Abstracts

Rationale: At therapeutic doses, certain antiepileptic drugs (AEDs) (e.g. phenobarbital (PB), phenytoin (PHE), valproic acid (VPA)) cause enhanced neuronal apoptosis (ENA) in the rodent brain between postnatal days (P) 6-14 - during the period in humans corresponding to the 3rd trimester of gestation through infancy. Other AEDs (e.g. lamotrigine (LTG) and carbamazepine (CBZ)) do not cause ENA. ENA affects brain regions that play key roles in mood, cognition, and motor coordination (ie, frontal cortex, amygdala, striatum, hippocampus, cerebellum). Other investigators reported adverse behavioral outcomes with autism-like features following exposure of immature mice to VPA at P14 (Wagner, GC. J Autism Dev Disord. 2006), and an epidemiological study which linked early life seizures to schizophrenia noted the possibility that AED treatment might represent a confounding risk factor (Vestergaard et al., Schizphr Res. 2005). We therefore investigated the long term behavioral outcomes of rat pups given AEDs alone during the 2nd postnatal week. Methods: Sprague-Dawley rat pups were treated chronically (P7-14) with PB (75mg/kg), PHT (50mg/kg), LTG (20mg/kg), CBZ (50mg/kg), diazepam (DZP, 1mg/kg), or vehicle (0.1ml/kg, ip). They were tested as adults (P60+) in the: elevated plus maze (EPM, anxiety test, 5 min), rotorod (accelerating 0-50 RPM over 300 sec), fear conditioning (contextual and cued, 1kHz tone, 0.6mA footshock), prepulse inhibition of the acoustic startle response (PPI, sensory-motor gating, prepulse 3-18dB above background), and social approach (15 min of free access to a compartment with a novel conspecific or a compartment with bedding from their homecage). Results: Results are outlined in the table below. Conclusions: Exposure of immature animals to PB resulted in the most pervasive adverse behavioral outcomes in adulthood, causing abnormalities in all behavioral functions including a deficit in PPI, a schizophrenia-like symptom. Exposure to PHT or CBZ resulted in a subset of deficits in adults. The fact that LTG and DZP exposure did not alter any of the behavioral outcomes examined may be related to the fact that these drugs do not cause ENA at the doses used. However, the absence of ENA is not a guarantee of the absence of behavioral toxicity, given the results with CBZ. Our data support the growing concerns about behavioral toxicity of gestational and neonatal exposure to certain AEDs. Moreover, our data raise the possibility that exposure of the immature brain to PB, PHT, and possibly CBZ may predispose to psychopathology or exacerbate psychiatric conditions that are comorbid with epilepsy. The fact that certain drugs, such as LTG, are devoid of behavioral toxicity in our behavioral screen, suggests that careful choice of AEDs may minimize adverse neuropsychiatric outcomes.