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1.  The Impact of Exposure to Addictive Drugs on Future Generations: Physiological and Behavioral Effects 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.06.016.
It is clear that both genetic and environmental factors contribute to drug addiction. Recent evidence indicating trans-generational influences of drug abuse highlight potential epigenetic factors as well. Specifically, mounting evidence suggests that parental ingestion of abused drugs influence the physiology and behavior of future generations even in the absence of prenatal exposure. The goal of this review is to describe the trans-generational consequences of preconception exposure to drugs of abuse for five major classes of drugs: alcohol, nicotine, marijuana, opioids, and cocaine. The potential epigenetic mechanisms underlying the transmission of these phenotypes across generations also are detailed.
PMCID: PMC3864776  PMID: 23810828
Transgenerational; epigenetic; drugs of abuse; alcohol; nicotine; marijuana; opioids; cocaine
2.  Increased BDNF Expression in the Ventral Tegmental Area During Cocaine Abstinence is Associated with Increased Histone Acetylation at BDNF Exon I-Containing Promoters 
Journal of neurochemistry  2011;120(2):202-209.
Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine-seeking behavior coincides with increased brain-derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time-dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear. The goal of these experiments was to determine whether VTA BDNF transcript levels are altered following cocaine abstinence and identify the molecular mechanisms regulating cocaine-induced changes in VTA BDNF transcription. Rats were allowed to self-administer cocaine (0.25 mg/infusion, i.v.) for 14 d on a fixed-ratio schedule of reinforcement followed by 7 days of forced drug abstinence. BDNF protein and exon I-containing transcripts were significantly increased in the VTA of cocaine-experienced rats following 7 days of forced drug abstinence compared to yoked saline controls. Cocaine-induced changes in BDNF mRNA were associated with increased acetylation of histone 3 (AcH3) and binding of CREB binding protein (CBP) to exon I-containing promoters in the VTA. Taken together, these results suggest that drug abstinence following cocaine self-administration remodels chromatin in the VTA resulting in increased expression of BDNF, which may contribute to neuroadaptations underlying cocaine craving and relapse.
PMCID: PMC3243782  PMID: 22043863
self-administration; transcription; chromatin remodeling; addiction; neurotrophic factor; psychostimulant
3.  GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction 
Translational Psychiatry  2012;2(7):e142-.
Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.
PMCID: PMC3410621  PMID: 22806213
animal model; GABAergic signaling; gamma oscillation; neuropsychiatric disease; NMDA-receptor
4.  Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow In Vivo 
The balance between GABA-mediated inhibitory and glutamate-mediated excitatory synaptic transmission represents a fundamental mechanism for controlling nervous system function, and modulators that can alter this balance may participate in the pathophysiology of neuropsychiatric disorders. Pregnenolone sulfate (PS) is a neuroactive steroid that can modulate the activity of ionotropic glutamate and GABAA receptors either positively or negatively, depending upon the particular receptor subtype, and modulates synaptic transmission in a variety of experimental systems. To evaluate the modulatory effect of PS in vivo, we infused PS into rat striatum for 20 min via a microdialysis probe while monitoring local extracellular dopamine (DA) levels. The results demonstrate that PS at low nanomolar concentrations significantly increases extracellular DA levels. The PS -induced increase in extracellular DA is antagonized by the NMDA receptor antagonist, D-AP5, but not by the σ receptor antagonist, BD 1063. The results demonstrate that exogenous PS, at nanomolar concentrations, is able to increase DA overflow in the striatum through an NMDA receptor mediated pathway.
PMCID: PMC2864155  PMID: 18772319
5.  Cocaine-induced chromatin remodeling increases BDNF transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine 
Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague-Dawley rats were allowed to self-administer cocaine (0.25 µg/infusion) two hours per day for fourteen days followed by seven days of forced abstinence. Compared to yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). In order to examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio (PR) schedule of reinforcement was assessed following shRNA-induced suppression of BDNF expression in the mPFC. Decreased mPFC BDNF expression in the mPFC increased the cocaine self-administration break point. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Taken together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine.
PMCID: PMC2943400  PMID: 20810894
BDNF; cocaine; chromatin remodeling; medial prefrontal cortex; addiction; histones; transcription; self-administration
6.  Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking 
A growing body of evidence indicates that enhanced AMPA-mediated glutamate transmission in the core of the nucleus accumbens is critically involved in cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. However, the extent to which increased glutamate transmission in the other major subregion of the nucleus accumbens, the shell, contributes to the reinstatement of cocaine seeking remains unclear. In the present experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.03 or 0.3 μg) into either the core or the shell of the nucleus accumbens prior to a systemic cocaine priming injection (10 mg/kg, i.p.) dose-dependently attenuated the reinstatement of drug seeking. Cocaine priming-induced reinstatement of cocaine seeking also was associated with increases in GluR2-pSer880 in the nucleus accumbens shell. The phosphorylation of GluR2 by PKC at Ser880 plays an important role in the trafficking of GluR2-containing AMPA receptors from the plasma membrane. The current results showed that administration of a cell-permeable peptide that disrupts GluR2 trafficking (Pep2-EVKI) into either the accumbens core or shell attenuated cocaine-induced reinstatement of drug seeking. Taken together, these findings indicate that changes in AMPA receptor-mediated glutamate transmission in both the nucleus accumbens core and shell are necessary for the reinstatement of drug seeking induced by a priming injection of cocaine. The present results also demonstrate that the reinstatement of cocaine seeking is associated with increases in the phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens.
PMCID: PMC2601563  PMID: 18945913
relapse; addiction; psychostimulant; glutamate; CNQX; Pep2-EVKI
7.  Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats 
Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 hours daily for 21 days and then cocaine seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 μAmps. DBS began immediately after a priming injection of cocaine (0, 5, 10 or 20 mg/kg, i.p.) and continued throughout each 2-hour reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer-specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Taken together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.
PMCID: PMC2585378  PMID: 18753374
Deep brain stimulation; relapse; addiction; psychostimulant; striatum; accumbens shell

Results 1-7 (7)