2006 - 2007 Publications > Genetics of Cocaine and Psychostimulant Addiction

Genetics of Cocaine and Psychostimulant Addiction

Previous work has shown that cocaine induces CREB in nucleus accumbens and at the same time decreases excitability.  However, Dong et al (2006) reports that  overexpression of CREB in medium spiny neurons increases the excitability of neurons in the nucleus accumbens by increasing sodium currents and decreasing potassium currents. Overexpression of a potassium channel in medium spiny neurons of the nucleus accumbens mimicked the effect of cocaine by decreasing neuronal excitability and increased the locomotor response to cocaine.  Dong et al (2006) suggests that CREB induced increases in excitability are an adaptive response to limit the sensitivity to cocaine. Nat Neurosci. 2006 Apr;9(4):475-7

Previous work by Sora et al (2001) suggested that a genetic deletion of both the dopamine transporter and serotonin transporter is require to block cocaine reward as measured by conditioned place preference.  However, Chen et al., (2006) has reported that cocaine reward is abolished in mice carrying a cocaine-insensitive dopamine transporter.  To further examine the role of dopamine in mediating cocaine reward Hnasko et al (2007) examined cocaine reward in dopamine deficient mice that carry a deletion of tyrosine hydroxylase and dopamine decarboxylase.    Dopamine-deficient (DD) mice exhibited conditioned place preference in response to cocaine that was not blocked by a dopamine D1 receptor antagonist as is the case for mice that are not dopamine deficient. A serotonin transporter (SERT) inhibitor fluoxetine produced conditioned place preference (CPP) in DD mice, suggesting serotonin mediates cocaine CPP effect in DD mice. Inhibition of dopamine neuron firing with quinpirole blocked both cocaine and fluoxetine induced CPP in DD mice.  These results suggest that in the absence of dopamine, cocaine-mediated SERT blockade activates dopamine neurons, which release some other neurotransmitter such as glutamate, neurotensin, and/or cholecystokinin that contributes to cocaine reward in DD mice. Hnasko TS., et al (2007).. J Neuroscience 46: 12484-12488.

Freeman et al (2007) show persistent changes in mesolimbic gene expression that lasts longer than 100 days following 10 days of chronic cocaine administration in rats.   At 100 days the expression of fos, arc, egr1, and Nr4a1 in the nucleus accumbens and prefrontal cortex were all significantly reduced when compared to controls.  Future research will determine whether these decreases in gene expression are causally related to relapse and whether changes in chromatin remodeling effect these changes.   Neuropsychopharmacology. 2007 Sep 12.

Roybal et al (2007) reports that mice carrying a null mutation in CLOCK display similar behavioral profile to human mania including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and increase in reward value for cocaine.  Many of these behaviors are returned to normal levels following chronic administration of mood stabilizers like lithium or can be rescued by expressing a functional Clock protein in the VTA.   These observations suggest that Clock mutant mice are a good model for human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood. Roybal K., et al (2007). PNAS 15: 6406-6411.

Dynamic induction and release of BDNF from NAc neurons during cocaine use promotes the development and persistence of addictive behavior. Graham DL., et al (2007). Nat Neurosci 8:1029-1037

Ubiquitination and proteolysis are critical for synaptic plasticity by regulating protein stability and localization of proteins in synapses.  Shen et al (2007) show that translocation of the ubiquitin-proteome system (UPS) from the nucleus to dendritic spines requires NAC1.  NAC1, a cocaine regulated transcription factor promotes translocation of the UPS from the nucleus to the dendritic spines by forming complex with cullins, Mov34, and other proteins.  This discovery may point to how proteolysis plays a role in synaptic plasticity.  J Neurosci. 2007 Aug 15;27(33):8903-13

Mackler et al (2007) reports that NAC1, a cocaine-regulated transcription factor is required for the acute but not the chronic effects of cocaine and amphetamine.  Targeted disruption of the NAC1 gene blocks increased locomotor activity in response to cocaine and amphetamine when administered acutely but not chronically.  The rewarding properties of cocaine and amphetamine are abrogated in mutant mice when these psychostimulants are administered acutely but not chronically.  Similarly, increases in extracellular dopamine release are diminished in the targeted deletions of NAC1 in response to acute administration of psychomotor stimulants but the blockade is overcome with chronic administration.  These results point to the important role that NAC1 plays in mediating acute but not chronic effects of the response to psychomotor stimulants. Behav Brain Res. 2008 Feb 11;187(1):48-55

Winstanley et al (2007) reports that acute cocaine produces cognitve dysfunction in rats as measured by the five-choice serial reaction time task (5CSRT) and a delayed discounting task. Chronic cocaine produced tolerance to the cognitive dysfunction observed with acute cocaine exposure. The tolerance to the cognitive dysfunction produced by cocaine was paralleled by increase expresseion of deltaFosB in the orbitofrontal cortex. Overexpression of deltaFosB in the orbitofrontal cortex mimicked the effect of chronic cocaine while the expression of the dominant negative inhibitor of deltaFosB, delta JunD, in the orbitofrontal cortex blocks the development of tolerance to the cognitive deficits produced by cocaine. Gene expression profiling experiments suggest that chronic cocaine by activating deltaFosB produces tolerance to the cocaine induced cognitive dysfunction by increasing the expression of mGluR5 and GABA(A) receptors and by increasing Substance P.J Neurosci. 2007 Sep 26;27(39):10497-507

Casein kinase 1 is a key regulator of DARPP32 that modulates dopaminergic neurotransmission in the striatum.  Mice bread for methamphetamine sensitivity show a linkage to chromosome 15 that contains the casein kinase 1.  In these mice the expression of casein kinase 1 is increased 10 fold.   Veenstra-VanderWeele et al 2006 report that human subjects with more copies of rs135745 C allele, a noncoding SNP 3 kb 3' of the 3'-UTR of of the casein kinase 1 gene were more sensitive to low doses of oral D-amphetamine Neuropsychopharmacology. 2006 May;31(5):1056-63. Consistent with these results is the observation  by Zhang et al 2006 that Ser130A-DARPP-32 a mutation blocking the phosphorylation of DARPP-32 alters the reinforcing effects of cocaine J Neurosci. 2006 Mar 8;26(10):2645-51

Previous studies have shown that deletion of the dopamine transporter in mice is not necessary for mediating the rewarding properties of cocaine, suggesting that the serotonin and norepinephrine transporter may compensate for the loss of the dopamine transporter.  Chen et al 2006 reports that cocaine reward is abolished in mice engineered with a knockin of a dopamine transporter that is insensitive to cocaine but still can transport dopamine.  Because dopamine is not elevated in mice carrying the  cocaine-insensitive dopamine transporter as is the case in the null dopamine transporter mice, Chen et al 2006 argues that the dopamine transporter is necessary for cocaine mediated reward. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9333-8

Soria et al 2006 reports that rewarding properties of cocaine as measured by self-administration are reduced in mice lacking A2A adenosine receptors.  Thus, A2A receptors colocalized with D2 receptor may play a role in the addictive properties of cocaine and are a possible pharmacological target for treatment of addiction. Neuropsychopharmacology. 2006 May;31(5):978-87

Zanetti et al 2006 show that Inhibition of both alpha7* and beta2* nicotinic acetylcholine receptors is necessary to prevent development of sensitization to cocaine elicited increases in extracellular dopamine levels in the ventral striatum. Psychopharmacology (Berl). 2006 Aug;187(2):181-8