Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

Sensory reinforcment as an animal model of sensation seeking: Strength of association to cocaine self-administration

Rationale. Animal drug self-administration (SA) possesses both face and predictive validity and is widely used to model drug abuse in humans. In humans, many individuals experiment with drugs, but relatively few become drug abusers. Because of the observation of strong individual differences in drug addiction there has been increasing interest in identifying individual differences that predispose individuals toward uncontrolled drug abuse. A personality trait that predisposes individuals to drug use is Sensation Seeking, generally described as preference for novel sensations and experiences. Individuals who score high on Sensation Seeking scales have greater drug use compared to those who score low on these scales. In rodents, locomotor response to a novel environment (Loco) has been found to be predictive of drug SA and has been hypothesized to be an animal model of Sensation Seeking. In animal SA procedures, drug delivery is often paired with the onset of visual stimuli. Interestingly, a number of studies have demonstrated that animals will respond to produce visual stimuli alone. In previous research, we have found that Loco and responding to produce a visual reinforcer are related. The primary goal of this research is to evaluate the hypothesis that sensitivity to the reinforcing effects of a visual stimulus predicts acquisition of drug SA in rats and may be used as an animal model for Sensation Seeking. Goal. The goal of this research was to evaluate the relationships between Loco, light reinforced responding, and acquisition and maintenance of responding for cocaine and water reinforcers. Methods. Experiment 1 examined the association between Loco and light reinforced responding. Experiment 2 tested the ability of Loco and light reinforced responding to predict acquisition and maintenance of cocaine self-administration. Experiment 3 tested the ability of loco and light reinforced responding to predict acquisition and maintenance of a water reinforcer. Results. In Experiment 1, we found that Loco was positively associated with the rate of responding for a novel light reinforcer. In Experiment 2, it was determined that neither Loco nor Light reinforcement predicted acquisition of cocaine self-administration. However, there was some evidence that responding for a visual reinforcer predicted the rate of cocaine SA in animals that acquired the cocaine SA behavior. In Experiment 3, it was determined that both Loco and light reinforcement performance predicted the rate of water SA. Conclusions. The association found between Loco and light reinforcement indicates that these behaviors may be mediated by similar behavioral processes. The finding of no association between Loco and acquisition of cocaine self-administration was unexpected, as there is a large literature indicating the two are related. A second unexpected result was that Loco and light reinforced responding were predictive of the rate of responding for water. A number of factors that may have contributed to these discrepant results are discussed. One possibility supported by the data is that this relationship may be dependent on the use of visual or other sensory cues to signal drug delivery. Light reinforcement was a better predictor of both cocaine and water SA than Loco. These results provide some evidence for the use of light reinforcement as an animal model of Sensation Seeking. KEYWORDS: operant conditioning, sensory reinforcement, drug abuse, vulnerability, rat, psychomotor stimulant

Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization.

The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction

Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice

Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c­[Asp-His-DPhe-Arg-Trp-Lys]-NH₂) MC4R agonist and agouti-related peptide [AGRP­(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm. To our knowledge, this is the first study to test how central administration of these ligands directly to the spinal cord affects energy homeostasis. Results showed, as expected, that MTII IT administration caused a decrease in food and water intake and an overall negative energy balance without affecting activity. As anticipated, IT administration of AGRP caused weight gain, increase of food/water intake, and increase respiratory exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP was notably shorter (2 days) compared to mice given ICV injections of the same concentrations in previous studies (7 days or more).− It appears that IT administration results in a more sensitive response that may be a good approach for testing synthetic compound potency values ranging in nanomolar to high micromolar in vitro EC₅₀ values. Indeed, our investigation reveals that the spine influences a different melanocortin response compared to the brain for the AGRP ligand. This study indicates that IT administration can be a useful technique for future metabolic studies using melanocortin ligands and highlights the importance of exploring the role of melanocortin receptors in the spinal cord