Cocaine-induced plasticity deficits in the male offspring of cocaine-experienced sires
Monday, Nov 11, 2013, 3:00 PM - 4:00 PM
++C.18.i. Cocaine: Neural mechanisms of addiction
*M. E. WIMMER
, F. M. VASSOLER
, P. I. ORTINSKI
, S. L. WHITE
, H. D. SCHMIDT
, G. SADRI-VAKILI
, C. PIERCE
Ctr. for Neurobio. & Behavior, Univ. Pennsylvania, PHILADELPHIA, PA;
Biomed. Sci., Tufts Univ., North Grafton, MA;
Psychiatry, Univ. of Pennsylvania, Philadelphia, PA;
Inst. for Neurodegenerative Dis., Mass Gen. Hosp., Charlestown, MA
Cocaine abuse remains a major public health problem in the United States. A growing body of evidence suggests that environmental information, including that related to cocaine exposure, can be inherited epigenetically. We recently established a rat model to examine the influence of paternal cocaine self-administration on the behavior of the progeny. Here, we combined behavioral, electrophysiological and molecular approaches to examine cocaine-induced behavioral and neuronal plasticity in the offspring of cocaine-experienced sires (F1 CocSired) and controls (saline sired, F1 SalSired). Repeated exposure to cocaine produces behavioral sensitization, which is characterized by an augmented locomotor response to a subsequent psychostimulant challenge injection. Here, we show that male, but not female, CocSired rats showed deficits in cocaine sensitization, indicating a resistance in the long-lasting behavioral responses consecutive to cocaine exposure. Expression of sensitization is accompanied by neuroadaptations in the nucleus accumbens (NAc), which is critically involved in the development of addiction. In particular, AMPA receptors (AMPARs) and their composition influence cocaine sensitization. We used whole-cell patch clamp recordings to examine the AMPAR component of stimulus-evoked excitatory post-synaptic currents (EPSCs) in NAc slices of F1 rats. EPSCs at negative potentials were larger than those measured at the symmetrical positive potentials in naïve CocSired animals compared to naïve SalSired rats. This increased rectification index suggests that some AMPAR are lacking the GluA2 subunit in naïve CocSired rat. Consistent with these results, GluA2 mRNA expression was reduced in naïve male CocSired rats compared to control, suggesting that epigenetic mechanisms contribute to the inheritance of this phenotype. GluA2-lacking AMPARs exhibit several unique properties such as permeability to calcium (Ca2+) and are critically involved in the expression of cocaine-induced behavioral sensitization. Following 10 days of cocaine self-administration, SalSired rats show an increase in rectification index, which was not present in CocSired rats. Taken together, these findings indicate that the offspring of cocaine-experienced rats show deficits in cocaine-induced behavioral and neuronal plasticity and that epigenetic mechanisms may contribute to this phenomenon.
NIH Grant R01DA033641
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