Changes in Gene Expression and Addiction

As I discussed in a post last week, addiction seems to correspond to abnormalities in dopamine (DA) transmission throughout the reward areas of the brain. Specifically, initial uses of a drug tend to correlate with low levels of dopamine receptor availability in the nucleus accumbens (NAc), while long-term use affects DA transmission throughout the entire striatum (the NAc is located in the ventral portion of the striatum, or the part nearer the front of the brain).

The striatum is a subcortical region of the brain, and part of the mesocorticolimbic DA pathway, which is integral to the evaluation and appreciation of rewards (like drugs). Striatum is from Latin, and means striped. It is so named because the entire region has a striped appearance, due to the alternating bands of gray and white matter that make it up.

The changes that occur in the striatum are postulated to be responsible for the long-lasting behavioral changes that drug addicts can experience, such as cravings for drug use, an inability to enjoy previously rewarding experiences, and proneness to relapse. It has been suggested that these changes must be preceded by some sort of synaptic remodeling in order to have such a long-lasting effect, and those synaptic changes could be a result of fluctuations in DA transmission. How exactly they occur, however, has yet to be elucidated.

A study to be published in an upcoming issue of Nature may shed some light on the mechanism behind these changes. It involves gene expression, and a phosphoprotein known as DARPP32 (dopamine-and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa).

A phosphoprotein is a protein that has had a phosphate group attached to it, through a process known as phosphorylation. Phosphorylation is an important event in cells, as it often is the catalytic process that activates enzymes and receptors. Dephosphorylation can “turn off” these enzymes, and involves proteins called phosphatases.

When dopamine 1 receptors (D1R) are stimulated, they in turn activate DARPP32, which inhibits a phosphatase known as protein phosphatase 1 (PP1). This signaling cascade affects the phosphorylation of numerous proteins in the cytoplasm and nucleus of a cell.

In the Nature study, the researchers found that the administration of amphetamine, cocaine, or morphine to mice caused DARPP32 to accumulate in the nuclei of striatal neurons. Further studies of neural cultures indicated that dopamine prevents a specific DARPP32 phosphorylation site, Ser97, from being phosphorylated. Ser97 appears to be responsible for exporting DARPP32 from the nucleus of the cell, thus DARPP32 builds up inside the nucleus.

When DARPP32 accumulates in the nucleus, it causes the phosphorylation of a histone, H3. Histones are proteins that DNA winds around to make chromatin, the protein and DNA complex that makes up chromosomes. Phosphorylation of histones often affects chromatin structure, and gene expression as a result.

Mice with mutations in the Ser97 site demonstrated long-lasting aberrations in their behavioral responses to drugs and other rewards. They showed decreased acute locomotor responses to morphine administration, along with a reduced locomotor sensitization to cocaine. Their motivation to obtain a food reward was also diminished.

Thus, this signaling pathway may be responsible for one of the most potent behavioral changes in addiction, when euphoria achieved from the drug diminishes along with the pleasure once obtained from other rewards. This change can contribute to compulsive drug seeking, as an addict obsessively continues to seek the pleasure once associated with their drug of choice. If altered gene expression is responsible for these changes, it would help to explain why they can persist for such a long period of time after the cessation of drug use—sometimes continuing to affect the behavior of an addict for years, and often making their efforts to stay sober much more difficult.