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PubMed2003

Dopamine depletion abolishes apomorphine- and amphetamine-induced increases in extracellular serotonin levels in the striatum of conscious rats: a microdialysis study.

We investigated how serotonergic neurotransmission was affected by 6-hydroxydopamine (6-OHDA) lesioning of the adult rat brain dopamine (DA) system. In this animal model for Parkinson's disease (PD), the effect of destroying ascending DA pathways on extracellular levels of serotonin (5-HT) and 5-HT innervation in rat striatum were examined. Profound unilateral lesions of the nigrostriatal DA pathways were made by infusing 6-OHDA unilaterally into either the right medial forebrain bundle or the right substantia nigra. At 5 weeks after lesioning extracellular levels of DA and 5-HT were determined with microdialysis and high-pressure liquid chromatography under basal conditions and after systemic injections of apomorphine or amphetamine. DA nerve-terminal destruction and 5-HT innervation were determined with quantitative autoradiography. 6-OHDA lesioning reduced extracellular levels of DA below detection limits and led to statistically significant increases in extracellular 5-HT. Apomorphine, and amphetamine, respectively increased extracellular 5-HT to 8.2- and 2.2-fold above baseline levels in intact animals; these effects were absent in 6-OHDA-lesioned animals. Basal levels of [(3)H]paroxetine binding to 5-HT transporters in caudate-putamen increased by 41% in 6-OHDA-lesioned animals. These results suggest that 6-OHDA lesioning led to hyperinnervation of 5-HT nerve terminals and increases in basal extracellular 5-HT levels, but also to an unexplained loss of apomorphine and amphetamine-induced release of 5-HT. Addressing whether this impairment has significance in the onset of PD might lead to development of new strategies to manage parkinsonian symptoms.

Afferent Pathways↗

PubMed1999

Dissociative effects of apomorphine infusions into the medial prefrontal cortex of rats on latent inhibition, prepulse inhibition and amphetamine-induced locomotion.

Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition and latent inhibition. The present study investigated, in rats, the effects of increasing dopamine receptor activation within the medial prefrontal cortex by local administration of the dopamine receptor agonist apomorphine (9 microg/side) on prepulse inhibition and latent inhibition, as well as on spontaneous and amphetamine-induced activity. Apomorphine infusions decreased spontaneous locomotor activity and blocked amphetamine-induced increase in locomotor activity in the open field, which is in line with the suggestion that dopamine receptor activation in the medial prefrontal cortex inhibits mesolimbic dopamine activity. However, apomorphine infusions induced a disruption of prepulse inhibition, an effect associated with increased dopaminergic activity in the nucleus accumbens, and left the latent inhibition effect intact. While these results support previous evidence that the medial prefrontal cortex is a component of the neural circuitry mediating prepulse inhibition but plays no role in latent inhibition, they show that dopamine receptor activation in the medial prefrontal cortex of the rat produces behavioural outcomes that cannot be explained by postulating a simple reciprocal relationship between the mesocortical and mesolimbic dopamine systems.

Amphetamine↗

PubMed2000

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.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1982

Selected ion monitoring of apomorphine in whole rat brain.

Mass fragmentography was used for quantitation of apomorphine in whole rat brain. Following extraction with 0.45 N perchloric acid, the components were derivatized to the O,O-bis(trimethylsilyl) (TMS) derivatives with N,O-bis(trimethylsilyl)trifluoroacetamide at 30 degrees C. The molecular ions of the TMS derivatives of apomorphine (m/z 411) and N-n-propylnorapomorphine (m/z 439), as an internal standard, were assayed simultaneously by selected ion monitoring. Total chromatography time is 5 min. By this method 50 ng/ml can be determined with a coefficient of variation of 12.0%. Application of the method to apomorphine disposition study in whole rat brain was demonstrated.

Animals↗

PubMed1999

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).

Absorption↗

PubMed1998

Increased cortical inhibition induced by apomorphine in patients with Parkinson's disease.

