raclopride and Substance-Related-Disorders

Behavioral neuroimaging is a rapidly evolving discipline that represents a marriage between the fields of behavioral neuroscience and preclinical molecular imaging. This union highlights the changing role of imaging in translational research. Techniques developed for humans are now widely applied in the study of animal models of brain disorders such as drug addiction. Small animal or preclinical imaging allows us to interrogate core features of addiction from both behavioral and biological endpoints. Snapshots of brain activity allow us to better understand changes in brain function and behavior associated with initial drug exposure, the emergence of drug escalation, and repeated bouts of drug withdrawal and relapse. Here we review the development and validation of new behavioral imaging paradigms and several clinically relevant radiotracers used to capture dynamic molecular events in behaving animals. We will discuss ways in which behavioral imaging protocols can be optimized to increase throughput and quantitative methods. Finally, we discuss our experience with the practical aspects of behavioral neuroimaging, so investigators can utilize effective animal models to better understand the addicted brain and behavior.

Topics: Animals; Brain; Disease Models, Animal; Dopamine; Fluorodeoxyglucose F18; Humans; Neuroimaging; Raclopride; Radionuclide Imaging; Substance-Related Disorders

Not everyone who tries addictive drugs develops a substance use disorder. One of the best predictors of risk is a family history (FH) of substance use problems. In part, this might reflect perturbed mesolimbic dopamine responses.. We measured amphetamine-induced changes in [(11)C]raclopride binding in 1) high-risk young adults with a multigenerational FH of substance use disorders (n = 16); 2) stimulant drug-naïve healthy control subjects with no known risk factors for addiction (n = 17); and 3) subjects matched to the high-risk group on personal drug use but without a FH of substance use problems (n = 15).. Compared with either control group, the high-risk young adults with a multigenerational FH of substance use disorders exhibited smaller [(11)C]raclopride responses, particularly within the right ventral striatum. Past drug use predicted the dopamine response also, but including it as a covariate increased the group differences.. Together, the results suggest that young people at familial high risk for substance use disorders have decreased dopamine responses to an amphetamine challenge, an effect that predates the onset of addiction.

Topics: Amphetamine; Case-Control Studies; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Dopamine Antagonists; Family Health; Female; Functional Neuroimaging; Humans; Male; Positron-Emission Tomography; Prodromal Symptoms; Raclopride; Substance-Related Disorders; Young Adult

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knockin mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1 (PP1), but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of PP1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.

Topics: Analysis of Variance; Animals; Anisomycin; Cocaine; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agonists; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Administration Routes; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Green Fluorescent Proteins; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Motor Activity; Narcotics; Point Mutation; Protein Synthesis Inhibitors; Raclopride; Receptors, Dopamine D1; Substance-Related Disorders; Threonine; Time Factors

Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise.. To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain.. Positron emission tomography with [(11)C]raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory.. Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.. Modafinil decreased mean (SD) [(11)C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [(11)C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters.. In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.

Topics: Adult; Benzhydryl Compounds; Brain; Carbon Radioisotopes; Caudate Nucleus; Central Nervous System Stimulants; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Male; Middle Aged; Modafinil; Nucleus Accumbens; Pilot Projects; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Substance-Related Disorders; Young Adult

Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

Topics: Animals; Behavior, Animal; Cocaine; Dopamine Agonists; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Male; Mazindol; Mice; Mice, Inbred C57BL; Motor Activity; Protein Binding; Quinolines; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Substance-Related Disorders

A small group of Parkinson's disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa-induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.. We used a two-scan positron emission tomography protocol to calculate the percentage change in (11)C-raclopride binding potential from a baseline withdrawal (off drug) state to the binding potential after an oral dose of levodopa. We related the subjective effects of levodopa to the effects on endogenous dopamine release of a pharmacological challenge with levodopa in eight control PD patients and eight patients with DDS.. PD patients with DDS exhibited enhanced levodopa-induced ventral striatal dopamine release compared with levodopa-treated patients with PD not compulsively taking dopaminergic drugs. The sensitized ventral striatal dopamine neurotransmission produced by levodopa in these individuals correlated with self-reported compulsive drug "wanting" but not "liking" and was related to heightened psychomotor activation (punding).. This provides evidence that links sensitization of ventral striatal circuitry in humans to compulsive drug use.

Topics: Aged; Brain Mapping; Dopamine; Dopamine Agents; Dopamine Antagonists; Exploratory Behavior; Female; Humans; Levodopa; Male; Middle Aged; Neostriatum; Positron-Emission Tomography; Psychological Tests; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Substance-Related Disorders; Synaptic Transmission

1-Benzylpiperazine (also known as 'Legal X', 'Legal E', or 'A2') is a psychoactive compound increasingly encountered on the clandestine market. Previous experimental data suggest that the compound possesses addictive properties. In the present study, we used the conditioned place preference method in the rat to test whether 1-benzylpiperazine possesses rewarding properties. Furthermore, the mechanisms of the 1-benzylpiperazine reward were investigated using selected dopamine and serotonin receptor antagonists. 1-Benzylpiperazine (1.25, 5, and 20 mg/kg) induced dose-dependently place preference. This place preference was attenuated by the antagonists SCH23390 (0.2 mg/kg; dopamine D1-like receptors) and MDL72222 (1.0 mg/kg; serotonin3 receptors), but not by raclopride (0.8 mg/kg; dopamine D2-like receptors) or ketanserin (2 mg/kg; preferentially serotonin2 receptors). Our results show that 1-benzylpiperazine possesses rewarding properties in the rat, which suggests the compound to be susceptible to human abuse. The brain dopaminergic and serotonergic systems appear to be involved in the 1-benzylpiperazine reward.

Topics: Animals; Behavior, Animal; Benzazepines; Conditioning, Psychological; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ketanserin; Male; Piperidines; Psychotropic Drugs; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Receptors, Serotonin, 5-HT3; Reward; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Substance-Related Disorders; Tropanes

Topics: Corpus Striatum; Humans; Raclopride; Receptors, Dopamine D2; Risk Factors; Substance-Related Disorders; Tomography, Emission-Computed

This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans.. [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg).. Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects.. These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.

Topics: Adult; Carbon Radioisotopes; Central Nervous System Stimulants; Corpus Striatum; Dopamine Antagonists; Humans; Male; Methylphenidate; Raclopride; Receptors, Dopamine D2; Reinforcement, Psychology; Reward; Salicylamides; Substance-Related Disorders; Tomography, Emission-Computed

Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.

Topics: Adult; Behavior, Addictive; Cocaine; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Humans; Male; Methylphenidate; Raclopride; Salicylamides; Self-Assessment; Substance-Related Disorders; Thalamus; Tomography, Emission-Computed

Topics: Animals; Behavior; Brain; Brain Chemistry; Cocaine; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Humans; Methylphenidate; Opioid-Related Disorders; Raclopride; Receptors, Dopamine; Research Design; Reward; Salicylamides; Substance-Related Disorders

A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics.

Topics: Aminobenzoates; Anesthetics, Local; Animals; Benzazepines; Binding, Competitive; Carrier Proteins; Cocaine; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Propanolamines; Raclopride; Regression Analysis; Saimiri; Salicylamides; Substance-Related Disorders