Genetic factors contribute significantly to the risk of cocaine abuse in humans. However, the potential role of epigenetic influences on addiction phenotypes remains unclear. A growing body of evidence indicates that environmental information can be inherited. Thus, epigenetic changes in the mammalian germline can act as a transgenerational carrier of environmental perturbations. Here, we describe a rat model developed in order to delineate a heritable phenotype resulting from the self-administration of cocaine. We found that while the male offspring of cocaine-experienced sires (BCocSired) had delayed acquisition and reduced maintenance of cocaine self-administration relative to the offspring of yoked saline controls (BSalSired), there was no difference in the acquisition of cocaine self-administration in female offspring. These novel results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring.
The specific aims outlined in this application will assess specific mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self-administration. The experiments in Specific Aim 1 are designed to assess epigenetic and behavioral mechanisms through which paternal cocaine self-administration may influence the behavior of their descendants.
In Specific Aim 2 we will evaluate the acquisition of cocaine and food self-administration in the offspring (F1) and grand offspring (F2) of male rats that self-administered cocaine.
Specific Aim 3 focuses on the potential role of medial prefrontal cortical brain-derived neurotrophic factor in the acquisition of cocaine self-administration in F1 and F2 CocSired rats. The preliminary data described in this application are novel and establish the inheritance of an addiction-related phenotype using an animal model. Our finding that the cocaine self-administration is reduced in BCocSired relative to BSalSired rats is robust and has significant implications in terms of human health. The next step is to determine the cellular and molecular mechanisms underlying this phenotype. The experiments described in this application will use state-of-the-art cellular, molecular and behavioral methodologies to i) examine epigenetic and behavioral mechanisms whereby cocaine-associated information can be transmitted from sires to offspring, ii) determine if the inherited cocaine resistance phenotype is transgenerational, and iii) assess specific neuronal mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self- administration.

Public Health Relevance

A growing body of evidence indicates that environmental information can be inherited, which suggests that changes in the mammalian germline can act as a trans-generational carrier of environmental information. Here, we describe a rat model developed in order to delineate heritable behavioral characteristics resulting from the self-administration of cocaine. Our results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring. The experiments described in this application will use state-of- the-art cellular, molecular and behavioral methodologies to examine the mechanisms whereby cocaine- associated information can be transmitted from sires to offspring and assess specific neuronal changes that may underlie this paternally transmitted phenotype associated with cocaine self-administration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033641-03
Application #
8627155
Study Section
Special Emphasis Panel (ZDA1-MXL-F (07))
Program Officer
Volman, Susan
Project Start
2012-04-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$444,603
Indirect Cost
$108,001
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schmidt, H D; McFarland, K N; Darnell, S B et al. (2015) ADAR2-dependent GluA2 editing regulates cocaine seeking. Mol Psychiatry 20:1460-6
Vassoler, F M; Sadri-Vakili, G (2014) Mechanisms of transgenerational inheritance of addictive-like behaviors. Neuroscience 264:198-206
Sadri-Vakili, Ghazaleh (2014) Cocaine triggers epigenetic alterations in the corticostriatal circuit. Brain Res :
Rasakham, Khampaseuth; Schmidt, Heath D; Kay, Kevin et al. (2014) Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration. PLoS One 9:e102524
Polter, Abigail M; Bishop, Rachel A; Briand, Lisa A et al. (2014) Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. Biol Psychiatry 76:785-93
Mietlicki-Baase, Elizabeth G; Ortinski, Pavel I; Reiner, David J et al. (2014) Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling. J Neurosci 34:6985-92
Vassoler, F M; Byrnes, E M; Pierce, R C (2014) The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects. Neuropharmacology 76 Pt B:269-75
Pierce, R Christopher; Vassoler, Fair M (2014) Reduced cocaine reinforcement in the male offspring of cocaine-experienced sires. Neuropsychopharmacology 39:238
Schmidt, Heath D; Schassburger, Rachel L; Guercio, Leonardo A et al. (2013) Stimulation of mGluR5 in the accumbens shell promotes cocaine seeking by activating PKC gamma. J Neurosci 33:14160-9
Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J et al. (2013) Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation. J Neurosci 33:14446-54

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