PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity,☆☆

https://doi.org/10.1016/j.bbrc.2005.12.114Get rights and content

Abstract

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85α/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naïve rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D1/D2 agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT3 antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85α/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.

Section snippets

Materials and methods

Animals and drugs. Male Sprague–Dawley rats, initially weighing 150–200 g (Charles River Laboratories), were acclimated for 1 week prior to the experiments. Rats were housed in pairs in plastic cages in a humidity- and temperature-controlled room on a 12-h light/dark cycle. All experiments were conducted with an approved protocol from the Duke University Institutional Animal Care and Use Committee and were performed in accordance with NIH guideline (NIH publication 865-23). Cocaine HCl (NIDA)

Pergolide/ondansetron reverses cocaine-induced locomotor activation

In our experimental design, animals were given saline or cocaine for 4 days followed by a 9-days withdrawal period to establish behavioral sensitization in the cocaine group. Both cocaine and saline groups were then given pergolide/ondansetron, pergolide/saline or vehicles (DMSO/saline), followed by another 9-days withdrawal before being challenged with acute cocaine for sensitization assessment. The locomotor stimulation by cocaine challenge was measured for 30 min (Fig. 1). One-way ANOVA

Discussion

Cocaine dependence is a common and serious public health problem. To date, no pharmacological treatment is available that can consistently lead to long-term cocaine abstinence [26], [27]. This general lack of effective pharmacotherapy is largely due to the fact that the molecular basis of continued cocaine vulnerability following long-term withdrawal has been only partially elucidated. In rats, repeated administration of cocaine leads to behavioral sensitization, and this behavioral alteration

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    This work was supported by National Institute on Drug Abuse (DA-10327 and DA-14323 to EHE and NS-42124 to THL).

    ☆☆

    Abbreviations: DA, dopamine; PI3K, phosphatidylinositol 3-kinase; PFC, prefrontal cortex; NAc, nuclear accumbens; 5-HT, serotonin; NE, norepinephrine.

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