Increased accumbens Cdk5 expression in rats after short-access to self-administered cocaine, but not after long-access sessions

Abstract

Upregulation of cyclin-dependent kinase 5 (Cdk5) after chronic cocaine administration has led to speculation that Cdk5 plays an important role in drug addiction. However, as Cdk5 involvement is implicated in a variety of neural events, including neuronal development, synaptic plasticity and learning, a specific role in drug abuse is yet to be determined. The present study utilized cocaine self-administration and food-reinforced operant procedures to assess possible relationships between cocaine intake, food-reinforced operant responding, behavioral activity, and Cdk5 levels in the nucleus accumbens (NAcc), ventral tegmental area (VTA), and prefrontal cortex (PFC) in rats. In Experiment 1, animals undergoing daily cocaine self-administration (1-h/30 days) or food-reinforced operant sessions (20-min/30 days) showed significant between-group differences in operant responding and behavioral activity, but no significant differences in NAcc, VTA or PFC Cdk5 levels compared to a Handled Control group. In Experiment 2, animals that had self-administered cocaine in 10 daily 1-h sessions (Short-Access Cocaine) showed significantly greater NAcc Cdk5 expression compared to an Unhandled Control group, and no evidence of cocaine-induced behavioral sensitization. Animals given 4-h daily access to cocaine over the same number of sessions (Long-Access Cocaine) showed significantly enhanced cocaine-reinforced responding and locomotor activation by the end of the sessions, but no significant differences in Cdk5 expression compared to Control animals. These findings suggest that overexpression of Cdk5 may be a transient adaptation to cocaine experience that subsides with increased cocaine exposure and does not correspond with measures of cocaine-induced behavioral sensitization.

Fig 1

Coronal (A) and sagittal (B) sections of the rat brain sections isolated for western blot analyses with distances from bregma. A. NAcc and VTA regions collected using a 2.5 mm tissue biopsy punch. B. PFC region removed using a razor blade cut.

Fig 2

Lever presses and locomotor activity during operant sessions. Panel A/Experiment 1. Top: Rats responded significantly more for sucrose pellets during 20-min operant sessions than for cocaine in 1-hr self-administration sessions. Bottom: Significantly higher locomotor activity during cocaine-compared to during food-reinforced sessions. Panel B/Experiment 2. Top: Rats responded significantly more for cocaine during 4-hr sessions (Long-Access) than during 1-hr sessions (Short-Access). Long-Access rats showed significantly greater response rates during Days 8-10 (** = p<0.01) than during Days 1-3. Insert: Cumulative 1-hr response totals (10 sessions) for Long-Access Cocaine (1st hr of 4-hr session; white) and Short-Access Cocaine (black) were not significantly different. Bottom: Total locomotor activity counts were significantly higher during 4-hr compared to 1-hr cocaine self-administration sessions. At Day 10, locomotor activity was significantly greater than during Days 2-5 (* = significantly greater than Days 2-5 at p<0.05). Insert: Cumulative 1-hr locomotor activity totals for Long-Access Cocaine (white) and Short-Access Cocaine (black) were not significantly different.

Fig 3

Cdk5 expression in the NAcc, VTA and PFC. Bars show mean protein content (± SEM) expressed as a percentage of controls. Representative Western blots of NAcc Cdk5 and actin content. A/Experiment 1. Lanes 1, 2 and 3 correspond to Handled Control, Cocaine and Food groups, respectively. No group differences in Cdk5 protein content were detected in any brain region sampled between rats that were handled for 30 days and those with 30 cocaine self-administration or food-reinforced operant sessions. B/Experiment 2. Lanes 1, 2 and 3 correspond to Unhandled Control, Short-Access Cocaine and Long-Access Cocaine, respectively. Significant differences in NAcc Cdk5 protein content were detected between Unhandled Control and Short-Access Cocaine (* = p< 0.05). No other group differences in Cdk5 expression were detected in any other brain regions sampled.