a rate of presentation leads to a rapid uncoupling of the system as occurs with 
multiple injections of cocaine. Recent studies with once-daily injections suggest 
that even with this more mild treatment schedule full uncoupling can occur if 
cocaine is administered for a long enough duration (e.g., 14 days) (Hope et al. 
1992). 
The second area for speculation is the potential impact the induction and 
suppression processes may have on the human abuse situation. Because 
the uncoupling switches the cell from a transmitter-regulated mode of IEG 
expression to a purely constitutive mode, the normal response to hedonic cues 
at the molecular level is short circuited. Thus, certain gene products may 
accumulate to abnormal levels or fail to accumulate as necessary and thereby 
establish a new but abnormal complement of neuronal gene products. If the 
drug is abused continually , then maintenance of the new state (constitutive 
mode only) is relatively ensured, especially given the long duration of the 
suppression effect. In fact, the suppression could carry over from one session 
to another, even with a hiatus of 1 or more days as often occurs in human 
abuse (Spotts and Shontz 1980; Gawin and Ellinwood 1988; Gawin 1991). 
Such a scenario could yield a very prolonged state of dysregulation. Thus, it is 
possible that one or more of the problems related to addiction and craving may 
result, not from the prominent induction of lEGs seen with a single injection, 
but from the prolonged blockade of regulated expression engendered by the 
suppression process. 
REFERENCES 
Barton, A.C., and Sibley, D.R. Agonist-induced desensitization of D^dopamine 
receptors linked to adenylyl cyclase activity in cultured NS20Y 
neuroblastoma cells. Mol Pharmacol 38:351 -354, 1 990. 
Cohen, D.R., and Curran, T. Fra-1: A serum-induced, cellular immediate-early 
gene that encodes a fos-related antigen. Mol Cell Biol 8:2063-2069, 1 988. 
Curran, T.; Gordon, M.B.; Rubino, K.L.; and Sambucetti, L.C. Isolation and 
characterization of the c-fos (rat) cDNA and analysis of post-translational 
modification in vitro. Oncogene 2:79-84, 1987. 
Draisci, G., and ladarola, M.J. Temporal analysis of increases in c-fos, 
preprodynorphin and preproenkephalin mRNAs in rat spinal cord. Mol 
Brain Res 6:31 -37, 1 989. 
Foltin, R.W., and Fischman, M.W. Smoked and intravenous cocaine in 
humans: Acute tolerance, cardiovascular and subjective effects. 
J Pharmacol Exp Ther 257:247-261, 1991. 
Foulkes, N.S.; Borrelli, E.; and Sassone-Corsi, P. CREM gene: Use of 
alternative DNA-binding domains generates multiple antagonists of cAMP- 
induced transcription. Cell 64:739-749, 1991a. 
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