Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

Hu, Xiu‐Ti; Ford, Kerstin A.; White, Francis J.

doi:10.1038/sj.npp.1300654

Cited by 47 publications

(45 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability of the calcineurin inhibitor, cyclosporine, to potentiate both the locomotor response to acute cocaine exposure and the early response to repeated cocaine exposure suggests that calcineurin is part of a feedback pathway that limits the effects of cocaine. This is consistent with previous work showing decreased calcineurin expression in the nucleus accumbens of rats after repeated cocaine exposure and withdrawal (Hu et al 2005). Similarly, calcineurin over-expression in the mouse forebrain disrupts locomotor sensitization and the conditioned place preference associated with the administration of amphetamine, another psychostimulant (Biala et al 2005), suggesting that increased calcineurin activity may have more general effects that limit psychostimulant action.…”

Section: Discussionsupporting

confidence: 91%

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

et al. 2008

View full text Add to dashboard Cite

Rationale-Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.Objective-This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling in order to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.Methods-Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n=48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine treated animals from this initial experiment (n=24) also received an acute cocaine challenge on day 18 of testing.Results-Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 mins after cocaine injection and attenuated the sustained locomotor response 15 to 40 mins after cocaine. Further, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 mins after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.Conclusion-Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.

show abstract

Section: Discussionsupporting

confidence: 91%

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

et al. 2008

View full text Add to dashboard Cite

show abstract

“…N-and R-type calcium channel activity is also reduced (Zhang et al, 2002). Sodium channel phosphorylation is enhanced (Hu et al, 2005), leading to a reduction in sodium channel activation (Zhang et al, 1998). These multiple alterations likely converge to regulate the net output from the NAcc after cocaine administration.…”

Section: Contingent and Noncontingent Psychostimulant Administration mentioning

confidence: 99%

“…Accumulating evidence suggests that a common feature of many drugs of abuse is that they produce alterations in excitatory signaling, both directly through the regulation of synaptic function (Lu et al, 1997Hyman and Malenka, 2001;Winder et al, 2002;Lovinger et al, 2003), and indirectly through the regulation of cellular excitability (Zhang et al, 2002;Hu et al, 2004Hu et al, , 2005 in reward circuitry. Evidence to date suggests that psychostimulants differentially regulate glutamatergic synaptic transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAcc), two key components of the reward circuitry.…”

Section: Introductionmentioning

confidence: 99%

Cocaine Self-Administration Reduces Excitatory Responses in the Mouse Nucleus Accumbens Shell

Schramm-Sapyta

Olsen

Winder

2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.

show abstract

“…Most of these pre-and postsynaptic neuroadaptations have been characterized under experimental conditions that are quite different from those of the present study. However, certain are expected to be inhibitory (eg Hu et al, 2005;McClung and Nestler, 2003;Nestler, 2005). Others are expected to be excitatory (Pierce et al, 1996;Grimm et al, 2003;Boudreau and Wolf, 2005;McClung and Nestler, 2003;Ferrario et al, 2005).…”

Section: Core Vs Shellmentioning

confidence: 99%

Accumbal Neurons that are Activated during Cocaine Self-Administration are Spared from Inhibitory Effects of Repeated Cocaine Self-Administration

Peoples

Kravitz

Lynch

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

Hypoactivity of the accumbens is induced by repeated cocaine exposure and is hypothesized to play a role in cocaine addiction. However, it is difficult to understand how a general hypoactivity of the accumbens, which facilitates multiple types of motivated behaviors, could contribute to the selective increase in drug-directed behavior that defines addiction. Electrophysiological recordings, made during sessions in which rats self-administer cocaine, show that most accumbal neurons that encode events related to drugdirected behavior achieve and maintain higher firing rates during the period of cocaine exposure (Task-Activated neurons) than do other accumbal neurons (Task-Non-Activated neurons). We have hypothesized that this difference in activity makes the neurons that facilitate drug-directed behavior less susceptible than other neurons to the chronic inhibitory effects of cocaine. A sparing of neurons that facilitate drug-directed behavior from chronic hypoactivity might lead to a relative increase in the transmission of neuronal signals that facilitate drug-directed behavior through accumbal circuits and thereby contribute to changes in behavior that characterize addiction (ie differential inhibition hypothesis). A prediction of the hypothesis is that neurons that are activated in relation to task events during cocaine self-administration sessions will show less of a decrease in firing across repeated self-administration sessions than will other neurons. To test this prediction, rats were exposed to 30 daily (6 h/day) cocaine self-administration sessions. Chronic extracellular recordings of single accumbal neurons were made during the second to third session and the 30th session. Between-session comparisons showed that decreases in firing were exhibited by Task-Non-Activated, but not by Task-Activated, neurons. During the day 30 session, the magnitude of the difference in firing rate between the two groups of neurons was positively related to the propensity of animals to seek and take cocaine. The findings of the present study are consistent with a basic prediction of the differential inhibition hypothesis and may be relevant to understanding cocaine addiction.

show abstract

Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

Cited by 47 publications

References 49 publications

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

Cocaine Self-Administration Reduces Excitatory Responses in the Mouse Nucleus Accumbens Shell

Accumbal Neurons that are Activated during Cocaine Self-Administration are Spared from Inhibitory Effects of Repeated Cocaine Self-Administration

Contact Info

Product

Resources

About