We had previously used small animal positron emission tomography (PET) neuroimaging in combination with 11C-Raclopride and fluorine-18 fluorodeoxyglucose (FDG) to examine methamphetamine-induced alterations in brain dopamine and metabolism. Adolescent laboratory rats (30 days old) received baseline microPET scans. The animals then received an injection of methamphetamine, followed by another set of microPET scans. Methamphetamine significantly increased striatal dopamine by approximately 22% and increased FDG uptake cortically, subcortically, and in the cerebellum. There were no effects of methamphetamine on occipital FDG uptake. Acute pretreatment with S-(+)-gamma-vinyl-GABA completely abolished these increases. This constitutes the first finding that racemic gamma-vinyl-GABA's effects on brain mechanisms may be due to actions of the S-(+)-gamma-vinyl-GABA enantiomer. As adults (>90 days old), the animals received another methamphetamine injection followed by microPET scanning. Adolescent exposure to S-(+)-gamma-vinyl-GABA attenuated methamphetamine-induced changes in FDG uptake in these adult animals. We also used a unqiue serial imaging strategy to obtain FDG microPET images both prior to and during the expression of methamphetamine-induced conditioned place preferences. We studied animals during both """"""""forced exposure"""""""" and """"""""free choice exposure"""""""" to the environmental cues previously associated with methamphetamine administration. We found that both types of exposure to amphetamine-paired environmental cues produced significant bilateral activations of motor cortex, temporal cortex, cerebellum, and thalamus. However, """"""""free choice exposure"""""""" preferentially activated the medial forebrain bundle and striatum, while """"""""forced exposure"""""""" preferentially activated the amygdala and sensory cortex. During the present reporting period, we continued our work with methamphetamine exposure and found that a single moderately-high dose of methamphetamine causes depletion of striatal dopamine levels, decreases in tyrosine hydroxylase and dopamine turnover, and significant increases in striatal glial fibrillary acidic protein levels. In contrast, methamphetamine did not alter dopamine transporter (DAT) levels, suggesting no severe degeneration of striatal dopamine terminals. The decreases in dopamine cellular markers were also preceded by excessive release of dopamine, but not glutamate, in the ventral striatum immediately after methamphetamine administration. Importantly, these doses of methamphetamine caused dose-dependent increases in cocaine self-administration under low fixed-ratio reinforcement conditions, and a dose-dependent decrease in """"""""break-point"""""""" for cocaine self-administration under progressive-ratio reinforcement. Further, we found that methamphetamine administration dose-dependently attenuates striatal dopamine response to acute cocaine admnistration. These findings indicate that a single injection of methamphetamine causes significant depletion of ventral striatal dopamine and a reduction in striatal dopaminergic response to cocaine, which subsequently augments cocaine-taking behavior in a compensatory manner. These new findings are congruent with previous work, in which we found that methamphetamine administration increases the incentive motivational value of cocaine, as assessed using the conditioned place preference preclinical model. We also contributed major review articles to the addiction medicine literature during this this reporting period - including one on the """"""""risk"""""""" of addiction during pain management with opioid medications, two on hypothesis-driven medication discovery for the treatment of addiction, and one on animal models of addiction. We also embarked upon a study of the anti-nicotine-addiction compound Varenicline, and found that it attenuates nicotine-enhanced brain-stimulation reward by activation of alpha-4-beta-2 nicotinic receptors in the brain. This study adds very significantly to understanding the mechanisms of action of an already-approved and already-introduced pharmacotherapy for nicotine addiction that is now widely available for prescription use by physicians in the United States. Such mechanistic knowledge can aid in the search for new and effective pharmacotherapeutic compounds for the treatment of nicotine addiction and dependence.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2009
Total Cost
$377,271
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Zallar, L J; Tunstall, B J; Richie, C T et al. (2018) Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model. Int J Obes (Lond) :
Xue, Xue; Yang, Jing-Yu; He, Yi et al. (2016) Aggregated single-walled carbon nanotubes attenuate the behavioural and neurochemical effects of methamphetamine in mice. Nat Nanotechnol 11:613-20
Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi et al. (2015) R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats. Neuropsychopharmacology 40:1762-71
Zhang, Hai-Ying; Bi, Guo-Hua; Li, Xia et al. (2015) Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology 40:1037-51
Blum, Kenneth; Thanos, Peter K; Oscar-Berman, Marlene et al. (2015) Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction. J Reward Defic Syndr 1:95-104
Blum, Kenneth; Gardner, Eliot; Oscar-Berman, Marlene et al. (2012) ""Liking"" and ""wanting"" linked to Reward Deficiency Syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry. Curr Pharm Des 18:113-8
Xi, Zheng-Xiong; Peng, Xiao-Qing; Li, Xia et al. (2011) Brain cannabinoid CB? receptors modulate cocaine's actions in mice. Nat Neurosci 14:1160-6
Gardner, Eliot L (2011) Addiction and brain reward and antireward pathways. Adv Psychosom Med 30:22-60
Xi, Zheng-Xiong (2010) Preclinical Pharmacology, Efficacy and Safety of Varenicline in Smoking Cessation and Clinical Utility in High Risk Patients. Drug Healthc Patient Saf 2010:39-48
Xi, Zheng-xiong; Spiller, Krista; Gardner, Eliot L (2009) Mechanism-based medication development for the treatment of nicotine dependence. Acta Pharmacol Sin 30:723-39

Showing the most recent 10 out of 13 publications