Differential effects of acute amphetamine and phencyclidine treatment and withdrawal from repeated amphetamine or phencyclidine treatment on social interaction and social memory in rats

Abstract

Although animal models based on amphetamine (AMPH) or phencyclidine (PCP) treatment have been used extensively to study the neurobiological and behavioral characteristics of schizophrenia, there are conflicting reports regarding their validity in modeling the negative symptoms and cognitive deficits of schizophrenia. The present study examined how acute AMPH or PCP treatment (Experiment 1) and withdrawal from repeated AMPH treatment (Experiment 2) or PCP treatment (Experiment 3) affects social behavior and social recognition memory in male Sprague‐Dawley rats. Each subject was tested on two consecutive days. On the first day, the rats were tested four times (5 min/each) at 10‐min intervals with the same partner rat (termed “AAAA” day). One day later, the rats were tested with the previous partner in the first three sessions and with a new partner rat in the final session (termed “AAAB” day). The results show that acute AMPH treatment (1.5 mg/kg, sc) significantly reduced the time spent on social interaction, but did not affect social recognition on the first day. Acute AMPH only disrupted social recognition on the second day of drug testing. In contrast, acute PCP treatment (2.0 mg/kg, sc) had no effect on time spent on social interaction, but did significantly disrupt social recognition on both days. Withdrawal from repeated AMPH (3.0 mg/kg/day for 7 days, ip) or PCP (5.0 mg/kg/twice daily for 7 days, ip) treatment did not affect social interaction or social recognition, indicating a lack of long‐term detrimental effect of repeated AMPH or PCP treatment. These results suggest that acute AMPH treatment at a low dose (1.5 mg/kg) may be useful in modeling social withdrawal symptoms of schizophrenia, whereas acute PCP treatment at a similar dose range (2.0 mg/kg) may be useful in modeling the social cognitive deficit of schizophrenia.

Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine

“…Collectively, these data suggest that both acute and repeated psychostimulant administration result in an increased anxiety-like state during the early withdrawal period. Our finding of social motivation impairment in AMPH-withdrawn rats, as indexed by lower levels of social sniff (i.e., cage) time, is consistent with prior reports, indicating suppression of rat social behaviors following acute AMPH administration [48,49] and decreased motivation for natural reinforcers in animals undergoing AMPH-W [50,51]. Since both high anxiety and low social motivation were present in AMPH-withdrawn rats, changes in social approach/social cage time likely reflect the anxiety state of the rat, suggesting that reducing the anxiety induced by AMPH-W may correct the increased anxiety-like behavior and the social behavior deficit observed.…”

Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood

“…The rationale was that if the drug treatment regimen induces a sensitization and also impairs social functioning, these two behavioral effects are likely related. We examined the total social interaction time and two measurements of social working memory used a paradigm that we validated in amphetamine and phencyclidine-based animal models of schizophrenia (Li, He, 2012a). In this task, a subject rat was given multiple encounters with a juvenile partner rat in a new testing cage.…”

“…1 for the general experimental procedure), all rats were tested for social interaction as described previously (Li, He, 2012a). The test was one in a quiet test room.…”

“…However, no studies have examined whether adolescent antipsychotic treatment would affect social functioning in adulthood, one of seven primary cognitive domains that are affected in schizophrenia (Floresco et al, 2005, Green et al, 2004). Therefore, the secondary goal of this study was to examine how intermittent and continuous haloperidol treatment may potentially impact social interaction and social memory used a paradigm that we validated in amphetamine and phencyclidine-based animal models of schizophrenia (Li et al, 2012a). Findings from this study could help determine the clinical significance of adolescent haloperidol sensitization and enhance our understanding of the positive and negative impacts of adolescent antipsychotic treatment on drug response and behavioral functions.…”

Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: Assessing for tolerance and cross-tolerance to clozapine

“…The injection solution of PCP (gift from National Institute on Drug Abuse Chemical Synthesis and Drug Supply Program) was obtained by mixing the drug with 0.9% saline. The doses of PCP (3.2 mg/kg for experiment 2; 1.5 mg/kg for experiment 3, sc) were chosen based on our previous work (Feng et al , 2013; Li et al , 2012a; Sun et al , 2009; Zhang and Li, 2012; Zhao and Li, 2010). These doses of PCP are shown to induce robust hyperlocomotion and disruptions in PPI without causing severe stereotypy (Gleason and Shannon, 1997; Kalinichev et al , 2008, 2009).…”