In vivo binding of N-n-propylnorapomorphine in the rat brain: Regional localization, quantification in striatum and lack of correlation with dopamine metabolism

doi:10.1016/0014-2999(83)90336-9

European Journal of Pharmacology

Volume 87, Issues 2–3, 18 February 1983, Pages 259-270

https://doi.org/10.1016/0014-2999(83)90336-9 Get rights and content

Abstract

The accumulation and retention of radioactivity in rat brain were studied after intravenous injection of the dopamine (DA) agonist [³H]N-n-propylnorapomorphine ([³H]NPA). Dose-dependent saturable accumulation of label was found in the striatum, nucleus accumbens and olfactory tubercle. DA agonists (apomorphine, N,N-dipropyl-5,6-ADTN) and antagonists (haloperidol, cis-flupenthixol) prevented this accumulation. Enhanced accumulation of radioactivity in the striatum was found after 6-OHDA lesions and short- and long-term treatment with reserpine. These results are an indication of specific NPA binding to presumably postsynaptically situated DA receptors. One hour after administration of the drug, the effect of NPA on striatal DA metabolism was not correlated with receptor saturation. Maximal numbers of in vivo NPA binding sites (about 30 and 22 pmol · g⁻¹) in striatal tissue were calculated from independent measurements at 15 and 60 min after NPA injection. Regional distribution of radioactivity after a tracer dose of [³H]NPA was assessed in 35 brain areas and parts of the spinal cord. In addition to the already mentioned DA-rich areas receptor-specific NPA binding was also found in several other brain parts.

