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- Effects of ningdong granule on DA, DRD2, and HVA in a rat model of Tourette's syndrome. [Journal Article, Research Support, Non-U.S. Gov't]
- J Tradit Chin Med 2012 Jun; 32(2):283-8.
Ningdong granule is a traditional Chinese medicine preparation for the treatment of Tourette's syndrome.Sixty-four rats were randomly assigned to a control group and three experimental groups, respectively. Rat models of Tourette's syndrome were established via intraperitoneal injection of apomorphine (Apo). The rats in the experimental groups were subsequently intragastrically injected with haloperidol at 10 mg/kg (haloperidol group), ningdong granule at 370 mg/kg (NDG group), and normal saline (0.9%) at 10 mL/kg (Apo group), respectively. Rat behaviors were observed and recorded on a daily basis. After 12 w, all rats were sacrificed, and sera and striatal tissues were harvested. Homovanillic acid levels in sera, as well as dopamine and dopamine D2 receptor mRNA expression in the striatum, were measured to determine possible mechanisms of Ningdong granule on the dopamine system in a rat model ofTourette's syndrome.Following intervention, stereotype actions of the Tourette's syndrome rats were significantly inhibited in the haloperidol and NDG groups, respectively (P < 0.01). Homovanillic levels were significantly greater in the haloperidol and NDG groups, respectively (P < 0.05). In addition, dopamine levels were significantly less in the NDG group (P < 0.01), and DRD2 mRNA expression was significantly reduced in the haloperidol and NDG groups, respectively (P < 0.05).Results demonstrated that Ning-dong granule effectively inhibited stereotype actions and Tourette's syndrome symptoms by promoting dopamine metabolism, reducing dopamine levels in the striatum, increasing homovanillic acid content in sera, and reducing mRNA expression of DRD2 in the striatum.
- Protective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models. [Journal Article, Research Support, Non-U.S. Gov't]
- Pharmacol Rep 2012; 64(1):191-204.
Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.
- Effects of Ningdong granule on the dopamine system of Tourette's syndrome rat models. [Journal Article, Research Support, Non-U.S. Gov't]
- J Ethnopharmacol 2009 Jul 30; 124(3):488-92.
Ningdong granula (NDG) is a traditional Chinese medicine (TCM) preparation for the treatment of Tourette's syndrome (TS).To explore the effects of NDG on stereotyped behavior, homovanillic acid (HVA) in sera, dopamine (DA) and dopamine D2 receptor (DRD2) in striatum in TS rats.Sixty-four rats were randomly divided into control group and three experimental groups. TS rat models were induced by intraperitoneal injection (i.p.) of Apomorphine (Apo, 2 mg/kg) in the experimental groups. After Apo i.p., rats were intragastrically injected (i.g.) with NDG at 370 mg/kg (NDG+Apo group), haloperidol (Hal) at 1.0 mg/kg (Hal+Apo group), and normal saline (0.9%) at 10 ml/kg (control group and Apo group), respectively, once a day for 12 weeks. The behaviors of the rats were observed and recorded each day. After 12 weeks, all rats were sacrificed and sera and striatum were collected. The levels of HVA in sera, DA in striatum were examined by ELISA, and the expression of DRD2 mRNA in striatum was measured by RT-PCR.NDG could increase the HVA content in sera (P<0.05), meanwhile downregulate the expression of DRD2 mRNA in striatum (P<0.05), and inhibit the stereotyped behaviors induced by Apo (P<0.01) in TS rats, the same effects with Hal. NDG could also reduce the DA content in striatum (P<0.01), while Hal could not.NDG could effectively inhibit the stereotyped behaviors in TS rats, and the mechanisms may be related to the suppression of DA system by increasing the content of HVA in sera, decrease the content of DA and repressing the expression of DRD2 mRNA in striatum.
- Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine. [Journal Article]
- Psychopharmacology (Berl) 2009 May; 203(4):723-35.
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. In rats, PPI deficits induced by dopamine (DA) agonists are reversed by antipsychotics. Inhibition of the striatum-rich phosphodiesterase (PDE)10A may represent a novel antipsychotic mechanism. Previous studies were controversial, showing antipsychotic-like profiles in measures of PPI for the preferential PDE10A inhibitor papaverine (PAP) but not the novel PDE10A inhibitor TP-10.The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI.PPI deficits were induced in rats by apomorphine (APO; 0.1, 0.5 mg/kg) or D: -amphetamine (AMPH; 4 mg/kg). PAP (3, 10, 30 mg/kg) or haloperidol (HAL; 0.1 mg/kg) was tested against these agonists in Sprague-Dawley (SD) or Wistar (WI) rats. Prepulse intervals ranged from 10 to 120 ms. Further tests evaluated the effects of PAP on spontaneous locomotion, AMPH (1 mg/kg)-induced hyperlocomotion, and core body temperature (T degrees ).HAL reversed APO-induced PPI deficits but PAP failed to reverse APO- and AMPH-induced PPI deficits at all doses, strains, pretreatment times, and prepulse intervals. PAP (30 mg/kg) significantly reduced AMPH hyperlocomotion in SD rats, and a similar pattern was detected in WI rats. This PAP dose also strongly reduced spontaneous locomotion and T degrees in SD rats.Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.
