Comparison between dopamine transporter affinity and self-administration potency of local anesthetics in rhesus monkeys
ABSTRACT Local anesthetics bind to dopamine transporters and inhibit dopamine uptake in rodent brain. Additionally, local anesthetics are self-administered in rhesus monkeys. The present study determined binding affinities of cocaine and five local anesthetics at dopamine transporters in rhesus monkey brain, and compared binding affinities to published self-administration potencies in rhesus monkeys. The affinity order at dopamine transporters was cocaine > dimethocaine > tetracaine > procaine > or = chloroprocaine > lidocaine. The correlation between dopamine transporter affinities and self-administration potencies was significant. Binding affinities were also determined at sodium (Na2+) channels in rhesus monkey brain. There was not a significant correlation between Na2+ channel affinities and self-administration potencies Local anesthetics with high dopamine transporter and low Na2+ channel affinities were self-administered, whereas those with either high or low affinity at both sites were not consistently self-administered. These data suggest that affinity at dopamine transporters is related to the reinforcing effects of local anesthetics in rhesus monkeys, and Na2+ channel effects may interfere with the reinforcing effect of these drugs.
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- "A goal of this study was to assess the regulation of high-and low-affinity DAT sites by chronic cocaine self-administration. The affinity of psychostimulants for DAT is positively correlated with the behavioral potency of those compounds in in rodents and nonhuman primates (Bergman et al., 1989; Ritz et al., 1987; Wilcox et al., 1999). However, some drugs that bind to DAT with high-affinity are not efficacious as cocaine in terms of behavioral stimulation, are weak positive reinforcers compared to cocaine (Stafford et al., 2001; Tella et al., 1996; Wilcox et al., 2000; Woolverton et al., 2001) and do not share subjective effects with cocaine (Katz et al., 1999; Newman et al., 1995). "
ABSTRACT: Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate (Vmax ) of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [(125) I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([(125) I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd ) and binding density (Bmax ) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. Synapse, 2014. © 2014 Wiley Periodicals, Inc.Synapse 10/2014; 68(10). DOI:10.1002/syn.21755 · 2.43 Impact Factor
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- "Unlike dimethocaine, and consistent with previous reports of marginal reinforcing effects (Ford and Balster 1977; Johanson 1980; Wilcox et al. 1999; Woolverton 1995), procaine was ineffective in maintaining self-administration and resulted in DAT occupancies between 10–41% (Wilcox et al. 2005). However, irrespective of the drug, in vivo microdialysis showed that reinforcing effects and DAT occupancy were closely related to drug-induced increases in extracellular dopamine. "
ABSTRACT: Neuroimaging techniques have led to significant advances in our understanding of the neurobiology of drug taking and the treatment of drug addiction in humans. Neuroimaging approaches provide a powerful translational approach that can link findings from humans and laboratory animals. This review describes the utility of neuroimaging toward understanding the neurobiological basis of drug taking and documents the close concordance that can be achieved among neuroimaging, neurochemical, and behavioral endpoints. The study of drug interactions with dopamine and serotonin transporters in vivo has identified pharmacological mechanisms of action associated with the abuse liability of stimulants. Neuroimaging has identified the extended limbic system, including the prefrontal cortex and anterior cingulate, as important neuronal circuitry that underlies drug taking. The ability to conduct within-subject longitudinal assessments of brain chemistry and neuronal function has enhanced our efforts to document long-term changes in dopamine D2 receptors, monoamine transporters, and prefrontal metabolism due to chronic drug exposure. Dysregulation of dopamine function and brain metabolic changes in areas involved in reward circuitry have been linked to drug taking behavior, cognitive impairment, and treatment response. Experimental designs employing neuroimaging should consider well-documented determinants of drug taking, including pharmacokinetic considerations, subject history, and environmental variables. Methodological issues to consider include limited molecular probes, lack of neurochemical specificity in brain activation studies, and the potential influence of anesthetics in animal studies. Nevertheless, these integrative approaches should have important implications for understanding drug taking behavior and the treatment of drug addiction.Psychopharmacology 03/2011; 216(2):153-71. DOI:10.1007/s00213-011-2222-7 · 3.99 Impact Factor
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- "inity of these drugs for the DAT than with their affinity for sodium channels ( Hernandez et al . 1991 ; Woodward et al . 1995 ; Wilcox et al . 1999 , 2005 ) . Indeed lidocaine , a local anesthetic without significant DAT affinity did not stimulate DA transmission ( Hernandez et al . 1991 ; Woodward et al . 1995 ) and was not self - administered ( Wilcox et al . 1999 ) . Thus , it is unlikely that actions at sodium channels and local anesthetic effects induced by the histamine antagonists played a significant role in the outcome of the present microdialysis studies ."
ABSTRACT: The pattern of activation of dopamine (DA) neurotransmission in the nucleus accumbens (NAc) of rats produced by H(1) histamine antagonists which have behavioral effects like those of psychostimulant drugs was examined. Diphenhydramine and (+)-chlorpheniramine were compared with triprolidine, a potent and selective H(1) antagonist and (-)-chlorpheniramine which is less active than its enantiomer at H(1) receptors. Affinities of the drugs to DA, serotonin, and norepinephrine transporters at H(1) receptors and potencies for DA uptake inhibition in striatal synaptosomes were determined to assess mechanisms by which the compounds increased DA levels. Intravenous diphenhydramine (1.0-3.0 mg/kg) (+)- and (-)-chlorpheniramine (1.0-5.6 mg/kg) but not triprolidine (1.0-3.0 mg/kg) elicited a cocaine-like pattern of stimulation of DA transmission with larger effects in the NAc shell than core. The absence of stereospecific effects with chlorpheniramine enantiomers along with the lack of an effect with triprolidine suggest that the effects on DA transmission were not related to H(1) receptor antagonism. Although in vivo potencies were not directly related to DA transporter affinities, it is hypothesized that actions at that site modulated by other actions, possibly those at the serotonin transporter, are primarily responsible for the neurochemical actions of the drugs on DA neurotransmission and might underlie the occasional misuse of these medications.Journal of Neurochemistry 08/2008; 106(1):147-57. DOI:10.1111/j.1471-4159.2008.05361.x · 4.24 Impact Factor