dopamine receptor blockade was followed by a progressive development of dopaminergic supersensitivity. Taken together, these results indicate that a functional pool of dopamine D(2) receptors is increased after prolonged haloperidol administration.

Animals↗
PubMedDate not supplied

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia.

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on-off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.

Adult↗
PubMed2001

Effect of chronic treatment with haloperidol on vasopressin release and behavioral changes by osmotic stimulation of the supraoptic nucleus.

Chronic treatment with dopamine D2 blockers in schizophrenic patients has been proposed as one of the causes of polydipsia and water intoxication, but this conclusion is still controversial. To investigate the relationship between dopamine D2 blockers and these syndromes, we designed a behavioral and neurochemical study using hyperosmotic stimulation in the supraoptic nucleus (SON) by microdialysis after chronic treatment with haloperidol in rats. Animals were injected with haloperidol decanoate (20 mg/kg, i.m.) or sesame oil at 2-week intervals for 8 successive weeks. During the 7th week, water-intake was increased 30-60 min after the hyperosmotic stimulation in both groups, but more so in haloperidol-treated animals compared to that in the control group. Moreover, arginine vasopressin (AVP) was released by the hyperosmotic stimulation in SON, but was not significantly different between groups. In addition, striatal dopamine levels 3-4 days after the microdialysis study showed a significant decrease in the haloperidol-treated animals. These results suggest that chronic treatment with haloperidol enhances water-intake produced by hyperosmotic stimulation in the SON but does not increase AVP levels in dialysates following hyperosmotic stimulation. Thus, these symptoms may be mediated by dopaminergic systems in brain.

Animals↗
PubMed2003

Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial dyskinesia.

Chronic treatment with neuroleptics leads to the development of abnormal orofacial movements described as vacuous chewing movements (VCMs) in rats. Vacuous chewing movements in rodents are widely accepted as one of the animal models of tardive dyskinesia. Oxidative stress and the products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. In the present study chronic haloperidol (1.0 mg kg(-1) for 21 days) treatment induced vacuous chewing movements and tongue protrusions in rats. Co-administration of quercetin, a bioflavonoid, dose dependently (25-100 mg kg(-1)) reduced haloperidol-induced vacuous chewing movements and tongue protrusions. Biochemical analysis revealed that chronic haloperidol treatment induces lipid peroxidation and decreases the glutathione (GSH) levels in the forebrains of rats. The antioxidant defense enzymes, superoxide dismutase (SOD) and catalase were also decreased due to chronic haloperidol treatment. Co-administration of quercetin (25-100 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione levels in these animals. Further quercetin (50-100 mg kg(-1)) also reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. The major findings of the present study suggested that oxidative stress plays a significant role in neuroleptic-induced orofacial dyskinesia and quercetin co-administration reverses these behavioral and biochemical changes. Quercetin, a naturally occurring bioflavonoid could prove to be a useful agent in neuroleptic-induced orofacial dyskinesia.

Animals↗
PubMed2003

Elevated neuronal nitric oxide synthase expression in chronic haloperidol-treated rats.

Long-term administration of neuroleptic drugs, such as haloperidol, in the management of psychiatric disorders may adversely cause an irreversible neurological syndrome of tardive dyskinesia, which is associated with dopamine (DA(2)) receptor supersensitivity in the basal ganglia. Recent studies also indirectly suggest an involvement of nitric oxide synthase (NOS) in dopaminergic supersensitivity; however, chronic neuroleptic effects on neuronal NOS (nNOS) expression in the basal ganglia have not been reported. In this investigation, we treated rats with saline or haloperidol (1 mg/kg, s.c.) daily for 21 days. Five days later, we detected a significant increase of NOS activity in the striatum of haloperidol-treated rats when compared to saline controls. This effect was associated with elevated levels of nNOS mRNA and protein expression in the striatum, but not in the nucleus accumbens, as evidenced by the use of in situ hybridization, Western blot and immunohistochemical techniques. The involvement of the nNOS system after chronic haloperidol treatment coincides with increases of striatal DA(2) receptor sites, calmodulin kinase II activity, animal locomotor and stereotypy behaviors. This study suggests an integral role between nNOS, DA(2) receptor and calmodulin system in the development of dopaminergic behavioral supersensitivity resulting from chronic neuroleptic drug treatment. Furthermore, the toxic effect of chronic haloperidol on NOS system selectivity takes place in the neostriatum.

Animals↗
PubMed1998

Pattern of development of hyperprolactinemia after initiation of haloperidol therapy.