- Antipsychotic-like properties of 5-alpha-reductase inhibitors. [Journal Article]
- Neuropsychopharmacology 2008 Dec; 33(13):3146-56.
Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-alpha-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.
- Apomorphine-induced myocardial protection is due to antioxidant and not adrenergic/dopaminergic effects. [Journal Article, Research Support, Non-U.S. Gov't]
- Free Radic Biol Med 2006 May 15; 40(10):1713-20.
Apomorphine (Apo), a dopaminergic agonist used for treatment of Parkinson disease, is a potent antioxidant. In addition to its antioxidative effects, the dopaminergic and adrenergic effects of Apo were studied. Isolated perfused rat hearts were exposed to 25 min of no-flow global ischemia (37 degrees C) and 60 min of reperfusion (I/R, control). Drugs were introduced for the first 20 min of reperfusion. The LVDP of the control group recovered to 54.6 +/- 3.3%. Apo-treated hearts had significantly improved recovery (61.6 +/- 5%, p < 0.05). The recovery of the work index LVDP x HR was even bigger: 67.8 +/- 3.7% (Apo treatment) vs 41.7 +/- 4.6% (control, p < 0.001). Haloperidol, a dopaminergic antagonist, did not affect the recovery with Apo. Propranolol, a beta-adrenergic blocker, initially inhibited the effect of Apo. However, the recovery of the combined group (Apo + propranolol) increased and reached significance (LVDP, p < 0.05 vs control group) after cessation of propranolol perfusion. At 60 min of reperfusion this group was superior to Apo-treated hearts (LVDP, p < 0.05). Propranolol (without Apo) did not improve the hemodynamic recovery. The same pattern of recovery applies also to the recovery of the +dP/dt during the reperfusion. L-DOPA was less effective than Apo. I/R caused significant increase in carbonylation of proteins. Apomorphine inhibited the increase in carbonylation. Haloperidol did not affect this beneficial effect of Apo. L-DOPA significantly decreased the carbonylation of proteins. We conclude that the antioxidative effect of Apo is its main mechanism of cardioprotection.
- Apomorphine-induced activation of dopamine receptors modulates FGF-2 expression in astrocytic cultures and promotes survival of dopaminergic neurons. [Journal Article, Research Support, Non-U.S. Gov't]
- FASEB J 2006 Jun; 20(8):1263-5.
Apomorphine (APO), a potent D1/D2 dopamine receptor agonist, is currently used as an antiparkinsonian drug. We have shown previously that APO stimulates synthesis and release of multiple trophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in both mesencephalic and striatal neurons, thereby effectively preventing dopaminergic neuron loss in vitro. The present study was designed to investigate the effects of APO on fibroblast growth factor-2 (FGF-2) expression and regulation in astrocytes, and furthermore, to identify signaling mechanisms underlying these effects. Here, we show that FGF-2 expression is robustly induced in cultured astrocytes in response to APO. FGF-2 expression was proportional to APO concentration and time-dependent. Conversely, treatment with S-APO, a derivative of R-APO lacking DA receptor agonist activity, did not alter FGF-2 levels. APO treatment resulted in enhanced cytosol FGF-2 immunoreactivity, export of high MW forms of FGF-2 to the cytoplasm from the nucleus and increased extracellular release of FGF-2. Interestingly, both high and low MW forms of FGF-2 were detectable in conditioned medium of APO-treated cultures. This APO-induced effect was correlated with activation of D1 and D2 receptors, as it could be either mimicked by dopamine receptor agonists (SKF38393, quinpirole) or partially blocked by antagonists (SCH23390, SKF83566, haloperidol). Activation of the D1 receptor preferentially increased PKA activity, whereas activation of the D2 receptor only promoted phosphorylation of MAPK. Importantly, APO-modulated FGF-2 expression was independent of Akt/phosphoinositide 3-kinase signaling. These data suggest that APO can enhance biosynthesis and release of FGF-2 through activation of dopamine receptors in striatal astrocytes. Both cAMP/PKA and MEK/MAPK signaling cascades are major steps mediating this process.
- Effects of ethanol and haloperidol on plasma levels of hepatic enzymes, lipid profile, and apolipoprotein in rats. [Journal Article, Research Support, Non-U.S. Gov't]
- Biochem Cell Biol 2004 Apr; 82(2):315-20.
