Different Roles of BDNF in Nucleus Accumbens Core versus Shell during the Incubation of Cue-Induced Cocaine Craving and Its Long-Term Maintenance

Brain-derived neurotrophic factor (BDNF) contributes to diverse types of plasticity, including cocaine addiction. We investigated the role of BDNF in the rat nucleus accumbens (NAc) in the incubation of cocaine craving over 3 months of withdrawal from extended access cocaine self-administration. First, we confirmed by immunoblotting that BDNF levels are elevated after this cocaine regimen on withdrawal day 45 (WD45) and showed that BDNF mRNA levels are not altered. Next, we explored the time course of elevated BDNF expression using immunohistochemistry. Elevation of BDNF in the NAc core was detected on WD45 and further increased on WD90, whereas elevation in shell was not detected until WD90. Surface expression of activated tropomyosin receptor kinase B (TrkB) was also enhanced on WD90. Next, we used viral vectors to attenuate BDNF-TrkB signaling. Virus injection into the NAc core enhanced cue-induced cocaine seeking on WD1 compared with controls, whereas no effect was observed on WD30 or WD90. Attenuating BDNF-TrkB signaling in shell did not affect cocaine seeking on WD1 or WD45 but significantly decreased cocaine seeking on WD90. These results suggest that basal levels of BDNF transmission in the NAc core exert a suppressive effect on cocaine seeking in early withdrawal (WD1), whereas the late elevation of BDNF protein in NAc shell contributes to incubation in late withdrawal (WD90). Finally, BDNF protein levels in the NAc were significantly increased after ampakine treatment, supporting the novel hypothesis that the gradual increase of BDNF levels in NAc accompanying incubation could be caused by increased AMPAR transmission during withdrawal

The rate of intravenous cocaine or amphetamine delivery does not influence drug-taking and drug-seeking behavior in rats

We studied the influence of rate of intravenous infusion of cocaine or amphetamine on drug-taking and seeking behavior. First, drug-naive rats were tested for acquisition of self-administration of increasing doses of amphetamine or cocaine infused over 5 or 100 s. Second, self-administration of cocaine or amphetamine infused over 5¿100 s was assessed on fixed or progressive-ratio (PR) reinforcement schedules. Finally, the ability of a single 5 or 100 s amphetamine or cocaine infusion to reinstate extinguished drug seeking was assessed. Although slower infusion rates produced a small effect on drug taking under continuous-reinforcement conditions, infusion rate did not alter drug taking on intermittent or PR reinforcement schedules, or the ability of cocaine or amphetamine to reinstate drug seeking. Taken together, our results suggest that variation in drug delivery rate over a range that we previously found alters the induction of behavioral sensitization, gene-expression and striatal dopamine activity, does not markedly alter drug-taking or seeking behavior

Probability of infection of a node with either one or both of the two diseases.

<p>We calculate the probability of infection of node (circled) by first calculating the probability that a neighbor is infected. We must account separately for cases in which caught the first disease from itself or from another of its neighbors, since these two cases have different implications for the spread of the second disease.</p

Phase diagram of the model for a network with a Poisson degree distribution with mean degree 3.

<p>The horizontal dashed line represents the parameter values used for Fig. 2.</p

Number of individuals infected with the two diseases on a network with a Poisson degree distribution.

<p>The network has mean degree and the transmissibility of the second disease is fixed at , while the transmissibility of the first disease is varied. The solid curves show the analytical solutions, Eqs. (7) and (17), while the points show the results of numerical simulations of the model. Each point is an average of simulations on 100 networks of a million nodes each. Error bars are smaller than the points in all cases. The two vertical dashed lines indicate the positions of the epidemic thresholds for the two diseases, from Eqs. (27) and (43).</p

