Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [11 C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for ϳ3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (Ϫ23 and Ϫ24%, respectively) and putamen (Ϫ25 and Ϫ16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
Greater putamen dopamine release was seen in adults with Tourette's syndrome than in comparison subjects after a pharmacologic challenge with amphetamine. These results suggest that the underlying pathobiology in Tourette's syndrome is a phasic dysfunction of dopamine transmission.
Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To Several neurodevelopmental disorders are thought to involve the neuropathology of the basal ganglia. Among them, the best known are Lesch-Nyhan disease (LND) and Rett syndrome. In both of these conditions, there is evidence for the dysfunction of the dopaminergic neurotransmission.LND is an X-chromosome-linked disease with infantile onset characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury (1). The underlying defect is a near absence of hypoxanthine-guanine phosphoribosyl transferase (HPRT) (2), an enzyme that is normally present in the brain in greater amounts than in other organs. Three lines of evidence suggest that HPRT deficiency is linked to abnormal dopamine (DA) function in LND: (i) an autopsy study of three LND subjects demonstrated a marked reduction in the DA content and in the activity of DA-synthesizing enzymes in the caudate and putamen (3); (ii) when neonatal rats are depleted of DA with the neurotoxin 6-hydroxydopamine, self-injurious behavior (similar to that seen in LND) occurs when the rats are challenged with 3,4-dihydroxyphenylalanine (L-dopa) as adults (4, 5); and (iii) in an HPRT-deficient mutant mouse strain, there is a reduction of striatal tyrosine hydroxylase and in the number of striatal dopamine transporters measured with 3H-N-[1-(2-benzo(,B)thiophenyl) cyclohexyl]piperidine (3H-BTCP) (6). The pertinence of the loss of brain DA in LND has been questioned due to the limited scope of the autopsy study and the fact that the HPRT-deficient mouse study showed only a modest reduction of DA with no self-injury, or other clinical symptoms of LND (6). Therefore the question of dopamine reduction in vivo remains unresolved.The availability of positron emission tomography (PET) ligands that bind to pre-or postsynaptic DA sites has made it possible to study the DA system in vivo in patients affected with disorders that involve the basal ganglia. For example, the DA transporter probe ,3-carbomethoxy-3,3-4-fluorophenyl-tropane (CFT; WIN-35,428) (7-11) has been used to detect the degeneration of DA nerve terminals in adult humans (12,13). It has also been used to measure the degeneration of nerve terminals in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in idiopathic Parkinson disease (14-16). In addition, 428 is suitable for evaluating the integrity of DAcontaining neurons in neurodevelopmental disorders.In the present investigation, the hypothesis-that HPRT deficiency in LND is associated with impaired development of dopaminergic projections to the striatum-was tested by determining the number of DA transporters in vivo by using PET with the radiolabeled DA transporter ligand 428. The measurement of the presynaptic DA sites of 428 using PET provides a relevant assessment of the degree of dopaminergic deficiency in LND.The binding of [1...
GBR12909 (GBR) is a high-affinity, selective, and long-acting inhibitor of dopamine (DA) uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA in the nucleus accumbens of rats. Prior studies showed that intravenous infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR that reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and positron emission tomography (PET). Each baboon underwent paired control/blocked PET scans (performed on three separate study days, 3-4 weeks apart). On the first scan the baboon received saline (3 ml/kg) 90 minutes before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes before the second [11C]WIN 35,428 study. The same experimental design was repeated with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 mg/kg (n = 2), and 10 mg/kg (n = 2) reduced binding potential by 26, 53, and 72%, respectively. GBR was well tolerated in all baboons. These results demonstrate that doses of GBR that suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. These data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that experimental human studies of orally administered GBR to test the DA hypothesis of cocaine addiction should use doses that produce at least 70% occupancy of the DA transporter.
Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.
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