Effects Of Apomorphine In Rats Research Articles

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats.

Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague-Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. The effects of APO (vehicle vs. 0.5mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5mg/kg) 20min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically. APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R = 0.49). A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.

Hippocampal lesions enhance startle gating-disruptive effects of apomorphine in rats: a parametric assessment

Prepulse inhibition of the startle reflex is an operational measure of sensorimotor gating that is impaired in schizophrenia patients and dopamine agonist-treated rats. Previous reports demonstrated an enhanced sensitivity to the prepulse inhibition-disruptive effects of the D 1/D 2 agonist apomorphine in adult rats four weeks after cytotoxic lesions of the hippocampus, but left unanswered several important questions regarding the nature of this apparent lesion-induced dopamine supersensitivity. Because of the potential importance of this model to current theories of the pathophysiology of schizophrenia, studies now assessed specific features of this effect of hippocampus lesions on prepulse inhibition in rats. The enhanced prepulse inhibition-disruptive effects of apomorphine in ventral hippocampus-lesioned rats were unaffected by startle pulse intensity, suggesting an independence of this lesion effect from potential ceiling effects of elevated startle magnitude. These lesion effects were observed four weeks post-lesion, but not two weeks post-lesion, suggesting a delayed development of this phenomenon. No enhancement of apomorphine sensitivity was observed in rats four weeks after lesions restricted to the dorsal hippocampus; in contrast, these lesions significantly increased “no-drug” levels of prepulse inhibition. Ventral hippocampus-lesioned rats exhibited a significant reduction in prepulse inhibition after subthreshold doses of either the selective D 2-family agonist quinpirole or the partial D 1 agonist SKF 38393, suggesting that activation of either receptor family is adequate for the expression of this effect of ventral hippocampus lesions. This may be an important paradigm for understanding the contribution of ventral hippocampus dysfunction to the neurobiology of impaired sensorimotor gating in neuropsychiatric populations.

Effect of the D1 receptor agonist SKF 38393 on some behavioural effects of apomorphine in rats

The dopamine receptor agonist apomorphine in experiments on rats in low doses (0.025-0.2 mg/kg, s.c.) induced yawning which reflected a selective activation of presynaptic dopamine receptors. In high doses (0.25-1.0 mg/kg) apomorphine induced stereotyped sniffing and yawning in consequence of postsynaptic D2 receptor activation. Dopamine D1 receptor agonist SKF 38393 inhibited yawning induced by low doses of apomorphine. The inhibitory effect of SKF 38393 on apomorphine-induced yawning was attenuated by pretreatment with specific D1 receptor antagonist SCH 23390 [2-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol). On the other hand however, SKF 38393 potentiated sniffing induced by the high doses of apomorphine without affecting gnawing. These data indicate that D1 receptor activation modulates both pre- and postsynaptic effects of apomorphine in opposite directions.

Chapter 8 A novel rotational behavior model for assessing the restructuring of striatal dopamine effector systems: are transplants sensitive to peripherally acting drugs?

Publisher Summary This chapter discusses the effects on apomorphine-induced turning behavior of rat fetal striatal tissue transplants into the lesioned striatum, and determines whether fetal striatal grafts might also possess a non-intact blood-brain barrier and permit the entry of drugs into the brain, which normally do not penetrate the blood-brain barrier, and therefore, are without central actions. The data presented in the chapter may indicate that the transplanted material possesses similar pharmacological properties as the original host tissue, and is capable of functionally restructuring damage to a complex neurochemical system. Domperidone, a dopamine receptor antagonist, which does not readily cross the bloodbrain barrier, significantly attenuated the behavioral effects of apomorphine in rats, which had received bilateral transplants of rat fetal striatal tissue into unlesioned striata prior to challenge with apomorphine. Thus, the transplants appeared to allow access to the brain of a drug, which normally acts in the periphery, and it is suggested that other therapeutic agents may be allowed site-selective entry into the brain via transplanted tissue.

IX. Neurochemical and functional consequences following 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and methamphetamine

The neurochemical and functional consequences following MPTP administration to the rat were evaluated and compared to similar effects following methamphetamine administration. It was observed that MPTP induced long lasting depletions of striatal dopamine concentrations and this neurotoxic effect could be prevented by pargyline pretreatment. The MPTP-induced neuronal damage produced a tolerance to the disruptive effects of amphetamine and a supersentivitity to the disruptive effects of apomorphine in rats responding in a schedule controlled paradigm. Methamphetamine, like MPTP, produced depletions of striatal dopamine but these actions were potentiated by pargyline pretreatment. These observations are discussed in reference to possible deleterious effects following the administration of pargyline to patients with Parkinson's Disease.

A caerulein-sensitive potentiation of the behavioral effects of apomorphine by dibutyryl-cAMP

The dopaminergic behavioral effects of apomorphine in rats were evaluated using a rating scale. Caerulein, a decapeptide physiologically similar to cholecystokinin, enhanced at lower doses and inhibited at higher doses the behaviors induced by apomorphine. Dibutyryl-cAMP, but not dibutyryl-cGMP, potentiated apomorphine behaviors. The potentiation was inhibited by a high dose of caerulein. These data provide evidence for an opposing effect of cAMP and caerulein or cholecystokinin in modulating dopaminergic systems.

Effect of benactyzine and galanthamine on behavioral effects of apomorphine in rats

Effect of benactyzine and galanthamine on behavioral effects of apomorphine in rats

Influence of midbrain raphe lession on some pharmacological and biochemical effects of apomorphine in rats.

The influence of apomorphine on body temperature, motor activity and forebrain content of serotonin and 5-hydroxyindoleacetic acid in midbrain raphe lesioned rats was investigated. Apomorphine elevates the brain concentration of serotonin and its metabolite and promotes hypothermia in normal and in sham-lesioned rats but it does not produce these biochemical effects and attenuates hypothermia in rats with lesions of the midbrain raphe nuclei. In the lesioned subjects apomorphine stimulates the locomotor activity more strongly. The results confirm the previously expressed hypothesis concerning the role of serotonin in the locomotor stimulation and hypothermia induced by apomorphine in rats.