TY - JOUR
T1 - Neural mechanisms of tolerance to the effects of cocaine
AU - Hammer, Ronald P.
AU - Egilmez, Yaprak
AU - Emmett-Oglesby, Michael W.
N1 - Funding Information:
We gratefully acknowledge support from USPHS Awards DA06645 to RPH and DA04137 to MWE-O. We thank Erick S. Cooke and Ron Henley, who contributed their expert technical assistance in various portions of the studies described above.
PY - 1997/3
Y1 - 1997/3
N2 - Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial self-stimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine D1-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.
AB - Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial self-stimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine D1-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.
KW - adaptation
KW - chronic
KW - cocaine
KW - deoxygluco se
KW - drug discrimination
KW - dynorphin
KW - immediate early gene
KW - reinforcement
KW - self-administration
KW - tolerance
UR - http://www.scopus.com/inward/record.url?scp=0343923442&partnerID=8YFLogxK
U2 - 10.1016/S0166-4328(97)83332-3
DO - 10.1016/S0166-4328(97)83332-3
M3 - Review article
C2 - 9079787
AN - SCOPUS:0343923442
SN - 0166-4328
VL - 84
SP - 225
EP - 239
JO - Behavioural Brain Research
JF - Behavioural Brain Research
IS - 1-2
ER -