The electromyographic silent period following the motor potential evoked by cortical magnetic stimulation is decreased in parkinsonian patients. In this study we investigated whether the decrease in the silent period is connected only with parkinsonian symptoms. We evaluated the effect of apomorphine (a potent and rapid dopamine-agonist) on the changes in the peripheral and central silent period in 29 patients with Parkinson's disease and in two patients affected by multisystem atrophy (MSA). Apomorphine injection was found to induce a significant improvement in the central silent period in parkinsonian patients but not in the MSA patients, suggesting a relation between the clinical parkinsonian symptoms (akinesia and rigidity) and the silent period duration. The central silent period changes after apomorphine injection could be used as an adjunctive, safe and effective diagnostic tool to assess dopamine responsiveness of parkinsonian syndromes.

Aged↗

PubMed2002

Oxidative behaviour of apomorphine and its metabolites.

The metabolism of apomorphine is quite complex due to interactions with proteins and other tissue components that affect its pharmacokinetic profile. The electrochemical oxidation mechanism of apomorphine and of some synthesised apomorphine derivatives was studied. It was found to be related to the reaction of o-diphenol and tertiary amine groups and strongly dependent on pH.

Apomorphine↗

PubMed1990

Interaction between recovery from behavioral asymmetries induced by hemivibrissotomy in the rat and the effects of apomorphine and amphetamine.

Spontaneous and drug-induced turning behavior and thigmotactic scanning were tested either acutely (4-6 hr) or chronically (9 days) after unilateral removal of vibrissae in rats. Rats that were tested acutely scanned more with the intact vibrissae side. This asymmetry was reduced in rats that were tested chronically, indicating behavioral recovery. The indirect dopamine agonist amphetamine induced a reversed asymmetry after 9 days because the animals then scanned more with the side lacking the vibrissae. Postsynaptic doses of apomorphine administered to acutely tested rats induced more scanning with, and more turning toward, the intact vibrissae side. A negative correlation was found in the chronically tested rats between the asymmetry in spontaneous scanning and the asymmetry after apomorphine. Nonrecovered rats showed indications of a reversal after apomorphine. The results are discussed in relation to mechanisms of neural plasticity in the basal ganglia, such as receptor supersensitivity and changes in nigrostriatal afferents.

Amphetamine↗

PubMed1985

Stereotyped behavior and diabetes mellitus in rats: reduced behavioral effects of amphetamine and apomorphine and reduced in vivo brain binding of [3H]spiroperidol.

Rats made diabetic with streptozotocin showed decreased stereotyped behaviors following administration of amphetamine or apomorphine. Spontaneous activity in an open field was lower in diabetics than in controls, but a low dose of apomorphine produced equivalent fractional decreases in activity in both groups. In vivo accumulation of amphetamine and apomorphine was generally similar in both groups: Reduced tissue access did not appear to be responsible for the decreased behavioral effects of these agents. The in vivo accumulation of spiroperidol in several brain regions was generally less in diabetics than in controls. These data are discussed in terms of altered catecholamine biochemistry and behavior in diabetics.

Animals↗

PubMed2004

Behavioral sensitization to apomorphine in pigeons (Columba livia): blockade by the D1 dopamine antagonist SCH-23390.

Repeated administration of apomorphine leads to a context-dependent pecking response sensitization. Previously sensitized pigeons (Columba livia) challenged with saline in the same context show a conditioned response (CR). The authors studied the effects of intrastriatal injections of the dopamine (D(1)) antagonist SCH-23390 on both the sensitized response and the CR. When coadministered with apomorphine, SCH-23390 inhibited the initial response to apomorphine, prevented the development of sensitization, and impaired the maintenance of an already developed sensitization. However, SCH-23390 had no effect on the retrieval of a previously established CR. It is concluded that the activation of D(1) receptors in the caudal avian striatum is necessary for the acquisition and maintenance of the sensitization, but not for the expression, of the CR.

Animals↗

PubMed1980

3H-apomorphine labels both dopamine postsynaptic receptors and autoreceptors.

