N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.
Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Rationale: Substance use disorder (SUD) is a chronic relapsing brain disorder that is characterised by loss of control over substance use. A variety of rodent models employing punishment setups have been developed to assess loss of control over substance use, i.e.
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA. Electronic address:
The prelimbic cortex is involved in operant reward seeking. However, the precise nature of its activity patterns and whether/how they differ between different types of rewards are largely unknown. We use miniscope calcium imaging to observe prelimbic activity during both food and cocaine seeking in freely behaving mice.
Cocaine use disorder (CUD) is a major public health issue, and there's currently no FDA-approved medication to treat it, highlighting the need for new treatments.
RDS04-010, a novel atypical dopamine transporter inhibitor, shows promise in animal models by significantly reducing cocaine-seeking behavior without producing addictive effects, unlike its analog RDS03-094 which has more cocaine-like properties.
The study’s results emphasize the importance of the binding conformation to the dopamine transporter and suggest RDS04-010 could be a potential therapeutic option for CUD due to its ability to lower motivation for cocaine use.
Background: Adenosine monophosphate-activated protein kinase (AMPK) signaling plays a vital role in regulating cellular metabolism and energy throughout the body. Ethanol and cocaine both reduce AMPK activity in addiction-related brain regions. Though AMPK activation has been found to reduce cocaine seeking, its role in harmful drinking and alcohol use disorder (AUD) progression remains unclear.
Rationale: Anticipation is a critical antecedent to drug use, in which the prospect of imminent drug availability can potently motivate instrumental actions directed to procure it. Models that capture the behavioral dynamics that precede drug access may allow for the dissociation of key neural mechanisms underlying appetitive or consummatory processes in drug self-administration.
Objectives: We aimed to isolate measurements attributed to the procurement and consumption of a reward by defining distinct actions for each using a chain-schedule of reinforcement.
