Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats

Abstract

Temporal lobe epilepsy may be associated with emotional difficulties such as depression or anxiety. Since the amygdala is involved in both epilepsy and emotion, common neural mechanisms in this temporal lobe structure may underlie the emotional disturbances observed in people with epilepsy. The neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) is implicated in many psychopathologies, and 5-HT also modulates amygdala excitability. Therefore, the present study used the fear potentiated startle (FPS) paradigm to investigate the effect of neuronal excitability on fear behavior in rats treated with p-chlorophenylalanine (PCPA) to chronically inhibit 5-HT synthesis. PCPA treatment selectively enhanced FPS in individually-housed rats. The exaggerated FPS response was reduced to control level by the anticonvulsant phenytoin (10mg/kg) and phenytoin (30 mg/kg) further decreased FPS behavior. These data suggest that a sub-seizure state of neuronal excitability mediated by low 5-HT in brain fear circuits may be associated with pathological fear behavior.

Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle

“…1, 6, 16, 21 These and other findings support a pivotal role for perturbed amygdala 5-HT and enhanced glutamatergic mechanisms in the pathophysiology of emotional disorders. In the present study, we investigated the specific effect of depleting 5-HT in the LA on fear- and anxiety-like behaviors.…”

“…Although the specific 5-HT receptor subtype(s) in the LA-mediating changes in GluR1 expression and exaggerated FPS are of interest, we did not attempt to delineate the role of 5-HT receptors in the present study. However, our previous investigation suggests that increased GluR1 and enhanced FPS following a decrease in 5-HT may be mediated by deficient 5-HT 2A signaling, 20 and future experiments beyond the scope of the present study will test this hypothesis.…”

“…In result, we found that treatment with 5,7-DHT induced exaggerated fear responses measured in the FPS paradigm, which is consistent with our previous study that reported low systemic 5-HT could enhance fear learning. 21 An important caveat to note is that our experiments do not fully distinguish whether the effects of low 5-HT influence mechanisms associated with acquisition or expression of fear. As the rats are infused before fear conditioning, the treatment could potentially influence mechanisms associated with acquisition and/or expression.…”

“…20, 21 On days 1 and 2, the rats were acclimated to the testing chambers (Acoustic Startle Reflex System, Med Associates Inc., St Albans, VT, USA) for 30 min followed by habituation. Habituation sessions consisted of 30 pseudo-random exposures to 90, 95 or 105 dB white noise bursts (30–50 ms duration) with an interstimulus interval of 30 s. On day 3, rats received fear-conditioning training.…”

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

“…While others have observed impaired extinction acquisition in response to 5-HT 2A receptor inhibition, they did not explore whether extinction was permanently impaired (Slipczuk et al 2013; Zhang et al 2013). Conversely, the extinction of fear memory is consistently enhanced by 5-HT 2A receptor agonists (Catlow et al 2013; Zhang et al 2013), which also diminish the expression of FPS (Hughes et al 2012). 5-HT axon terminals and 5-HT 2A receptors are densely expressed in the amygdala (Asan et al 2013; McDonald and Mascagni 2007), where they are particularly important for regulating fear behavior (Bocchio et al 2015).…”