OBJECTIVE: To determine the time it takes for prolactin (PRL) levels to increase after initiation of therapy with haloperidol (a neuroleptic medication) and the pattern and extent of the increase. METHODS: Seventeen individuals scheduled to be given treatment with neuroleptic drugs were enrolled. Baseline blood specimens were collected for PRL and TSH levels. Follow-up samples for PRL determinations were obtained every 3 days for 18 days after initiation of haloperidol therapy. RESULTS: There were 17 subjects: 14 women and three men. Two of the subjects were found to have hyperprolactinemia due to hypothyroidism and were excluded from the basic study. The 15 remaining subjects all had normal baseline PRL levels and normal TSH values. The PRL levels in all 15 showed a similar pattern: a rapid increase in PRL levels in the first 6-9 days, followed by a plateau that remained, with minor fluctuations, throughout the study. The highest mean peak level of PRL was 37.4 ng/mL and the maximum was 77 ng/mL. The two individuals with hypothyroidism had somewhat elevated baseline PRL levels; although they showed the same initial pattern of increase after haloperidol administration, their PRL levels reached values well above 100 ng/mL. CONCLUSION: There is a distinct pattern of response of PRL to haloperidol. The PRL level increases for 6-9 days, then plateaus, the peak being between 30 and 50 ng/mL, and always remains below 77 ng/mL. In our study, levels that continued to increase, or increased above 77 ng/mL, indicated the presence of hypothyroidism. The patterns and levels of the increase were uninfluenced by the therapeutic dose of the medication given. Given that the patients in our study with elevated levels of TSH had such high levels of PRL, all patients should have TSH determinations at the initiation of therapy with neuroleptic medications such as haloperidol.

Adult↗
PubMed1997

The role of striatal glutamatergic system in haloperidol-induced dopamine receptor supersensitivity and effects of monosialoganglioside GM1.

The mechanism underlying the action of ganglioside GM1 on the increase of haloperidol-induced dopamine receptor supersensitivity was studied using the method of chemically stimulated (3H)-D-aspartate release in rat striatal slices. After a 3-week chronic haloperidol treatment the transmitter release was reduced by about 30%, with a further reduction to 40% when GM1 was applied chronically as well. This suggests that the downregulation of the glutamatergic system by chronic haloperidol treatment is potentiated by gangliosides. The acute effect of gangliosides on the stimulated (3H)-D-aspartate release from striatal slices was tested by adding GM1 to the superfusion medium. When given at a concentration of 10(-4) M, GM1 did not alter the amino acid release itself. GM1 did, however, reduce the haloperidol-enhanced (3H)-D-aspartate release to control levels and elevated the glutamate-stimulated (3H)-D-aspartate release. Binding experiments indicate that gangliosides do not directly interact with glutamate or dopamine receptors. The data are discussed in view of earlier findings that GM1 potentiates the behavioral supersensitivity following chronic haloperidol treatment without directly altering dopamine receptor supersensitivity.

Animals↗
PubMed1998

Emergence of oral and locomotor activity in chronic haloperidol-treated rats following cortical N-methyl-D-aspartate stimulation.

Neuroleptic-induced orofacial movements in rats have been widely utilized as an animal model of tardive dyskinesia (TD). The present study investigated the role of the oral motor cortex in these movements by applying direct cortical stimulation in rats exposed to chronic haloperidol. Rats received depot i.m. injections of haloperidol decanoate or sesame oil vehicle every 3 weeks (10 rats per group). After 24 weeks of injections and a 3-week withdrawal period, bilateral guide cannulae were implanted into the primary oral motor cortex. After a 1-week recovery, bilateral microinfusions of saline vehicle followed by 1, 3, and 10 mM N-methyl-D-aspartate (NMDA) were given and observations of oral activity, locomotion, rearing, and grooming were recorded. Haloperidol-treated rats displayed a significant emergence of NMDA stimulated oral activity (nondirected oral movements, oral tremor, audible teeth grinding, and directed oral movements). In addition, rearing and locomotion were significantly elevated in these animals. In contrast to haloperidol-treated rats, sesame oil-treated rats showed no significant emergence of any motor activity. These results suggest that chronic haloperidol administration alters primary motor cortex efferents, and that this effect may be a factor in the manifestation of chronic neuroleptic induced motor side effects, such as TD.

Animals↗
PubMed1999

Modulatory effects of ascorbate, alone or with haloperidol, on a lever-release conditioned avoidance response task.

Pretreatment with ascorbate, a modulator of dopamine transmission in the striatum, enhances the ability of haloperidol, a dopamine antagonist, to induce catalepsy and block the motor-activating effects of amphetamine. The present study extended this line of work to a lever-release version of the conditioned avoidance response (CAR) task, which is highly sensitive to changes in striatal dopamine. Adult male rats were trained to avoid footshock by releasing a lever within 500 ms of tone onset. Ascorbate (100 and 1000 mg/kg, IP) or vehicle was tested either alone or in conjunction with haloperidol (0.01 and 0.05 mg/kg, SC). Compared to vehicle pretreatment, 1000 mg/kg ascorbate alone or in combination with haloperidol impaired CAR performance by increasing avoidance latency. Latency to escape footshock was not impaired, ruling out a generalized motor deficit. In contrast, 100 mg/kg ascorbate alone or in combination with haloperidol had no consistent effects on CAR performance, even at a haloperidol dose (0.005 mg/kg, SC) known to potentiate dopamine transmission by preferentially blocking autoreceptors. Collectively, these results support an antidopaminergic action of ascorbate on striatal function, but suggest that this effect requires relatively high systemic doses.

Analysis of Variance↗