Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 into the nucleus accumbens (NAcc) shell impairs expression of the sensitized locomotion and NAcc dopamine (DA) overflow normally observed in psychostimulant-exposed rats. Based on these results, we investigated the effect of NAcc shell KN-93 on the enhanced amphetamine (AMPH) intake normally observed in AMPH-relative to saline-exposed rats. Rats were administered five injections of either AMPH (1.5 mg/kg, i.p.) or saline, one injection every two-three days. Fourteen days following the last injection, they were trained to self-administer AMPH (200 μg/kg/infusion, i.v.) first on fixed ratio schedules (FR) and then on a progressive ratio schedule of reinforcement (PR). As expected, AMPH-exposed rats worked harder and obtained significantly more drug infusions than saline-exposed rats on the PR schedule. After four days of stable responding, all rats were bilaterally microinjected with (1 or 10 nmol/0.5 μl/side) into the NAcc shell, two minutes prior to the beginning of the self-administration session. Inhibiting CaMKII in this site reduced the enhanced drug intake observed in AMPH-exposed rats to levels no longer significantly different from those of saline-exposed rats. Responding in these latter controls was not affected by KN-93 nor did KN-93 affect responding in AMPH-exposed rats when it was infused into the NAcc core. Thus, in a manner similar to what has been reported for sensitized locomotion and NAcc DA overflow, these results suggest that inhibiting CaMKII in the NAcc shell attenuates the enhanced motivation to obtain a drug reinforcer that is normally displayed in AMPH-exposed rats. KeywordsNucleus accumbens; CaMKII; sensitization; amphetamine; self-administration; Repeated exposure to psychostimulants such as amphetamine (AMPH) enhances the ability of these drugs to produce locomotor activation and nucleus accumbens (NAcc) dopamine (DA) overflow, and also leads to enhanced drug taking [5,10,12,25,26,27]. These enhanced responses, manifestations of behavioral and neurochemical sensitization, have been proposed to model the transition from casual drug use to drug abuse and addiction [21,28]. Consistent with this view, rats previously exposed to AMPH that work harder than saline-exposed controls *Correspondence: Jessica Loweth, 5841 South Maryland Avenue, MC 3077, Chicago, IL 60637, TEL: (773) 702-2891, FAX: (773) 702-0857, E-MAIL: E-mail: jloweth@uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Together, the above findings suggest that CaMKII may ...