Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats

Abstract

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V_1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V_1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.

Fig. 1

Effect of oxytocin (OXY, 0.03, 0.1, and 0.3 mg/kg; s.c., administered after arena habituation) or vehicle (VEH, 0.154 M saline 1 ml/kg) administered according to the protocol shown in a on four occasions at 7 day intervals so that each rat received every dose on b total locomotor activity (LMA, cumulative ambulatory counts, mean ± SEM), and c change in body temperature (from basal recorded 5 min pre injection, mean ± SEM, °C) in adult Lister-hooded rats (n = 12, within-subjects design) recorded in an activity box for 90 min post injection. c *P < 0.05, ***P < 0.001 VEH vs. 0.3 or 0.1 mg/kg OXY; ^##P < 0.01, ^###P < 0.001, 0.3 mg/kg OXY vs. 0.1 mg/kg OXY; ⁺⁺P < 0.01 0.3 mg/kg OXY from 0.03 mg/kg OXY; Tukey’s post hoc test

Fig. 2

Determination of the effect of pre-treatment with the selective V_1a receptor antagonist, SR49059 (1 mg/kg), or the selective oxytocin receptor antagonist, L-368,899 (2 mg/kg), according to the experimental protocol shown in a on b the cumulative locomotor ambulatory counts, and c the change in body temperature (°C) over 90 min following injection of oxytocin (OXY, 0.3 mg/kg. s.c., administered 15 min after the antagonist) or vehicle (VEH, 1 ml/kg saline). Data are presented as mean ± SEM, n = 12 per treatment (within-subjects design). In b **P < 0.01 from VEH + VEH controls. In c * P < 0.05 and *** P < 0.001 from VEH + VEH controls, ⁺ P < 0.05, ⁺⁺ P < 0.01 and ⁺⁺⁺ P < 0.001 0.03 mg/kg OXY from 0.3 mg/kg OXY and ^###P < 0.001 0.1 mg/kg OXY from 0.3 mg/kg OXY, following Tukey’s post hoc test

Fig. 3

a Experimental protocol used to consecutively examine the effect of oxytocin on phencyclidine-induced behavior (this figure), social interaction (Fig. 4), and prefrontal cortex and nucleus accumbens dopamine and 5-HT efflux by microdialysis (Fig. 5), for full details of the methods see Figure S1. Comparative effect of oxytocin (OXY, 0.03–0.1 mg/kg; s.c) and vehicle (VEH, 0.154 M saline 1 ml/kg) on (mean ± SEM) the b time course of phencyclidine (PCP, 5.6 mg/kg; i.p.)-induced locomotor activity (LMA; cumulative counts/5 min epoch), c total ambulatory counts in 1 h (following injection with PCP/VEH), and d change in body temperature (from basal, 5 min prior to injection, °C) in adult Lister-hooded rats recorded in an activity box. In b and c *P < 0.05, **P < 0.01, ***P < 0.001 compared to VEH-SAL; ⁺P < 0.05, ⁺⁺P < 0.01 compared with VEH-PCP; ^#P < 0.05, ^##P < 0.01 compared with 0.03 mg/kg OXY-PCP; Tukey's post hoc) VEH = saline vehicle, OXY = oxytocin; n = 8 per group (between-subjects design) as indicated VEH-VEH; VEH-PCP; OXY 0.03 mg/kg-PCP; OXY 0.1 mg/kg-PCP

Fig. 4

Effect of oxytocin (OXY, 0.1 mg/kg; s.c.) and vehicle (VEH, 0.154 M saline 1 ml/kg) on social interaction between two male Lister-hooded rats from different litters paired by similar weight and the same previous drug treatment, recorded over 10 min. a individual behaviors (s), b total time in social interaction (s), c body temperature change from basal (immediately prior to injection), before (45 min post injection) and after the interaction trial (55 min post injection as indicated; °C) and d the number of pro-social 50 kHz ultrasonic vocalizations (USVs) emitted by both rats in each pair. All data are presented as mean ± SEM. e Representative spectrographs showing pro-social 50 kHz USVs emitted from rat pairs defined into three subtypes; flat, step and trill, following Fast Fourier transformation and pattern analysis. a *P = 0.05; Student’s unpaired t-test. c *P < 0.05 from OXY. d Following log₁₀ transformation, *P < 0.05 ***P < 0.001 VEH vs. OXY; Sidak post hoc; VEH = saline vehicle, OXY = 0.1 mg/kg oxytocin; n = 8 pairs/group. NB. A different time scale is used to show ano-genital and body sniffing from other, less frequent, behaviors

Fig. 5

Comparison of the effects of oxytocin (OXY, 0.1 mg/kg; s.c.) or vehicle (VEH, 0.154 M saline 1 ml/kg) on a dopamine and b serotonin (5-HT) overflow (mean ± SEM, pmol/ml) in the prefrontal cortex (PFC) and nucleus accumbens (NAc) measured by microdialysis, and concomitant c core body temperature (mean ± SEM; °C) in freely-moving rats. a Changes to dopamine from baseline in the PFC (0.0728 pmol/ml) and NAc (0.176 pmol/ml) over the 2 h period. b Changes in 5-HT levels from baseline in the PFC (2.212 pmol/ml) and NAc (3.677 pmol/ml). PFC: Dopamine: n = 7 VEH, n = 6 OXY, 5-HT: n = 7 VEH, n = 6 OXY; NAc: Dopamine: n = 7 VEH, n = 7 OXY, 5-HT: n = 8 VEH, n = 8 OXY; VEH = saline vehicle, OXY = 0.1 mg/kg oxytocin; PFC; Prefrontal Cortex, NAc; Nucleus Accumbens. c *P < 0.05 VEH vs OXY; Sidak post hoc. VEH = saline vehicle, OXY = 0.1 mg/kg oxytocin; n = 8 per treatment group; between-subjects design