Addiction to Cocaine and Amphetamine

Unlike CREB, which is constitutively synthesized and regulated largely by protein phosphorylation, proteins of the Fos family are induced from very low levels of expression by acute cocaine or amphetamine administration. With repeated stimulation, induction of c-fos, c-jun, junB, and zif/268 is markedly down-regulated (Hope et al. 1992xHope, B.T, Kosofsky, B, Hyman, S.E, and Nestler, E.J. Proc. Natl. Acad. Sci. USA. 1992; 89: 5764–5768Crossref | PubMed | Scopus (347)See all ReferencesHope et al. 1992). In contrast, certain Fos-related antigens accumulate with chronic cocaine treatment or other chronic stimuli (“chronic Fras”) and are expressed persistently (Hope et al. 1994xHope, B.T, Nye, H.E, Kelz, M.B, Self, D.W, Iadarola, M.J, Nakabeppu, Y, Duman, R.S, and Nestler, E.J. Neuron. 1994; 13: 1235–1244Abstract | Full Text PDF | PubMed | Scopus (411)See all ReferencesHope et al. 1994). Alterations in the composition of AP-1 complexes over time might permit cells to activate specific programs of adaptation appropriate to the strength and time course of the stimulus. However, an unsolved problem with respect to downstream effects of AP-1 proteins in the dorsal and ventral striatum is that increased expression of AP-1 proteins, per se, or increased binding of AP-1 proteins to DNA as measured by gel shift assays does not necessarily indicate increases in transcriptional activation. Thus, in transformed cell lines, phosphorylation of Ser-63 or Ser-73 within the c-Jun activation domain by Jun N-terminal kinases (JNKs) has been shown to increase its ability to activate transcription markedly without affecting its ability to heterodimerize or bind DNA. The degree to which cocaine- and amphetamine-induced Fos and Jun family members are active as transcription factors in DA receptive neurons has not yet been established (Figure 2Figure 2). Additional challenges include the identification of targets of both the CREB and AP-1 pathways that might lead to significant neural plasticity and behavioral change.Several other alterations in cellular proteins caused by chronic cocaine administration are of particular interest because they also occur with chronic morphine administration. Thus, for example, both cocaine and morphine increase levels of tyrosine hydroxylase and decrease levels of three neurofilament proteins in the VTA (reviewed bySelf and Nestler 1995xSelf, D.W and Nestler, E.J. Annu. Rev. Neurosci. 1995; 18: 463–496Crossref | PubMedSee all ReferencesSelf and Nestler 1995). Understanding the relationship of potential cytoskeletal changes to physiology or behavior remains an important goal.In addition to adaptations within the brain reward circuitry itself, drugs of abuse produce long-lived, positively biased, emotional memories that may be activated by environmental or interoceptive cues. The mesoaccumbens DA circuitry appears to be involved in producing memories associated with reinforcement. It is an open question whether cue-dependent drug craving activates the mesoaccumbens DA pathway or whether DA is involved in the production of such memories but not in their subsequent recall. Evidence exists on both sides of the issue (Brown and Fibiger, 1992xBrown, E.E, Robertson, G.S, and Fibiger, H.C. J. Neurosci. 1992; 12: 4112–4121PubMedSee all ReferencesBrown and Fibiger, 1992, and references therein). The resolution is important since development of pharmacological blockers of cue-dependent craving, which has been hypothesized (but not shown) to predispose to relapse in humans, will obviously differ depending on the receptors and circuits involved.In summary, progress is being made in understanding the molecular and cellular basis of addiction to cocaine and amphetamine. While the identification of significant molecular alterations and their relationship to behavior are in their early days, the field is progressing rapidly and should lead to the development of treatments for cocaine and amphetamine addiction.*Present address: Office of the Director, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland 20857.