Epigenetics and Drug Abuse

Gene expression and inheritance are not only a function of the DNA code, but also epigenetic mechanisms that regulate DNA accessibility, transcription, and translation of the genetic code into a functional protein. Epigenetic mechanisms are invoked by life experiences, including stress and exposure to drugs of abuse, and the resulting changes in gene expression can be inherited by future generations. This chapter highlights recent research demonstrating epigenetic changes in response to drug exposure with a focus on three different mechanisms: DNA methylation, histone modification, and noncoding RNAs. We briefly describe each of these mechanisms and then provide key examples of drug-induced changes involving these mechanisms, as well as epigenetic manipulations that alter effects of drugs. We then review cutting-edge technologies, including viral-mediated gene transfer and gene editing, that are being used to manipulate epigenetic processes with temporal and cell-type specificity. We also describe and provide examples of intergenerational epigenetic modifications, a topic that has interesting implications for how addiction-related traits may be passed down across generations. Finally, we discuss how this research provides a greater understanding of drug addiction and may lead to novel molecular targets for preventions and interventions for drug abuse

Dual Effect of 5-HT

BACKGROUND: Serotonin (5-HT) 1B/1D receptor (5-HT METHODS: We examined the ability of 5-HT RESULTS: We report a bidirectional modulation of VTA DA neuronal firing through the interaction of VTA 5-HT CONCLUSIONS: This study revealed dual effects of CP94253 on VTA DA neurons that are dependent on

Stimulation of 5-HT1Breceptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior

ADC ArcheoProjecten heeft een Archeologische Begeleiding (conform protocol Opgraven)1 uitgevoerd. Dit ten behoeve van de stadsvernieuwing binnen het gebied van de Koningsstraat, Schuttersgracht en Molenstraat in Ijsselstein. De Archeologische Begeleiding behelsde het toezicht houden op het uitgraven van kabels- en leidingsleuven, zie hiervoor PVE fase2. Het onderzoeksgebied heeft een oppervlakte van ca. 6100 m² en was vóór de werkzaamheden in gebruik als openbare weg en parkeerterrein. Het gebied behelst het Koningshof, het zuidoost deel van de Molenstraat en de Schuttersgracht. Tijdens de begeleiding zijn sporen van bewoning uit de Late Middeleeuwen B en de Nieuwe Tijd B aangetroffen. In dit gebied komen dergelijke resten veel voor en geven aan dat hier in deze periode twee verschillende bewoningsfase te onderscheiden zijn

Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat.

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.National Institutes of Health [DA026451, DA011064, DA035069]12 Month EmbargoThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Protracted Withdrawal from Cocaine Self-Administration Flips the Switch on 5-HT1B Receptor Modulation of Cocaine Abuse-Related Behaviors

Contains fulltext : 213908.pdf (publisher's version ) (Open Access

HIV gp120 impairs nucleus accumbens neuroimmune function and dopamine D3 receptor-mediated inhibition of cocaine seeking in male rats

Cocaine Use Disorders (CUDs) are associated with an increased risk of human immunodeficiency virus (HIV) infection. Cocaine and the HIV envelope protein gp120 each induce distinct deficits to mesocorticolimbic circuit function and motivated behavior; however, little is known regarding how they interact to dysregulate these functions or how such interactions impact pharmacotherapeutic efficacy. We have previously shown that the selective, weak partial agonist of the dopamine D3 receptor (D3R), MC-25-41, attenuates cocaine-seeking behavior in male rats. Here, we sought to characterize changes in striatal neuroimmune function in gp120-exposed rats across abstinence from operant access to cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg/pellet), and to examine the impact of gp120 exposure on MC-25-41-reduced cocaine seeking. After establishing a history of cocaine or sucrose self-administration, rats received intracerebroventricular gp120 infusions daily the first 5 days of abstinence and were sacrificed either on day 6 or after 21 days of forced abstinence and a cue-induced cocaine seeking test. We demonstrated that MC-25-41 treatment attenuated cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, postmortem analysis of nucleus accumbens (NAc) core neuroimmune function indicated cocaine abstinence- and gp120-induced impairments, and the expression of several immune factors within the NAc core significantly correlated with cocaine-seeking behavior. We conclude that cocaine abstinence dysregulates striatal neuroimmune function and interacts with gp120 to inhibit the effectiveness of a D3R partial agonist in reducing cocaine seeking. These findings highlight the need to consider comorbidities, such as immune status, when evaluating the efficacy of novel pharmacotherapeutics

HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology