These changes in signal transduction can trigger longer-term molecular neuroadaptations via transcription factors that modify gene expression. A well characterised example is that chronic exposure to various drugs of abuse increases the activation of cAMP response element binding protein in the nucleus accumbens and deactivates it in the central nucleus of the amygdala. Introduction of cAMP response element binding protein in the nucleus accumbens decreases the reinforcing value of natural and drug rewards, and this change plausibly contributes to withdrawal/negative affect stage-related decreases in reward pathway function, which leave a drug-abstinent individual in an amotivational, dysphoric, or depressed-like state.138,139 These substance-related changes in susceptibility to negative emotional states might begin early: alcohol use during adolescence might lead to epigenetic modifications that alter amygdalar gene expression and dendritic density, increasing susceptibility to anxiety-like behaviours and alcohol ingestion in adulthood.140
