Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala

Is there a future for mGlu5-positive allosteric modulators in absence epilepsy? A comparison with ethosuximide

Contains fulltext : 175798.pdf (Publisher’s version ) (Open Access)Ethosuximide is the drug of choice in the treatment of various types of absence seizures. However, there is plenty of room for other anti-absence drugs, considering that not all subjects (57-74%) become seizure-free and about 47% of ethosuximide therapy fails. New anti-absence drugs may target or modulate glutamatergic and or GABAergic neurotransmission, the key players in the circuitry involved in the cortico-thalamo-cortical oscillations responsible for the highly stereotyped spike-wave discharges (SWDs). Cortical highly excitable cells in the focal region form the trigger for the occurrence of SWDs. In contrast, enhanced tonic inhibition is dominant in the thalamus. Biochemical studies have shown that symptomatic WAG/Rij rats differ from age-matched controls in metabotropic glutamate (mGlu) receptor expression and function: mGlu5 receptor expression and function are increased in the somatosensory cortex, and mGlu1 receptor expression is decreased in the thalamus. The two group I mGlu receptor-positive allosteric modulators (PAMs) VU0360172 and RO0711401 have an interesting profile in acute and (sub)chronic pharmacological studies and produce a dose-dependent decrease of SWDs. Moreover, both compounds are effective in reducing SWDs in the cortex and thalamus. Interestingly, the GABA reuptake blocker tiagabine reduces SWDs in the cortex and not in the thalamus, while the efficacy of ethosuximide is higher in the cortex than in the thalamus. It is thought that VU0360172 stimulates cortex GABA interneurons, which inhibit highly excitable cortical neurons in the focal area. In the thalamus, VU0360172 most likely reduces tonic inhibition. Thus, group I mGlu receptor PAMs might be further developed as anti-absence drugs, with putative disease-modifying effects on epileptogenesis. The preclinical profile of group I mGlu receptor PAMS deserves to be further explored in models of generalized epilepsy and focal types of epilepsy