| dc.description.abstract | In contrast to other atypical antipsychotics, aripiprazole (ARZ) acts as a partial agonist, rather than an antagonist, at dopamine D2 receptors (Burris et al, 2002; Jordan et al, 2002). This unique pharmacology is thought to be essential to its multi-faceted use in the treatment of other disorders, particularly in its use as an adjunctive treatment for Major Depressive Disorder (Biler & Blondeau, 2011). Currently, little treatment is available to attenuate cognitive dysfunction in schizophrenic individuals (Schatzberg et al, 2010). However, clinical and neurocognitive studies have reported ARZ to improve cognition in schizophrenic subjects (Leuchet et al, 2003; Schatzberg et al, 2010), as well as attenuate working memory impairments and attentional deficits in animal models of psychosis (Carli et al, 2010; Nordquest et al, 2008; Nagi et a, 2008). Further evaluation of ARZ is needed to assess its ability to ameliorate higher-order cognitive processes in a laboratory behavioral pharmacological context. Differential-reinforcement-of-low-rates (DRL) is an operant timing schedule that requires animals to produce inter-response-times (IRTs) greater than a criterion temporal interval to obtain a reward. Because animals must temporally regulate their responses and internally estimate the criterion duration, successful performance on the DRL task is dependent on both temporal processing and controlled timing behaviors. Since individuals with schizophrenia exhibit temporal processing deficits (Carroll et al, 2008; Elveag et al, 2008; Tysk et al, 1990), the DRL schedule can be utilized to evaluate the effects of ARZ to attenuate timing behaviors in a laboratory animal model of psychosis. In the studies presented here, water-deprived male Sprague-Dawley rats were trained to perform a DRL-72 second schedule that was either signaled (DRLS-72; n = 8) or unsignaled (DRLU-72; n = 8). Upon making a correct response (IRT ≥ 72s), rats were given a small amount (0.06mL) of distilled water as reinforcement. Subjects were trained to perform the task in operant chambers with force-plate technology (Fowler et al, 2001), which allowed for high-precision measurements of locomotor activity (e.g., spatial patterning, distance traveled) and response characteristics (e.g., response durations, peak force of responses). Before drug treatment, DRLS-72 rats were significantly more successful at operant performance (e.g., higher reinforcement rates, longer IRTs) than DRLU-72 rats. In addition, DRLS-72 rats were less restricted in their spatial patterning and engaged in more locomotion, suggesting rats under the signaled contingency were less likely to engage in timing behaviors than DRLU-72 rats. These results reflect a difference of task difficulty between the two DRL schedules: The ability to perceive and respond to an external stimulus (DRLS-72 condition) was less demanding and difficult than internally estimating the temporal criterion (DRLU-72 condition). The acute administration of ARZ (1.0, 3.0, and 6.0mg/kg) at the beginning of the session induced right-ward shifts in IRT frequency distributions and lengthened median IRT values, though this effect was greater in the DRLU-72 group. This latter finding is likely due to the increased reliance of DRLU-72 rats on timing behaviors and temporal processing--behaviors and processes that are sensitive to the pharmacological modulation of brain dopamine systems (Hinton & Meck, 1997; Meck, 1983). Similar to other antipsychotics on DRL-mediated behavior (Wiley et al, 2000; O'Donnell & Seiden, 1983), ARZ generally altered operant behavior by dose-dependently reducing non-burst and burst response rates and reinforcement rates in both DRL groups. However, the 1mg/kg dose improved DRLU-72 operant performance by significantly increasing reinforcement rates and decreasing response rates--an effect that is similar to antidepressants (O'Donnell & Seiden, 1983). In a separate experiment, 16 naive rats were again trained to perform the DRLS-72 (n = 8) and DRLU-72 (n = 7) task. After completing seven 4-hr sessions of DRLS-72 or DRLU-72 (28 hours of training), rats were administered 5.0mg/kg amphetamine (AMPH) over several sessions to model a state of psychosis (Young et al, 2010). To evaluate the effects of ARZ to attenuate schizophrenic-like cognitive and behavioral deficits, rats were first administered AMPH immediately preceding the operant session, followed 30 minutes later by acute injections of 1.0, 3.0, or 6.0mg/kg ARZ. AMPH treatment produced a consistent pattern of behavior in rats: Subjects engaged in focused stereotypy during the first portion (approximately 1.5-hr) of the session followed by hyperlocomotion and operant-directed behavior in the latter portion (approximately 2.5-hr). AMPH induced timing deficits in DRLU-72 rats by shifting IRT distributions to the left and reducing median IRT values. In addition, AMPH treatment significantly impaired DRLU-72 performance by increasing non-burst responses rates, reducing reinforcement rates, and disrupting space usage relative to non-AMPH behavioral sessions. However, AMPH treatment did not induce timing deficits in DRLS-72 rats. AMPH did not significantly alter DRLS-72 IRT distributions, median IRTs, space usage, and reinforcement rates when compared to non-AMPH treatment sessions. This result implies that AMPH treatment induced schizophrenic-like timing deficits in DRLU-72 rats, but not DRLS-72 rats. It is likely that AMPH induced greater impairments in the DRLU-72 condition because the unsignaled DRL contingency was substantially more cognitively demanding than the DRLS-72 condition. In AMPH-treated rats, ARZ administration dose-dependently reduced hyperlocomotion and hastened recovery time from focused stereotypy. ARZ partially reversed the effects of AMPH in both DRL groups by significantly reducing non-burst responses, increasing median IRT values, and shifting IRT distributions to the right. However, ARZ could not completely attenuate AMPH-induced impairments in operant performance and collateral activity for DRLU-72 rats, suggesting that ARZ was limited in its capacity to attenuate schizophrenic-like cognitive and behavioral deficits that were induced by AMPH. | |
