Biol1F25 November 4 , 2013
Molecular and Cellular Mechanisms of Cocaine Addiction
Last Lecture: Chronic administration of cocaine up regulates CREB and increases
dynorphon release from NAcL impairs reward pathways.
Produces decreased sensitivity to rewarding effects of subsequent drug exposure
Role of FosB: Transcription factor in NAc
c-Fos induced in NAc by acute cocaine use, but proteins are unstable and levels
return to normal within 8-12 hours
Chronic cocaine induced a novel FoB protein: FosB in NAc – very stable
FosB induced in Nac by many drugs of abuse and non-drug rewards
Experimental evidence for role of FosB:
Over-expressed FosB in NAc in mice
Produced increased cocaine self administration
Because of stability of FosB – may drive behavioural changes for weeks and months
SUSTAINED MOLECULAR SWITCH
- Initiates and maintains state of addiction?
Mechanisms of permanent plastic changes in brain:
Changes in FosB not long-lived enough to account for life-long addictions
What underlies the stable changes in brain?
Hypothesis: Structural changes in neurons of reward pathway are responsible.
Structural changes in reward pathways of brain:
Chronic cocaine use: increases # of dendrites of NAc neurons – persist for months
BUT- no current direct evidence that increased # of dendrites underlie long-lived
Analogous to learning and memory field – difficult to associate cellular changes with
Amphetamine or cocaine limits the ability of later experience to promote structural
plasticity in the neocortex and nucleus accumbens (Nac)
Data from 1960’s showed that experience produces more extensive branches of
Increased length of dendrites + increased density of spines: Advantageous to
Changes in den