Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks.

Because sites of seizure origin may be unknown or multifocal, identifying targets from which activation can suppress seizures originating in diverse networks is essential. We evaluated the ability of optogenetic activation of the deep/intermediate layers of the superior colliculus (DLSC) to fill this role. Optogenetic activation of DLSC suppressed behavioral and electrographic seizures in the pentylenetetrazole (forebrain+brainstem seizures) and Area Tempestas (forebrain/complex partial seizures) models; this effect was specific to activation of DLSC, and not neighboring structures. DLSC activation likewise attenuated seizures evoked by gamma butyrolactone (thalamocortical/absence seizures), or acoustic stimulation of genetically epilepsy prone rates (brainstem seizures). Anticonvulsant effects were seen with stimulation frequencies as low as 5 Hz. Unlike previous applications of optogenetics for the control of seizures, activation of DLSC exerted broad-spectrum anticonvulsant actions, attenuating seizures originating in diverse and distal brain networks. These data indicate that DLSC is a promising target for optogenetic control of epilepsy.

Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats.

Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. However, mounting preclinical evidence suggests that even brief exposure to phenobarbital in the neonatal period can induce neuronal apoptosis, alterations in synaptic development, and long-lasting changes in behavioral functions. In the present report, we treated neonatal rat pups with phenobarbital and evaluated behavior in adulthood. Pups were treated initially with a loading dose (80 mg/kg) on postnatal day (P)7 and with a lower dose (40 mg/kg) on P8 and P9. We examined sensorimotor gating (prepulse inhibition), passive avoidance, and conditioned place preference for cocaine when the animals reached adulthood. Consistent with our previous reports, we found that three days of neonatal exposure to phenobarbital significantly impaired prepulse inhibition compared with vehicle-exposed control animals. Using a step-though passive avoidance paradigm, we found that animals exposed to phenobarbital as neonates and tested as adults showed significant deficits in passive avoidance retention compared with matched controls, indicating impairment in associative memory and/or recall. Finally, we examined place preference conditioning in response to cocaine. Phenobarbital exposure did not alter the normal conditioned place preference associated with cocaine exposure. Our findings expand the profile of behavioral toxicity induced by phenobarbital.

Comprehensive identification of delusions and olfactory, tactile, gustatory, and minor hallucinations in Parkinson's disease psychosis.

INTRODUCTION: Psychotic symptoms are underdiagnosed in Parkinson's disease (PD), and there is a need for a comprehensive PD psychosis rating scale. METHODS: Cross-sectional analysis of 199 consecutive PD outpatients. After a routine clinical visit that included the Unified Parkinson's Disease Rating Scale (UPDRS) and Non-Motor Symptoms Questionnaire (NMS-Quest), subjects completed the enhanced Scale for the Assessment of Positive Symptoms in PD (eSAPS-PD), a structured clinical interview that included the standard SAPS-PD with additional prompts for delusions and olfactory, gustatory, and minor hallucinations. Based on the combined results of these assessments, subjects were categorized as having major psychotic symptoms (hallucinations or delusions; PDP-major), isolated minor psychotic symptoms (passage hallucinations, presence hallucinations, or illusions; PDP-minor), or no psychotic symptoms (PD-controls). RESULTS: We identified 58 subjects (29%) with psychotic symptoms, including 28 (14%) with major psychotic symptoms and 30 (15%) with isolated minor psychotic symptoms. Hallucinations were present in 56 subjects (28%); most commonly visual (24%, of which 21% were minor only), followed by olfactory (6%), tactile (4%), auditory (2%), and gustatory (1%). The eSAPS-PD detected psychotic symptoms in more subjects (n = 55, 28%) than all other assessments combined (clinical visit, UPDRS part 1, and NMS-Quest) (n = 22, 11%). Compared with PD-controls, PDP-minor subjects had a higher burden of other non-motor symptoms on the Non-Motor Symptoms Scale (37 [27-51] vs. 18 [9-36], p < 0.001) and lower quality of life scores on the PD Quality of Life Questionnaire (138 [125-151] vs. 149 [137-165], p = 0.01). CONCLUSION: The eSAPS-PD can markedly improve detection of psychotic symptoms in PD.

Profile of anticonvulsant action of levetiracetam, tiagabine and phenobarbital against seizures evoked by DMCM (methyl-6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate) in neonatal rats.

Levetiracetam (LEV) and tiagabine (TGB) are utilized for the treatment of seizures, including neonatal seizures. However, relatively little is known about the preclinical therapeutic profile of these drugs during brain development. The relative paucity of information regarding these drugs in neonatal animals may be due to their unusual profile of anticonvulsant action in experimental models. LEV and TGB are without effect against seizures in several common screening models (e.g., the maximal electroshock test, maximal pentylenetetrazole seizures), instead showing preferential efficacy against models of partial seizures. We have recently described a method for reliably evoking partial seizures in neonatal animals by systemic administration of the chemoconvulsant, DMCM (Kulick et al., 2014, Eur. J. Pharmacol., doi:10.1016/j.ejphar.2014.06.012). DMCM is a negative allosteric modulator of GABAA receptors, and offers a wide separation between doses required to evoke complex partial as compared to tonic-clonic seizures. Here we used DMCM to evaluate the effect of LEV and TGB against seizures in postnatal day (P) 10 rat pups. We compared the profile of LEV and TGB to that of phenobarbital (PB), the most widely utilized anticonvulsant in neonates. We found that LEV significantly protected against DMCM seizures when administered in doses of 10mg/kg and greater. TGB protected against DMCM-evoked seizures when administered in doses of 1mg/kg or greater. PB protected against DMCM-evoked seizures when administered in doses of 5mg/kg or greater. These data provide preclinical evidence for the efficacy of LEV and TGB in neonates and underscore the utility of DMCM for screening anticonvulsant action in neonatal animals.