Summary Persistent drug-seeking behavior is hypothesized to co-opt the brain's natural reward-motivational system. Although ventral tegmental area (VTA) dopamine (DA) neurons represent a crucial component of this system, the synaptic adaptations underlying natural rewards and drug-related motivation have not been fully elucidated. Here we show that self-administration of cocaine, but not passive cocaine infusions, produced a persistent potentiation of VTA excitatory synapses, which was still present after 3 months abstinence. Further, enhanced synaptic function in VTA was evident even after 3 weeks of extinction training. Food or sucrose self-administration induced only a transient potentiation of VTA glutamatergic signaling. Our data show that synaptic function in VTA DA neurons is readily but reversibly enhanced by natural reward-seeking behavior, while voluntary cocaine self-administration induced a persistent synaptic enhancement that is resistant to behavioral extinction. Such persistent synaptic potentiation in VTA DA neurons may represent a fundamental cellular phenomenon driving pathological drug-seeking behavior.

Approximately 90% of alcoholics relapse within 4 years, in part because of an enhanced motivation to seek alcohol (EtOH). A novel G protein modulator (Gpsm1/AGS3) was up-regulated in the rat nucleus accumbens core (NAcore) but not in other limbic nuclei during abstinence from operant EtOH self-administration. Furthermore, NAcore AGS3 knockdown reduced EtOH seeking to preabstinence levels in a novel rat model of compulsive, human EtOH seeking. AGS3 can both inhibit G protein Gi␣-mediated signaling and stimulate G␤␥-mediated signaling. Accordingly, sequestration of G␤␥, but not Gi␣ knockdown, significantly reduced EtOH seeking to pre-abstinence levels. Thus, AGS3 and G␤␥ are hypothesized to gate the uncontrolled motivation to seek EtOH during abstinence. AGS3 up-regulation during abstinence may be a key determinant of the transition from social consumption to compulsionlike seeking during relapse.self-administration ͉ reinstatement ͉ alcohol deprivation effect ͉ Gi␣ ͉ G protein

Background-Addiction has been considered a disorder of motivational control over behavior, and the ventral tegmental area (VTA), in conjunction with other limbic brain structures, is thought to play a critical role in the regulation of a number of motivated behaviors including seeking of addictive drugs such as alcohol. Of particular interest is the ability of prolonged exposure of addictive drugs to enhance the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic receptors (AMPAR) in the VTA, as glutamate receptor activation can significantly regulate VTA neuron activity. Here, we examined whether voluntary ethanol intake altered VTA AMPAR function.

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 ...