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Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D2 ligand, [11C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [11C]-raclopride binding. In this study, we use [11C]-raclopride imaging in awake rodents to capture cue-induced changes in dopamine release associated with the conditioned place preference model of drug craving. Ten animals were conditioned to receive cocaine in a contextually distinct environment from where they received saline. Following conditioning, each animal was tested for preference and then received two separate [11C]-raclopride scans. For each scan, animals were confined to the cocaine and/or the saline-paired environment for the first 25 min of uptake, after which they were anesthetized and scanned. [11C]-raclopride uptake in the saline-paired environment served as a within-animal control for uptake in the cocaine-paired environment. Cocaine produced a significant place preference ( p = 0.004) and exposure to the cocaine-paired environment decreased [11C]-raclopride binding relative to the saline-paired environment in both the dorsal (20%; p < 0.002) and ventral striatum (22%; p < 0.05). The change in [11C]-raclopride binding correlated with preference in the ventral striatum (R2 = -0.87; p = 0.003). In this region, animals who showed little or no preference exhibited little or no change in [11C]-raclopride binding in the cocaine-paired environment. This noninvasive procedure of monitoring neurochemical events in freely moving, behaving animals advances preclinical molecular imaging by interrogating the degree to which animal models reflect the human condition on multiple dimensions, both biological and behavioral. [ABSTRACT FROM AUTHOR]

Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic γ vinyl-GABA (R,S-GVG, vigabatrin) shows enormous potential as it blocks both the neurochemical and behavioral effects of a variety of drugs, including METH, heroin, morphine, ethanol, nicotine, and cocaine. Using the reinstatement of a conditioned place preference (CPP) as an animal model of relapse, the present study specifically investigated the ability of an acute dose of R,S-GVG to block METH-triggered reinstatement of a METH-induced CPP. Animals acquired a METH CPP following a 20-day-period of conditioning, in which they received 10 pairings of alternating METH and saline injections. During conditioning, rats were assigned to one of four METH dosage groups: 1.0, 2.5, 5.0, or 10.0 mg/kg (i.p., n = 8/group). Animals in all dosage groups demonstrated a robust and consistent CPP. This CPP was subsequently extinguished in each dosage group with repeated saline administration. Upon extinction, all groups reinstated following an acute METH challenge. On the following day, an acute dose of R,S-GVG (300 mg/kg, i.p.) was administered 2.5 h prior to an identical METH challenge. R,S-GVG blocked METH-triggered reinstatement in all four groups. Given that drug re-exposure may potentiate relapse to drug-seeking behavior, the ability of R,S-GVG to block METH-triggered reinstatement offers further support for its use in the successful management of METH dependence. Synapse 63:87-94, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5pmol/ml (0.35μg), with an ED50 of 8.55±5.62pmol/ml. These data also provide evidence that BP may be compromised by masses of raclopride below 2.0pmol/ml (0.326μg). Increases in ECF DA were produced by mass doses of raclopride over 3.9pmol/ml (0.329μg) with an ED50 of 8.53±2.48pmol/ml. Taken together, it appears that an optimal range of raclopride mass exists between 2.0 and 3.5pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound. [Copyright &y& Elsevier]

The aim of the present study was to investigate the effect of toluene inhalation on dopaminergic transmission in two distinct brain areas presumably involved in mediating the reward processes important for toluene abuse. Extracellular dopamine (DA) levels were measured in prefrontal cortex (PFC) and nucleus accumbens (NACC) of freely moving rats using in vivo microdialysis. Inhalation of a behaviorally relevant concentration of toluene (3000 ppm) produced a significant increase in the PFC but not in the NACC. However, the odorant isoamyl acetate, increased PFC DA levels by only 37%, significantly less than the 96% increase observed following toluene exposure. When toluene inhalation was combined with cocaine administration (20 mg/kg i.p.), the response to the combined challenge was not different from the response to toluene alone in the PFC. However, the combination of these two drugs produced a supradditive response of 802% in the NACC, compared with the 450% increase observed following cocaine alone. Recent reports indicate that toluene influences the function of several ionotropic receptors in a subunit specific manner. As further evidence of specific effects, our results indicate regionally specific changes in dopaminergic transmission following toluene exposure. [Copyright &y& Elsevier]