Evaluating early preventive antipsychotic and antidepressant drug treatment in an infection-based neurodevelopmental mouse model of schizophrenia

Abstract

Current pharmacotherapy of schizophrenia remains unsatisfactory with little hope for complete functional restoration in patients once the disease has developed. A preventive approach based on intervention in the prodromal stage of the disease aiming to preserve functional integrity by halting the progress of the disease is therefore extremely attractive. Here, we investigated the effects of preventive antipsychotic or antidepressant drug treatment in a well-established neurodevelopmental mouse model of multiple schizophrenia-related abnormalities. Pregnant mice on gestation day 9 were exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (2 mg/kg, intravenously) or corresponding vehicle treatment, and the resulting offspring from both prenatal treatment conditions were subjected to chronic antipsychotic (haloperidol or clozapine), antidepressant (fluoxetine), or placebo treatment during the periadolescent stage of development. The effects of the preventive pharmacotherapy on behavioral and pharmacological functions were then investigated in adulthood using paradigms relevant to schizophrenia, namely prepulse inhibition, latent inhibition, and sensitivity to psychostimulant drugs. We show that periadolescent treatment with the reference antipsychotic and antidepressant drugs can successfully block the emergence of multiple psychosis-related behavioral and pharmacological abnormalities in subjects predisposed to adult brain pathology by exposure to prenatal immune challenge. At the same time, however, our study reveals numerous negative influences of the early pharmacological intervention on normal behavioral development in control subjects. Hence, even though preventive pharmacotherapy may be beneficial in individuals with predisposition to psychosis-related brain dysfunctions, chronic antipsychotic or antidepressant drug treatment in false-positive subjects is associated with substantial risk for long-term behavioral disturbances in adulthood.

Fig. 1.

Experimental Design Used to Study Early Preventive Antipsychotic and Antidepressant Drug Treatment in the Present Infection-Based Neurodevelopmental Mouse Model of Schizophrenia-Like Disorder. Pregnant mice on GD 9 were exposed to PolyI:C (2 mg/kg, intravenously) or corresponding control (CON, saline) treatment. The resulting offspring from both treatment conditions (ie, PolyI:C offspring and CON offspring) were then subjected to chronic antipsychotic (haloperidol or clozapine), antidepressant (fluoxetine), or vehicle treatment during the periadolescent stage of development, ie, between postnatal days (PNDs) 35 and 65. On PND 65, the periadolescent drug regime was stopped. Behavioral and pharmacological testing of the offspring was conducted in adulthood (ie, between PNDs 90 and 120) in a drug-free state.

Fig. 2.

Modulation of Prepulse Inhibition (PPI) of the Acoustic Startle Reflex by Periadolescent Antipsychotic and Antidepressant Drug Treatment in Offspring Born to PolyI:C-Treated and Control (CON) Mothers. Inhibition of the startle reflex to a 120-dB_A stimulus was achieved through prepulses of distinct intensities (71, 77, and 83 dB_A, which corresponded to 6, 12, and 18 dB_A above background, respectively). (a) The figure shows percentage PPI (%PPI) as a function of prepulse intensity for CON offspring and offspring born to PolyI:C-treated mothers; in addition, the mean %PPI is depicted for all experimental groups. Prenatal PolyI:C exposure significantly reduced %PPI in vehicle (VEH)-treated animals compared with prenatal CON treatment. The prenatal PolyI:C-induced PPI disruption was normalized by periadolescent clozapine (CLZ) or fluoxetine (FLX) treatment but not by periadolescent haloperidol (HAL) treatment. The latter drug significantly reduced %PPI in adulthood when given to periadolescent offspring born to CON mothers. *P < .05, **P < .01, and ***P < .001, based on Fisher post hoc tests. (b) The figure depicts startle reactivity to prepulse-alone trials as a function of prepulse intensity. Periadolescent CLZ treatment increased the startle reactivity to prepulse-alone trials relative to VEH treatment during periadolescence. This effect was seen in both CON offspring and offspring born to PolyI:C-challenged mothers. HAL-treated PolyI:C offspring displayed a significant reduction in the startle reactivity to prepulse-alone trials relative to periadolescent VEH treatment in PolyI:C offspring. ^#P < .05 between VEH-treated CON or PolyI:C offspring and CLZ-treated CON or PolyI:C offspring; ^§P < .05 between HAL-treated PolyI:C offspring and VEH-treated PolyI:C offspring. Significance is based on Fisher post hoc tests at each of the 3 prepulse levels. (c) The figure shows the mean startle reactivity to the pulse-alone trials. Periadolescent FLX treatment significantly reduced the startle reactivity to the pulse-alone trials regardless of the prenatal treatment histories. ⁺P < .05 between FLX- and VEH-treated animals based on subsequent Fisher post hoc tests. The number of subjects in each group is listed in table 1. All values are means ± standard error of the mean.

Fig. 3.