Evidence points to the existence of multiple classes of dopamine (DA) receptor in mammalian brain which can be distinguished by their pharmacological specificities and localizations, and by the actions they mediate. Among them, dopaminergic autoreceptors are regulatory receptors presumed to be present in the membrane of the DA neurones themselves, and believed to mediate an inhibition of these neurones' activity, either at nerve endings or on cell bodies. However, the pharmacology of autoreceptors remains to be established because attempts to characterize autoreceptors by 3H-ligand binding techniques have produced controversial data. Thus Seeman and co-workers stated that 3H-apomorphine selectively labels autoreceptors, whereas Creese et al. concluded that this ligand selectively labels postsynaptic DA receptors. In addition, large differences in the capacity and drug specificity of 3H-apomorphine receptor sites in rat striatum have been reported. We demonstrate here that 3H-apomorphine labels two classes of DA receptor, distinguishable using domperidone, a selective DA antagonist. Lesion studies indicate that they correspond to a certain class of postsynaptic receptor and to autoreceptors, respectively. Each of these classes displays a clearly distinct pharmacological specificity for antipsychotics and DA agonists.

Apomorphine↗

PubMed1981

Alterations in local cerebral glucose utilisation in specific thalamic nuclei following apomorphine.

The alterations in local cerebral glucose utilisation in eight discrete nuclei in the thalamus following the administration of apomorphine (0.5 mg kg-1) have been investigated with the autoradiographic 2-deoxyglucose technique in 11 conscious rats. In two thalamic nuclei (parafascicular and ventrolateral nuclei), glucose utilisation was significantly elevated following apomorphine; in two thalamic nuclei (the anterior medial and anterior ventral nuclei), glucose utilisation was significantly reduced following apomorphine; and in four nuclei (lateral geniculate, medial geniculate, mediodorsal, and lateral thalamic nuclei), glucose use was unchanged.

Animals↗

PubMed2003

Apomorphine enhances conditioned responses induced by aversive stimulation of the inferior colliculus.

Consistent evidence has shown that learning may be produced in paradigms using electrical stimulation of the inferior colliculus (IC) as unconditioned stimulus (UCS). Recent reports have also demonstrated that aversive stimulation of the IC, at the escape threshold, enhances dopamine (DA) release in the prefrontal cortex. The purpose of the present study was to determine whether dopaminergic mechanisms are involved in the Pavlovian conditioning and latent inhibition using IC stimulation as UCS and light as conditioned stimulus (CS). Rats were placed inside a shuttle box and subjected to a two-way avoidance paradigm. IC aversive electrical stimulation was used as UCS and shuttle box illumination as CS. The rats quickly learned to avoid or interrupt the IC stimulation. Apomorphine injections produced a dose-dependent increase in the number of avoidance responses. On the other hand, chlorpromazine administration promoted a dose-dependent reduction of the avoidance responses. Previous injections of chlorpromazine inhibited the effects of apomorphine. Also, previous exposure to unreinforced light weakened the strength of the conditioning. Apomorphine blocked this latent inhibition effect, which was antagonized by previous injections of chlorpromazine. These findings bring evidence for the involvement of DA in the setting up of adaptive responses to aversive states generated at the IC level, which may underlie stressful situations present in anxiety.

Animals↗

PubMed2003

Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH x WH cross, and subsequent offspring (N2) of an SDH x F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.

Animals↗

PubMed1996

Neonatal maternally deprived rats have as adults elevated basal pituitary-adrenal activity and enhanced susceptibility to apomorphine.

