Startle and sensorimotor gating in rats lacking CCK-A receptors.
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Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics. (+info)
The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist.
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The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. (+info)
Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats.
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The basolateral complex of the amygdala (BLA) plays a significant role in affective behavior that is likely regulated by afferents from the medial prefrontal cortex (mPFC). Studies suggest that dopamine (DA) is a necessary component for production of appropriate affective responses. In this study, prefrontal cortical and sensory cortical [temporal area 3 (Te3)] inputs to the BLA and their modulation by DA receptor activation was examined using in vivo single-unit extracellular recordings. We found that Te3 inputs are more capable of driving BLA projection neuron firing, whereas mPFC inputs potently elicited firing from BLA interneurons. Moreover, mPFC stimulation before Te3 stimulation attenuated the probability of Te3-evoked spikes in BLA projection neurons, possibly via activation of inhibitory interneurons. DA receptor activation by apomorphine attenuated mPFC inputs, while augmenting Te3 inputs. Additionally, DA receptor activation suppressed mPFC-induced inhibition of Te3-evoked spikes. Thus, the mPFC may attenuate sensory-driven amygdala-mediated affective responses via recruitment of BLA inhibitory interneurons that suppress sensory cortical inputs. In situations of enhanced DA levels in the BLA, such as during stress and after amphetamine administration, mPFC regulation of BLA will be dampened, leading to a disinhibition of sensory-driven affective responses. (+info)
The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.
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1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism. (+info)
Hypothermic action of bromocriptine.
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The body temperature of rats has been studied in a cold environment. In this setting, bromocriptine induced hypothermia. This fall in core temperature was inhibited by pimozide. It was concluded that bromocriptine has a dopamine-like action in areas of the brain concerned with the control of body temperature, as has previously been shown for apomorphine and amphetamine. (+info)
Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?
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The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis. (+info)
Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine.
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Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral sparing, these animals showed remarkable sparing of striatal DA, its metabolites, and the expression of the vesicular monoamine transporter, suggesting a decrease in the extent of DA neuron degeneration. Behavioral and neurochemical sparing appeared to be complete when the 7 d period of immobilization was initiated immediately after 6-OHDA infusion, only partial sparing was evident when immobilization was initiated 3 d postoperatively, and no sparing was detected when immobilization was initiated 7 d after 6-OHDA treatment. These results suggest that physical therapy may be beneficial in Parkinson's disease. (+info)
Effect of olanzapine on functional responses from sensitized D1-dopamine receptors in rats with neonatal dopamine loss.
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Previous work has suggested that the therapeutic efficacy of olanzapine might be partially dependent on action at the D(1)-dopamine (DA) receptor site. Because early DA loss can lead to supersensitive D(1)-DA receptors, effects of olanzapine were investigated in adult rats given lesions to DA-containing neurons as neonates. In these animals, locomotor effects of SKF-38393 (a D(1)-DA agonist) were attenuated by olanzapine, but at doses (5 and 10 mg/kg) that decreased activity when given alone. Olanzapine prevented induction of striatal Fos protein by SKF-38393 and partially attenuated the long-term "priming" effect of repeated SKF-38393 treatment. Olanzapine also antagonized the stimulant effects of quinpirole (a D(2)-type DA agonist) in animals lesioned as young adults, at doses lower than those necessary to antagonize SKF-38393-induced activity. In addition, olanzapine antagonized apomorphine-induced self-injurious behavior in neonate-lesioned rats in a dose-related fashion. Attenuation of self-injury in this animal model suggests that olanzapine should be tested against this symptom in patient populations. (+info)