Reversal of Cocaine-Induced Behavioral Sensitization and Associated Phosphorylation of the NR2B and GluR1 Subunits of the NMDA and AMPA Receptors

Abstract

Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.

Reversal of cocaine sensitization-induced behavioral sensitization normalizes GAD67 and GABAA receptor α2 subunit expression, and PKC ζ activity

“…Our previous studies have demonstrated that cocaine induces changes in expression and phosphorylated levels of the NR2B subunit of the NMDA receptors and the phosphorylated levels of GluR1 subunit of the AMPA receptors in the nucleus accumbens (NAc), and pergolide-ondansetron treatment normalizes these changes [3]. However, the mechanisms how a 5-HT 3 receptor antagonist influences NAc dopamine and glutamate transmission are unclear.…”

“…on day 10. As either pergolide or ondansetron alone does not exert consistent effects on established cocaine sensitization and/ or associated molecular markers (3,5,18), the data from these treatment groups were not included in the present study.…”

“…The animals were treated as previously described [3,4]. Briefly, animals were ranked according to their responses to cocaine (7.5 mg/kg, s.c.) on day 1 and then divided into three groups.…”

“…We have recently demonstrated in rats that sensitization established previously by 5 daily cocaine injections and a subsequent 9-day withdrawal period can be reversed by daily pergolide administration if each injection is followed 3.5 h later with the 5-HT 3 antagonist ondansetron [3,4]. Furthermore, similar treatment with ondansetron can decrease the break-point under progressive-ratio selfadministration [5] and reduce cocaine intake under oral self-administration [6].…”

“…However, the mechanisms how a 5-HT 3 receptor antagonist influences NAc dopamine and glutamate transmission are unclear. Previous studies revealed that 5-HT 3 receptors in the NAc mediate the modulatory action of 5-HT 3 antagonists on mesolimbic DA-mediated behaviors (e.g. locomotor activity) or accumbal DA outflow [7].…”