Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats

Abstract

Background and hypothesis: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats.

Study design: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded.

Study results: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress.

Conclusions: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Keywords: adolescence; dopamine system; levetiracetam; psychosis; ventral hippocampus.

Fig. 1.

Effects of levetiracetam on adolescent stress-induced anxiety-like responses in rats as adults. In the elevated plus-maze (n = 8–12/group), stress during adolescence did not change (A) % of entries and (B) time spent in the open arms. However, it decreased (C) the number of entries into the enclosed arms, which was not attenuated by levetiracetam. In the light-dark box test (n = 10–11/group), adolescent stress decreased (D) the number of entries and (E) time in the light zone. Levetiracetam attenuated these changes. *P < .05 vs naive-salina and #P < .05 vs stress-saline, two-way ANOVA followed by Tukey’s post-test.

Fig. 2.

Effects of levetiracetam on adolescent stress-induced changes in the novel object recognition test and social interaction in rats as adults. In the novel object recognition test (n = 8–12/group), (A) all groups explored equally the identical objects placed on the left and right sides of the arena in the acquisition trial. (B) In the retention trial, all groups explored more the novel object, except the stress-saline group. *P < .05, Student’s t-test between each group. This is reflected in (C) the discrimination index, with stress-saline animals showing a decrease in the discrimination index reversed by levetiracetam. Also, (D) adolescent stress decreased the social interaction time (n = 10–12/group) which was also reversed by levetiracetam. *P < .05 vs naive-saline and #P < .05 vs stress-saline, two-way ANOVA followed by Tukey’s post-test.

Fig. 3.

Effects of levetiracetam on the adolescent stress-induced changes in the VTA dopamine neuron activity. (A) The final location of the last track was marked by electrophoretic ejection of dye (indicated by the arrow) for histological verification. A 1-min segment of spontaneous activity and a representative waveform of VTA dopamine neuron neurons are shown. (B) Adolescent stress increased VTA dopamine neuron population activity, which was reversed by levetiracetam. No changes in (C) firing rate and (D) burst activity was found (naive-saline: 6 rats, 17 dopamine neurons; naive-levetiracetam: 6 rats, 21 dopamine neurons; stress-saline: 5 rats, 43 dopamine neurons; stress-levetiracetam: 6 rats, 18 dopamine neurons). *P < .05 vs naive-saline and #P < .05 vs stress-saline; two-way ANOVA, followed by Tukey’s post-test. Subregion analysis indicated that adolescent stress-induced changes (E) in population activity were confined to the lateral VTA, with no change in (F) firing rate, and (G) burst activity across VTA subregions. *P < .05 vs naive-saline; three-way ANOVA followed by Tukey’s post-test.

Fig. 4.

Effects of levetiracetam on the firing rate of vHip pyramidal neurons in adult animals exposed to adolescent stress. (A) The final location of the last track was marked by electrophoretic ejection of dye (indicated by the arrow) for histological verification. A 1-min segment of spontaneous activity and a representative waveform of vHip pyramidal neuron are shown. (B) Saline-treated stressed animals showed an increased firing rate of vHip pyramidal neurons, which was reversed by levetiracetam (naive-saline: 7 rats, 27 pyramidal neurons; naive-levetiracetam: 5 rats, 23 pyramidal neurons; stress-saline: 6 rats, 26 pyramidal neurons; stress-levetiracetam: 6 rats, 31 pyramidal neurons). *P < .05 vs naive-saline and #P < .05 vs stress-saline, Kruskal–Wallis test followed by the Dunn’s post-test.