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The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D_2,3 partial agonist (R)-N- [1-¹¹C]n-propylnorapomorphine ([¹¹C]NPA). The uptake of this tracer in brain of anesthetized Göttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [¹¹C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g⁻¹ min⁻¹ and an apparent distribution volume of 6 ml g⁻¹ in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [¹¹C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [¹¹C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.
The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies
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Citation Excerpt :
Reduced in vivo accumulation of D2 tracers were also reported following pretreatment with the DA uptake inhibitors amfonelic acid and methylphenidate [129]. The opposite effect (i.e., increased tracer accumulation) was induced by drugs that decrease DA endogenous concentration such as reserpine and γ-butyrolactone [127, 129, 136, 149, 162]. The development of PET and SPECT neuroreceptor imaging provided a tool for noninvasive measurements of these interactions.
Long-term sensitization is a process whereby exposure to a given stimulus such as a drug or a stressor results in an enhanced response at subsequent exposures. Sensitization of mesolimbic dopamine systems has been postulated by several authors to underlie the development of dopaminergic abnormalities associated with schizophrenia. In this review, core features of stimulant-induced sensitization of dopamine systems in rodents are briefly reviewed, as well as the behavioral and clinical evidence suggesting the relevance of this process to drug-induced psychosis and schizophrenia. Results of recent brain imaging studies relevant to the question of sensitization in schizophrenia are then discussed. These studies indicate that schizophrenia is associated with increased amphetamine-induced dopamine release. This exaggerated response was detected in patients experiencing an episode of clinical deterioration but not in clinically stable patients. Since increased stimulant-induced dopamine release is a hallmark of sensitization, these results support the view that schizophrenia is associated with a process of endogenous sensitization. Based on the preclinical evidence that dopamine projection to the prefrontal cortex acts as a buffer that oppose the development of sensitization in subcortical dopamine projections, we propose that, in schizophrenia, neurodevelopmental abnormalities of prefrontal dopaminergic systems might result in a state of enhanced vulnerability to sensitization during late adolescence and early adulthood. It is also proposed that D₂ receptor blockade, if sustained, might allow for an extinction of this sensitization process, with possible re-emergence upon treatment discontinuation. A better understanding of the neurocircuitry associated with endogenous sensitization and its consequence in schizophrenia might be important for the development of better treatment and relapse prevention strategies.
(-)-N-[<sup>11</sup>C]propyl-norapomorphine: A positron-labeled dopamine agonist for PET imaging of D<inf>2</inf> receptors
2000, Nuclear Medicine and Biology
Imaging neuroreceptors with radiolabeled agonists might provide valuable information on the in vivo agonist affinity states of receptors of interest. We report here the radiosynthesis, biodistribution in rodents, and imaging studies in baboons of [¹¹C]-labeled (−)-N-propyl-norapomorphine [(−)-NPA]. (−)-[¹¹C]NPA was prepared by reacting norapomorphine with [¹¹C]propionyl chloride and a lithium aluminum hydride reduction. [¹¹C]Propionyl chloride was prepared by reacting [¹¹C]CO₂ with ethylmagnesium bromide, followed by reacting with phthaloyl chloride. The radiochemical yield of (−)-[¹¹C]NPA was 2.5% at end of synthesis (EOS), and the synthesis time was 60 min. The specific activity was 1700±1900 mCi/μmol ( N=7; ranged 110–5200 mCi/μmol at EOS). Rodent biodistribution studies showed high uptake of [¹¹C](−)-NPA in D₂ receptor-rich areas, and the striatum/cerebellum ratios were 1.7, 3.4, and 4.4 at 5 min, 30 min, and 60 min postinjection, respectively. Pretreating the animals with haloperidol (1 mg/kg) decreased the striatum/cerebellum ratio at 30 min postinjection to 1.3. (−)-[¹¹C]NPA was also evaluated via baboon positron emission tomography (PET) studies. Under control conditions ( N=4), rapid uptake of the tracer was observed and the striatum/cerebellum ratio reached 2.86±0.15 at 45 min postinjection. Following haloperidol pretreatment (0.2 mg/kg IV), the striatum/cerebellum ratio was 1.29 at 45 min postinjection. The result demonstrated the existence of specific binding of this new tracer to the D₂ receptor. To our knowledge, the current finding of a striatum/cerebellum ratio of 2.8 in baboon was the highest reported with a radiolabeled D₂ agonist. (−)-[¹¹C]NPA is a promising new D₂ agonist PET tracer for probing D₂ receptors in vivo using PET.
Increased dopamine transmission in schizophrenia: relationship to illness phases
1999, Biological Psychiatry
Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified.
Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question.
Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase.
Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.
Imaging D<inf>2</inf> receptor occupancy by endogenous dopamine in humans
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The impact of endogenous dopamine on in vivo measurement of D₂ receptors in humans was evaluated with single photon emission computerized tomography (SPECT), by comparing the binding potential (BP) of the selective D₂ radiotracer [¹²³I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of 1 g every six hours for two days. AMPT increased [¹²³I]IBZM BP by 28 ± 16% (±SD, n = 9). Experiments in rodents suggested that this effect was due to removal of endogenous dopamine rather than D₂ receptor upregulation. Synaptic dopamine concentration was estimated as 45 ± 25 nM, in agreement with values reported in rodents. The amplitude and the variability of the AMPT effect suggested that competition by endogenous dopamine introduces a significant error in measurement of D₂ receptors in vivo with positron emission tomography (PET) or SPECT. However, these results also imply that D₂ receptor imaging coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration in the living human brain.
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During 12-week haloperidol treatment of rats, the cataleptic effect of an additional challenge dose becomes gradually weaker. We studied whether such a tolerance phenomenon is related to receptor supersensitivity—thus leaving more spare receptors—to a shift in affinity of the receptors towards agonist binding or to an attenuation of a postsynaptic response to dopamine (D₂-type) receptor blockade in the rat basal ganglia. Receptor occupancy was studied with the radioactive agonist [³H]N-propylapomorphine (NPA) and antagonist [³H]N-methylspiperone (MSPIP) to label free dopamine D₂ receptors in vivo. Fos protein served as an index of the postsynaptic response, which was histochemically quantified. This study does not support the concept that dopamine receptor supersensitivity may overcome neuroleptic receptor blockade, but there may be a shift towards higher agonist binding over time. The attenuation of Fos protein expression in the basal ganglia precedes the development of behavioral tolerance.

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In vivo binding of N-n-propylnorapomorphine in the rat brain: Regional localization, quantification in striatum and lack of correlation with dopamine metabolism

Abstract

Brain Res.

Life Sci.

European J. Pharmacol.

European J. Pharmacol.

Int. J. Appl. Radiat. Isotop.

Brain Res.

European J. Pharmacol.

Life Sci.

Life Sci.

Biochem. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Brain Res.

Brain Res.