2008 - 2009 Publications > Genetics of Cocaine and Psychostimulant Addiction

Recent Findings

A Variant in CHRNA5 associated with nicotine dependence is a protective allele for cocaine dependence

• Grucza et al Biol Psychiatry. 2008 Dec 1;64(11):922-9 reports that the minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence.

Molecular Genetics of Cocaine and Psychostimulant Abuse and Addiction

• Conrad et al Nature. 2008 Jul 3;454(7200):118-21 reports that number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2) that leads to increased reactivity of accumbens neurons to cocaine-related cues.

• Zweifel et al Neuron. 2008 Aug 14;59(3):486-96 demonstrates that inactivation of NMDARs using tissue specific and conditional KO of NR1 in DA neurons impairs contextual reward association for cocaine and withdrawal-induced increases in sensitization. Together, these findings support a role for NMDAR-dependent modulation of DA neurons in cue-induced relapse to drug seeking.

• Ramsey et al Neuropsychopharmacology. 2008 Oct;33(11):2701-14 reports that NMDA receptor-deficient mice (NR1-KD) disrupts the acute effects of cocaine but not amphetamine on locomotor activity.  In addition, NR1-KD) attenuate cocaine induced but not amphetamine induced sensitization and conditioned place preference. These results suggest that different signaling pathways are used by cocaine and amphetamine.

• Thanos et al  Synapse. 2008 Jul;62(7):481-6  reports that D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats

• Freeman et al Neuropsychopharmacology. 2008 Jul;33(8):1807-17  Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence

• Re-exposure to the chamber in which rats previously self-administered cocaine but not saline, increased the expression of c-fos, zif/268,and arc in the medial prefrontal cortex at 22 hours and 15 days. This was context dependent only occurring in the self-administration chamber.  Zif/268 and arc were also increased but not fos in the striatum and nucleus accumbens after 15 days when placed in the operant chamber. These results support convergent evidence that drug-seeking induced by a cocaine-paired context changes the activity of corticostriatal circuits Hearing et al Psychopharmacology (Berl). 2008 May;198(1):77-91; and Hearing et al Brain Struct Funct. 2008 Sep;213(1-2):215-27.

• Shen et al Neuroscience. 2008 Dec 2;157(3):644-55 reports that amphetamine produces HDACi-like effects that enhances general histone H4 acetylation and specific fosB promoter-associated H4 hyperacetylation in the striatum.  deltaFosB is increased in the striatum by amphetamine or by HDACi.  Both amphetamine and HDACi reduce the association of HDAC1 with CREB resulting in increased phosphorylation of CREB. Repeated administration of HDACi potentiated amphetamine induced locomotor sensitization but HDACi alone did not alter locomotor activity. Thus,psychostimulants may interact with HDACi at the levels of histone acetylation, CREB phosphorylation and ΔFosB induction via the CREB:HDAC1 protein complex.

• Uhl et al Archives Gen Psych 2008 Mar;65(3):345-55 conducted two GWAS studies for methamphetamine and found convergent results. Cell adhesion genes CSMD1 and CDH13 displayed the largest numbers of clustered nominally positive SNPs. "Methamphetamine dependence" genes overlapped, to extents much greater than chance, with genes identified in GWA studies of dependence on other addictive substances, success in quitting smoking, and memory.

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