Dopamine “Ups and Downs” in Addiction Revisited

Repeated drug use can change dopamine function in ways that promote the development and persistence of addiction. But in what direction? By one view, drug use blunts dopamine neurotransmission, producing a hypodopaminergic state that fosters further drug use to overcome a dopamine deficiency. Another view is that drug use enhances dopamine neurotransmission, producing a sensitized, hyperdopaminergic reaction to drugs and drug cues. According to this second view, continued drug use is motivated by sensitization of drug ‘wanting’. Here we discuss recent evidence supporting the latter view, both from preclinical studies using intermittent cocaine self-administration procedures that mimic human patterns of use, and related human neuroimaging studies. These studies have implications for modeling addiction in the laboratory, and for treatment

Withdrawal from cocaine self-administration alters NMDA receptor-mediated Ca2+ entry in nucleus accumbens dendritic spines.

We previously showed that the time-dependent intensification ("incubation") of cue-induced cocaine seeking after withdrawal from extended-access cocaine self-administration is accompanied by accumulation of Ca(2+)-permeable AMPA receptors (CP-AMPARs) in the rat nucleus accumbens (NAc). These results suggest an enduring change in Ca(2+) signaling in NAc dendritic spines. The purpose of the present study was to determine if Ca(2+) signaling via NMDA receptors (NMDARs) is also altered after incubation. Rats self-administered cocaine or saline for 10 days (6 h/day). After 45-47 days of withdrawal, NMDAR-mediated Ca(2+) entry elicited by glutamate uncaging was monitored in individual NAc dendritic spines. NMDAR currents were simultaneously recorded using whole cell patch clamp recordings. We also measured NMDAR subunit levels in a postsynaptic density (PSD) fraction prepared from the NAc of identically treated rats. NMDAR currents did not differ between groups, but a smaller percentage of spines in the cocaine group responded to glutamate uncaging with NMDAR-mediated Ca(2+) entry. No significant group differences in NMDAR subunit protein levels were found. The decrease in the proportion of spines showing NMDAR-mediated Ca(2+) entry suggests that NAc neurons in the cocaine group contain more spines which lack NMDARs (non-responding spines). The fact that cocaine and saline groups did not differ in NMDAR currents or NMDAR subunit levels suggests that the number of NMDARs on responding spines is not significantly altered by cocaine exposure. These findings are discussed in light of increases in dendritic spine density in the NAc observed after withdrawal from repeated cocaine exposure

Withdrawal from Cocaine Self-Administration Alters NMDA Receptor-Mediated Ca²⁺ Entry in Nucleus Accumbens Dendritic Spines

We previously showed that the time-dependent intensification (“incubation”) of cue-induced cocaine seeking after withdrawal from extended-access cocaine self-administration is accompanied by accumulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in the rat nucleus accumbens (NAc). These results suggest an enduring change in Ca2+ signaling in NAc dendritic spines. The purpose of the present study was to determine if Ca2+ signaling via NMDA receptors (NMDARs) is also altered after incubation. Rats self-administered cocaine or saline for 10 days (6 h/day). After 45–47 days of withdrawal, NMDAR-mediated Ca2+ entry elicited by glutamate uncaging was monitored in individual NAc dendritic spines. NMDAR currents were simultaneously recorded using whole cell patch clamp recordings. We also measured NMDAR subunit levels in a postsynaptic density (PSD) fraction prepared from the NAc of identically treated rats. NMDAR currents did not differ between groups, but a smaller percentage of spines in the cocaine group responded to glutamate uncaging with NMDAR-mediated Ca2+ entry. No significant group differences in NMDAR subunit protein levels were found. The decrease in the proportion of spines showing NMDAR-mediated Ca2+ entry suggests that NAc neurons in the cocaine group contain more spines which lack NMDARs (non-responding spines). The fact that cocaine and saline groups did not differ in NMDAR currents or NMDAR subunit levels suggests that the number of NMDARs on responding spines is not significantly altered by cocaine exposure. These findings are discussed in light of increases in dendritic spine density in the NAc observed after withdrawal from repeated cocaine exposure.</p