Letchworth SR, Nader MA, Smith HR, Friedman DP, Porrino LJ. Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys. J Neurosci 21: 2799-2807

Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2001; 21(8):2799-807.
Source: PubMed


The present study examined the time course of alterations in levels of dopamine transporter (DAT) binding sites that accompany cocaine self-administration using quantitative in vitro receptor autoradiography with [(3)H]WIN 35,428. The density of dopamine transporter binding sites in the striatum of rhesus monkeys with 5 d, 3.3 months, or 1.5 years of cocaine self-administration experience was compared with DAT levels in cocaine-naive control monkeys. Animals in the long-term (1.5 years) exposure group self-administered cocaine at 0.03 mg/kg per injection, whereas the initial (5 d) and chronic (3.3 months) treatment groups were each divided into lower dose (0.03 mg/kg per injection) and higher dose (0.3 mg/kg per injection) groups. Initial cocaine exposure led to moderate decreases in [(3)H]WIN 35,428 binding sites, with significant changes in the dorsolateral caudate (-25%) and central putamen (-19%) at the lower dose. Longer exposure, in contrast, resulted in elevated levels of striatal binding sites. The increases were most pronounced in the ventral striatum at the level of the nucleus accumbens shell. At the lower dose of the chronic phase, for example, significant increases of 21-42% were measured at the caudal level of the ventral caudate, ventral putamen, olfactory tubercle, and accumbens core and shell. Systematic variation of cocaine dose and drug exposure time demonstrated the importance of these factors in determining the intensity of increased DAT levels. With self-administration of higher doses especially, increases were more intense and included dorsal portions of the striatum so that every region at the caudal level exhibited a significant increase in DAT binding sites (20-54%). The similarity of these findings to previous studies in human cocaine addicts strongly suggest that the increased density of dopamine transporters observed in studies of human drug abusers are the result of the neurobiological effects of cocaine, ruling out confounds such as polydrug abuse, preexisting differences in DAT levels, or comorbid psychiatric conditions.

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    • "Previous studies suggest that the high-affinity binding site exerts a low-capacity uptake process that maintains extracellular dopamine at relatively low concentrations where as the low-affinity site contributes to a highcapacity uptake process. Previous studies have reported increased DAT binding following chronic cocaine self-administration in rats (Miguens et al., 2008) and monkeys (Letchworth et al., 2001). Such changes in binding could be due to increased abundance of DAT or an increase in the affinity of the binding sites for cocaine. "
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    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 · 2.13 Impact Factor
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    • "One important outcome of this series of studies was the finding that exposure to cocaine in and of itself can produce significant dysregulation in neurotransmitter systems and adaptations in the functional response to cocaine (Lyons et al., 1996; Porrino et al., 2002). These changes include increases in the density of norepinephrine (Beveridge et al., 2005) and dopamine transporters (Letchworth et al., 2001), increases in dopamine D 1 receptors (Nader et al., 2002), as well as decreases in the concentration of dopamine D 2 receptors (Nader et al., 2002). These alterations in brain structure and function can be directly attributable to the effects of cocaine, unlike studies of human addicts in which differences between users and control populations could result from a number of factors besides cocaine exposure, including co-morbid psychiatric disorders, use of other legal and illegal drugs, or pre-existing differences. "

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    • "This delayed recruitment of the DLS in the control over cocaine seeking suggests that low availability of ventral striatum dopamine D2 receptors might influence drug-induced adaptations underlying the progressive ventral to dorsal striatal shift that occurs in the course of addiction in humans (12,34) and during extended periods of cocaine self-administration in nonhuman primates (8,9,11,35) and rats (10). We and others have suggested that this ventral to dorsal striatal shift depends upon the dopamine-dependent ascending spiraling circuitry (36,37) functionally linking the ventral with the dorsolateral striatum (13,15,31,38), even though the mechanisms whereby this circuitry is recruited remain to be established. "
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    ABSTRACT: Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopamine-dependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown. High- and low-impulsive rats identified in the five-choice serial reaction-time task were trained to self-administer cocaine (.25 mg/infusion) with infusions occurring in the presence of a cue-light conditioned stimulus. Dopamine transmission was blocked in the DLS after three stages of training: early, transition, and late-stage, by bilateral intracranial infusions of α-flupenthixol (0, 5, 10, or 15 μg/side) during 15-min cocaine-seeking test sessions in which each response was reinforced by a cocaine-associated conditioned stimulus presentation. In early-stage tests, neither group was affected by DLS dopamine receptor blockade. In transition-stage tests, low-impulsive rats showed a significant dose-dependent reduction in cocaine seeking, whereas high-impulsive rats were still unaffected by α-flupenthixol infusions. In the final, late-stage seeking test, both groups showed dose-dependent sensitivity to dopamine receptor blockade. The results demonstrate that high impulsivity is associated with a delayed transition to DLS-dopamine-dependent control over cocaine seeking. This suggests that, if impulsivity confers an increased propensity to addiction, it is not simply through a more rapid development of habits but instead through interacting corticostriatal and striato-striatal processes that result ultimately in maladaptive drug-seeking habits.
    Biological psychiatry 10/2013; 76(1). DOI:10.1016/j.biopsych.2013.09.011 · 10.26 Impact Factor
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