This work studied the effects of ethanol in the absence and presence of haloperidol under two experimental conditions. In protocol 1, rats were treated daily with ethanol (4 g/kg, p.o.) for 7 days, and received only haloperidol (1 mg/kg, i.p.) from the 8th day to the 14th day. In protocol 2, animals received ethanol, and the treatment continued with ethanol and haloperidol from the 8th day to the 14th day. Results show increases in alanine transaminase (ALT; 48% and 55%) and aspartate transaminase (AST; 32% and 22%) levels after ethanol or haloperidol (14 days) treatments, as compared with controls. Apolipoprotein A-1 (APO A1) levels were increased by haloperidol, after 7- (148%) but not after 14-day treatments, as compared with controls. Levels of lipoprotein (high-density lipoprotein (HDL-C)) tended to be increased only by ethanol treatment for 14 days. ALT (80%) and AST (43%) levels were increased in the haloperidol plus ethanol group (protocol 2), as compared with controls. However, an increase in APO A1 levels was observed in the haloperidol group pretreated with ethanol (protocol 1), as compared with controls and ethanol 7-day treatments. Triglyceride (TG) levels were increased in the combination of ethanol and haloperidol in protocol 1 (234%) and 2 (106%), as compared with controls. Except for a small decrease in haloperidol groups, with or without ethanol, as related to ethanol alone, no other effect was observed in HDL-C levels. In conclusion, we showed that haloperidol might be effective in moderating lipid alterations caused by chronic alcohol intake.
- Haloperidol blocks the acquisition but not the retrieval of a conditioned sensitization to apomorphine. [Journal Article, Research Support, Non-U.S. Gov't]
- Behav Pharmacol 2003 Dec; 14(8):631-40.
The dopamine agonist apomorphine (apo) elicits stereotyped pecking bouts in pigeons, a response which increases with successive apo injections. The present study sought, first, to confirm the hypothesis that this sensitization arises through a Pavlovian conditioning driven by both external and internal cues; and, secondly, to advance the hypothesis that during this learning the dopaminergic activation only initiates a process that probably ends in glutamatergic synapse modifications. The conditioned nature of the sensitization to apo was examined in two separate experiments that compared context contingent and context uncontingent apo treatments. The role of dopaminergic mechanisms in the acquisition, maintenance and retrieval of sensitization-conditioned pecking was examined by administering the dopamine antagonist haloperidol (hal) either before, during or after apo sensitization treatments. A contingency between context and apo was found to be essential for the acquisition and retrieval of apo-sensitized pecking. A pretreatment with hal did not curtail a subsequent sensitization to apo. When hal was co-administrated with apo it suppressed the initial pecking response to apo and blocked the acquisition of sensitized responding. A pecking response normally observed when apo-sensitized pigeons are challenged with saline (sal) in the same cage in which they were sensitized, was also absent. When hal was co-administered with apo after the sensitization was complete this led at first to an only partial apo response suppression. When treated with hal in the same cage, already sensitized pigeons responded much as if they had been challenged with sal. The sensitization induced by apo was thus blocked by hal co-administered during acquisition, but during the maintenance or retrieval phase hal did not impair a previously sensitized responding. It is concluded that when pigeons are sensitized to apo, dopaminergic mechanisms are implicated in initiating the neural modifications that underlie the conditioned sensitization, but that they themselves are not importantly altered.
- "Typical" but not "atypical" antipsychotic effects on startle gating deficits in prepubertal rats. [Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.]
- Psychopharmacology (Berl) 2002 Apr; 161(1):38-46.
Dopamine (DA) agonists and NMDA antagonists disrupt sensorimotor gating in rats, as measured by a loss of prepulse inhibition of the startle reflex. These effects are used in predictive models for antipsychotic efficacy: clinically "typical" and "atypical" antipsychotics restore PPI in adult rats treated with DA agonists such as apomorphine (APO), while clinically "atypical" antipsychotics restore PPI in rats treated with NMDA antagonists such as phencyclidine (PCP). We previously reported that the PPI disruptive effects of both APO and PCP are evident in 16- to 18-day-old rat pups, suggesting that the brain substrates for these effects are functional very early in development.In the present study we assessed the developmental patterns of antipsychotic effects in these measures.The PPI-disruptive effects of APO and PCP, and their antagonism by the typical antipsychotic haloperidol, and the atypical antipsychotic quetiapine, were assessed across development in Sprague-Dawley rats.Similar to the pattern seen in adults, both haloperidol and quetiapine opposed APO-induced PPI deficits in 16- to 19-day-old rat pups. However, the "atypical" antipsychotic quetiapine did not oppose PCP-induced PPI deficits in pups or prepubertal (45 day) adolescents, but did oppose these PCP effects in postpubertal rats.While brain substrates mediating the PPI-disruptive effects of DA agonists and NMDA antagonists are functional early in development, some physiological event associated with puberty is a necessary condition for the "atypical antipsychotic profile" in this predictive model.