Maternal deprivation of neonatal rats for 24 h enhances the adrenocortical response to stress and/or adrenocorticotropin hormone (ACTH) stimulation during the stress hyporesponsive period (SHRP). The present study tests the hypothesis that such maternally deprived neonatal male rats show altered hypothalamic-pituitary-adrenal (HPA) regulation not only immediately after deprivation but also in later life. In addition, we found previously that neonatal changes in HPA activity preceded modulation of nigrostriatal dopamine function. Therefore, we also measured dopamine responsiveness in adult rats which were deprived of their mother during infancy. Neonatal male rats were maternally deprived for 24 h at the age of 3 days, whereas rats of the control group were left undisturbed. At 60 days of age deprived and non-deprived rats were decapitated and brain, adrenal glands and thymus were removed. Trunk blood was collected for determination of plasma ACTH, corticosterone and prolactin concentrations using radioimmunoassay procedures. mRNA levels of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), corticotropin-releasing hormone (CRH) mRNA and tyrosine hydroxylase (TH) mRNA were measured in brain sections with in situ hybridization. In a second group of male deprived and non-deprived rats apomorphine-induced stereotypic gnawing behaviour was examined at 60 days of age as a measure for functional activity of the dopamine system. Deprived neonatal rats showed the following characteristics as compared with non-deprived rats: (i) lower basal CRH mRNA concentration in parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVN), while basal plasma ACTH and corticosterone concentrations were significantly elevated. Basal prolactin levels were not different. (ii) Similar hippocampal MR and GR mRNA levels. (iii) Significantly reduced GR mRNA levels in PVN and anterior pituitary. (iv) Significantly enhanced apomorphine-induced stereotypic gnawing behaviour and (v) higher TH mRNA levels in substantia nigra, while no changes were found in the ventral tegmental area (VTA). It is concluded that maternally deprived neonatal male rats display as young adults elevated basal pituitary-adrenal activity and enhanced apomorphine susceptibility.

Animals↗

PubMed1976

Dopamine receptors in human and calf brains, using [3H]apomorphine and an antipsychotic drug.

In order to develop a better dopamine receptor radioligand, [3H[apomorphine was prepared and tested for dopamine-like binding properties in both calf and human brain tissues. Specific binding of [3H]apomorphine was defined as that binding which occurred in the presence of 1 muM (-)-butaclamol (an inactive neuroleptic) minus that occurring in the presence of 1 muM (+)-butaclamol (active neuroleptic). The specific binding was saturable, the number of sites being double that of specific [3H]dopamine binding, and occurred primarily in dopamine-rich regions of postmortem human brains. The binding had a dissociation constant of 0.9 nM for human caudate (2 nM for calf caudate) and was blocked by dopamine and norepinephrine, but not by isoproterenol or (-)-propranolol, distinguishing it from a beta-adrenergic receptor. Since there was little desorption of [3H]apomorphine, the ligand permits extensive washing during routine assays for dopamine receptors, and facilitates biochemical purification of the receptor.

Affinity Labels↗

PubMedDate not supplied

Protection by apomorphine in two independent models of acute inhibition of oxidative metabolism in rodents.

Apomorphine was administered by continuous infusion in the mouse following acute inhibition of oxidative metabolism induced by systemic administration of MPTP, and in the gerbil following transient occlusion of the carotid arteries. The dosage employed was comparable to the one used in the treatment of severe on-off fluctuations in Parkinson's disease. The results show that apomorphine significantly diminishes the striatal lesion caused by MPTP and the size of the infarct associated with the transient global ischemia. These data suggest that apomorphine is neuroprotective, probably by means of an antioxidant effect, at doses that are clinically used. The finding may be relevant to brain ischemia as well to chronic neurodegeneration.

Animals↗

PubMed2003

Neuroprotective, anti-apoptotic effects of apomorphine.

There is increasing experimental and clinical evidence that oxidation plays a pivotal role in causing neurodegeneration in general and Parkinson's disease in particular. The protective role of antioxidants in such conditions has not been fully examined, but certain neuroprotective agents that have antioxidant action are now being credited with an ability to prevent oxidation-induced neuronal dysfunction. One such agent is the dopamine agonist apomorphine, which is already in clinical use, providing symptomatic relief in Parkinson's disease patients. Far from having simple antioxidants properties, apomorphine is described as a pluripotent agent that can also afford neuroprotection through mechanisms independent of its antioxidant actions. It can, for example, salvage dopaminergic receptors and terminals, upregulate expression of neurotrophic factors, limit the rate of neuronal loss by interfering with several steps of apoptotic cascades, reduce excitotoxicity by modulating nitric oxide metabolism, and reverse ubiquitine-proteasome dependent pathology. This paper reviews the wide range of apomorphine's neuroprotective benefits, suggesting that it is a promising agent with regards to its potential to prevent, reduce, and retard age-related neurodegeneration.

Antiparkinson Agents↗