Risperidone administered during asymptomatic period of adolescence prevents the emergence of brain structural pathology and behavioral abnormalities in an animal model of schizophrenia

Abstract

Schizophrenia is a disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations precede onset of symptoms, raising a question of whether schizophrenia can be prevented. Early treatment with atypical antipsychotics may reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We have recently shown, using in vivo structural magnetic resonance imaging, that treatment with the atypical antipsychotic clozapine during an asymptomatic period of adolescence prevents the emergence of schizophrenia-like brain structural abnormalities in adult rats exposed to prenatal immune challenge, in parallel to preventing behavioral abnormalities. Here we assessed the preventive efficacy of the atypical antipsychotic risperidone (RIS). Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Their male offspring received daily RIS (0.045 or 1.2 mg/kg) or vehicle injection in peri-adolescence (postnatal days [PND] 34-47). Structural brain changes and behavior were assessed at adulthood (from PND 90). Adult offspring of poly I:C-treated dams exhibited hallmark structural abnormalities associated with schizophrenia, enlarged lateral ventricles and smaller hippocampus. Both of these abnormalities were absent in the offspring of poly I:C dams that received RIS at peri-adolescence. This was paralleled by prevention of schizophrenia-like behavioral abnormalities, attentional deficit, and hypersensitivity to amphetamine in these offspring. We conclude that pharmacological intervention during peri-adolescence can prevent the emergence of behavioral abnormalities and brain structural pathology resulting from in utero insult. Furthermore, highly selective 5HT(2A) receptor antagonists may be promising targets for psychosis prevention.

Fig. 1.

Experimental Design Used to Study the Effects of Preventive RIS Treatment in the Offspring of Poly I:C– or Saline (CON)-Treated Dams. Pregnant rats were exposed to poly I:C (4 mg/kg) or saline (CON) treatment on gestation day 15. The resulting offspring from both treatment conditions (poly I:C offspring and CON offspring) were then subjected to chronic treatment with vehicle, 0.045 mg/kg RIS (RIS-low), or 1.2 mg/kg (RIS-high) during the peri-adolescent stage of development between postnatal days (PND) 34 and 47. MRI and behavioral testing of the offspring were conducted in adulthood, from PND 90, in a drug-free state. LI, latent inhibition; DR, discrimination reversal; AIA, amphetamine-induced activity.

Fig. 2.

RIS Treatment in Peri-adolescence Prevents the Enlargement of Lateral Ventricular Volume in Adult Offspring of Poly I:C–Treated Dams. (A) Representative T₂-weighted images at the level of the lateral ventricles (LV) of an adult (4 months) offspring of saline- or poly I:C–injected dams treated with vehicle, 0.045 mg/kg RIS (RIS-low), or 1.2 mg/kg rispridone (RIS-high) in peri-adolescence. (B) LV volume of adult offspring of saline- or poly I:C–injected dams treated with vehicle, RIS-low, or RIS-high. All values are means ± standard error of the mean. *, Significant difference between poly I:C-vehicle and the other 5 conditions (all P values < .002).

Fig. 3.

RIS Treatment in Peri-adolescence Prevents the Reduction of Hippocampal Volume in Adult Offspring of Poly I:C–Treated Dams. (A) Representative T₂-weighted images at the level of the hippocampus (HP) of an adult (4 months) offspring of saline- or poly I:C–injected dams treated with vehicle, 0.045 mg/kg RIS (RIS-low), or 1.2 mg/kg rispridone (RIS-high) in peri-adolescence. (B) HP volume of adult offspring of saline- or poly I:C–injected dams treated with vehicle, RIS-low, or RIS-high. All values are means ± standard error of the mean. *, Significant difference between poly I:C-vehicle and saline-vehicle, poly I:C-low RIS, and poly I:C-high RIS conditions (all P values < .005).

Fig. 4.

RIS Treatment in Peri-adolescence Prevents Behavioral Abnormalities in Adult Offspring of Poly I:C–Treated Dams. (A) RIS prevents LI loss. Times (logarithmically transformed) to complete 25 licks in the presence of a tone that was previously paired with shock in 6 experimental conditions denoted according to prenatal treatment received by the pregnant dams (saline and poly I:C) and preventive treatment received by the offspring (vehicle, Veh; 0.045 mg/kg RIS [RIS-low]; and 1.2 mg/kg RIS [RIS-high]). In each condition, preexposed (PE) rats received 40 nonreinforced tone presentations prior to tone-shock conditioning, whereas non-preexposed (NPE) rats did not receive any tones. LI is manifested as shorter log times to complete 25 licks after tone onset of the PE compared with the NPE group. *, Significant difference (P values < .003) between the PE and NPE groups. (B) RIS prevents rapid reversal learning. Number of trials to criterion on day 1 discrimination (inset) and on day 2 discrimination and reversal in the 6 experimental conditions denoted according to prenatal treatment received by the pregnant dams (saline and poly I:C) and preventive treatment received by the offspring (vehicle, Veh; 0.045 mg/kg RIS [RIS-low]; and 1.2 mg/kg RIS [RIS-high). *, Significant difference between poly I:C-vehicle and the other 5 conditions (all P values < .03). (C) RIS prevents increased locomotor response to amphetamine induced by prenatal poly I:C treatment. Total activity counts in the 6 experimental conditions before (6 bars on the left) and after amphetamine injection. **, Significant difference in amphetamine-induced activity between poly I:C-vehicle and saline-vehicle, poly I:C-low RIS, and poly I:C-high RIS (all P values < .0009). *, Significant difference in spontaneous and amphetamine-induced activity between saline-vehicle and saline-high RIS, and saline-low RIS and saline-high RIS conditions (all P values < .03). All values are means ± standard error of the mean.