Peter W. Kalivas, Ph.D.
Washington State University
Pullman, WA

Behavioral sensitization induced by repeated cocaine administration is associated with long-term alterations in neurotransmission in the nucleus accumbens (Pierce and Kalivas 1997a). Notably, both presynaptic and postsynaptic dopamine transmissions are enhanced in cocaine-sensitized rats.

Recent data collected primarily by Margaret Gnegy at the University of Michigan, as well as by our own group, demonstrate that the increased releasability of dopamine in the nucleus accumbens or striatum of cocaine- or amphetamine-sensitized rats arises from an increase in calcium transduction. Specifically, there is an enduring increase in CaM-KII activity and the CaM-KII phosphorylated form of synapsin I in rats treated with repeated amphetamine (Pierce and Kalivas 1997b). The increased release of dopamine is antagonized by calcium channel blockers and CaM-KII inhibitors (Iwata et al. 1996). Furthermore, microinjection of these antagonists into the nucleus accumbens inhibits the expression of behavioral sensitization to cocaine (unpublished observations).

In addition to increased releasability of transmitter, repeated psychostimulant administration alters postsynaptic dopamine transduction in the nucleus accumbens, as evidenced by increased electrophysiological responsiveness to D1 dopamine receptor agonists (Henry and White 1991).

More recently, a number of laboratories have shown that repeated psychostimulant administration produces a change in gene expression. However, to date only two changes in gene expression parallel the time course of behavioral sensitization by enduring for weeks after discontinuing repeated drug administration. Both gene products are apparently transcription factors including a long-lasting AP-1 DNA binding complex (probably related to persistent expression of delta-FosB-related protein) (Nye et al. 1995) and NAC-1 (Cha et al. 1997). Recently, FosB-mutant mice were shown to have a heightened behavioral sensitivity to contingent and noncontingent cocaine administration (Hiroi et al. 1997). NAC-1 is a recently isolated mRNA that contains a POZ binding domain and is upregulated for at least 3 weeks after discontinuing repeated cocaine administration (Cha et al. 1997). Similar to the FosB mutant mice, reducing NAC-1 gene expression by microinjecting antisense oligonucleotide into the nucleus accumbens dramatically augmented the stimulant effects of acute and repeated cocaine administration (unpublished data). The fact that the inhibition and abolition of NAC-1 and FosB gene expression, respectively, enhanced the behavioral effects of cocaine indicates a possible role for either protein in both the acute rewarding and psychostimulant effects of cocaine, as well as in long-term behavioral alterations such as paranoia and drug- craving.

Acknowledgment

This research was supported by National Institute on Drug Abuse Grant No. DA-03906.

References

Cha, X-Y.; Pierce, R.C.; Kalivas, P.W.; and Mackler, S.A. NAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration. J Neurosci 17:6864-6871, 1997.

Henry, D.J., and White, F.J. Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J Pharmacol Exp Ther 258:882-890, 1991.

Hiroi, N.; Brown, J.R.; Haile, C.N.; Ye, H.; Greenberg, M.E.; and Nestler, E.J. FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc Natl Acad Sci U S A 94:10397-10402, 1997.

Iwata, S.; Hewlett, G.H.; Ferrell, S.T.; Czernik, A.J.; Meiri, K.F.; and Gnegy, M.E. Increased in vivo phosphorylation state of neuromodulin and synapsin I in striatum from rats treated with repeated amphetamine. J Pharmacol Exp Ther 278:1428-1434, 1996.

Nye, H.E.; Hope, B.T.; Kelz, M.B.; Iadorola, M.; and Nestler, E.J. Pharmacological studies of the regulation of chronic FOS-related antigen induction by cocaine in the striatum and nucleus accumbens. J Pharmacol Exp Ther 275:1671-1680, 1995.

Pierce, R.C., and Kalivas, P.W. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192-216, 1997a.

Pierce, R.C., and Kalivas, P.W. Repeated cocaine modifies the mechanism by which amphetamine releases dopamine. J Neurosci 17:3254-3261, 1997b.

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