Modulation of the Latent Inhibition (LI) Effect by Periadolescent Antipsychotic and Antidepressant Drug Treatment in Offspring Born to PolyI:C-Treated and Control (CON) Mothers. LI was assessed in a 2-way active avoidance procedure, in which a white noise stimulus served as the to-be-conditioned stimulus (CS) and electric footshock as the unconditioned stimulus. To index conditioned avoidance learning, the mean number of avoidance shuttles performed on successive 10-trial blocks was analyzed and depicted in the figure. LI is manifested when subjects pre-exposed to the CS (PE) display retarded active avoidance learning relative to non-preexposed (NPE) subjects. (a) A clear LI effect was observed in adult CON offspring treated with vehicle (VEH) during periadolescence, as well as in CON offspring exposed to periadolescent haloperidol (HAL) or clozapine (CLZ) treatment. Chronic treatment with fluoxetine (FLX) led to the complete abolition of LI in adult offspring born to CON mothers. (b) Prenatal immune challenge by PolyI:C led to the loss of LI in VEH-treated offspring. Chronic HAL or CLZ treatment, but not FLX treatment during periadolescence, prevented from the emergence of PolyI:C-induced LI disruption in adulthood. *P < .05, **P < .01, and ***P < .001, based on restricted ANOVAs. The number of subjects in each group is listed in table 1. All values are means ± standard error of the mean.

Fig. 4.

Modulation of the Sensitivity to Systemic Amphetamine (2.5 mg/kg, Intraperitoneally) Challenge by Periadolescent Antipsychotic and Antidepressant Drug Treatment in Offspring Born to PolyI:C-Treated and Control (CON) Mothers. The graph illustrates the distance traveled in the open field after nontreatment (bins 1–4), saline (SAL) treatment (bins 5–8), and AMPH treatment (bins 9–24) for CON (a) and PolyI:C offspring (b); the mean distance traveled after AMPH challenge is shown in (c). Periadolescent exposure to haloperidol (HAL) significantly increased basal locomotor activity (ie, after nontreatment and SAL treatment) compared with periadolescent vehicle (VEH) treatment regardless of the prenatal treatment histories. ^#P < .01 between HAL-exposed and VEH-treated subjects, based on Fisher post hoc tests. Prenatal PolyI:C exposure significantly enhanced the locomotor reaction to acute AMPH challenge compared with prenatal CON treatment, ie, VEH-treated PolyI:C offspring displayed an increase in distance traveled in the open field compared with VEH-treated CON offspring following AMPH administration. This effect was attenuated by periadolescent HAL and fluoxetine (FLX) treatment but not by clozapine (CLZ) exposure. In addition, periadolescent HAL treatment (but not CLZ or FLX treatment) potentiated the locomotor reaction to AMPH in CON offspring. *P < .05 between VEH-treated CON offspring and VEH-treated PolyI:C offspring; ⁺P < .05 between HAL-treated and VEH-treated CON offspring; and ^§P < .05 between VEH-treated PolyI:C offspring and HAL- or FLX-treated PolyI:C offspring. The number of subjects in each group is listed in table 1. SED in (a) and (b) refers to twice the standard error of difference derived from the error variance associated with the prenatal treatment × periadolescent treatment × 5-min bins interaction term from the overall ANOVA. All values in (c) are means ± standard error of the mean.

Fig. 5.

Modulation of the Sensitivity to Systemic Dizocilpine (MK-801; 0.15 mg/kg, Intraperitoneally) Challenge by Periadolescent Antipsychotic and Antidepressant Drug Treatment in Offspring Born to PolyI:C-Treated and Control (CON) Mothers. The graph illustrates the distance traveled in the open field after nontreatment (bins 1–4), saline (SAL) treatment (bins 5–8), and MK-801 treatment (bins 9–24) for CON (a) and PolyI:C offspring (b); the mean distance traveled after MK-801 challenge is shown in (c). Periadolescent exposure to haloperidol (HAL) significantly increased basal locomotor activity (ie, after nontreatment and SAL treatment) compared with periadolescent vehicle (VEH) treatment regardless of the prenatal treatment histories. ^#P < .05 between HAL-exposed and VEH-treated subjects, based on Fisher post hoc tests. Prenatal PolyI:C exposure led to a significant increase in the locomotor reaction to acute MK-801 challenge compared with prenatal CON treatment, ie, VEH-treated PolyI:C offspring displayed a significant increase in mean distance traveled in the open field compared with VEH-treated CON offspring following MK-801 administration. The prenatal PolyI:C-induced potentiation of MK-801 sensitivity was blocked by chronic HAL treatment during periadolescence but not by periadolescent exposure to CLZ or FLX. On the other hand, HAL and FLX (but not CLZ) treatment significantly increased the sensitivity to acute MK-801 challenge in CON offspring. ^*P < .05 between VEH-treated CON offspring and VEH- or CLZ-treated PolyI:C offspring; ⁺P < .05 between VEH-treated CON offspring and HAL or FLX-treated CON offspring; ^#P < .05 between CLZ-treated CON offspring and HAL- or FLX-treated CON offspring; and ^§P < .05 between HAL-treated PolyI:C offspring and VEH- or CLZ-treated PolyI:C offspring. The number of subjects in each group is listed in table 1. SED in (a) and (b) refers to twice the standard error of difference derived from the error variance associated with the prenatal treatment × periadolescent treatment × 5-min bins interaction term from the overall ANOVA. All values in (c) are means ± standard error of the mean.