The neuroplastic changes outlined previously are triggered and sustained by molecular and cellular adaptations that can presumably also interact with genetic and environmental vulnerability to addiction. In the binge/intoxication stage, both signal transduction mechanisms and changes in gene transcription have been identified. For example, chronic exposure to a wide variety of abused drugs upregulates cAMP formation, cAMP-dependent protein kinase A (PKA) activity, and PKA-dependent protein phosphorylation in the nucleus accumbens. Numerous interventions that tonically activate nucleus accumbens cAMP/PKA signalling promote escalations in drug self-administration or compulsive-like drug-seeking behaviour, and the upregulation of a postsynaptic Gs/cAMP/PKA signalling pathway in the nucleus accumbens might constitute a critical neuroadaptation that is central to the establishment and maintenance of the addicted state.136,137
