Behavioral side effects of prophylactic therapies against soman-induced seizures and lethality in rats

• Published in: Toxicology reports Vol. 1; no. C; pp. 102 - 113
• Main Authors: Myhrer, Trond, Enger, Siri, Aas, Pål
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier 01.01.2014
• Subjects: Cholinergic drugs; Glutamatergic drugs; Nerve agent; Novelty test; Prophylactics; Novelty test; Cholinergic drugs; Prophylactics; Nerve agent; Glutamatergic drugs
• ISSN: 2214-7500; 2214-7500
• DOI: 10.1016/j.toxrep.2014.04.004

Four medical therapies previously shown to exert varying degrees of protection against a convulsant dose of soman were assessed for potential behavioral side effects in a novelty test. In Experiment 1, HI-6 (1-[([4-(aminocarbonyl)pyridino] methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) (125 mg/kg), scopolamine (1 mg/kg), physostigmine (0.1 mg/kg), levetiracetam (50 mg/kg), and procyclidine (20 mg/kg) were tested separately. In Experiment 2, the combination of HI-6, scopolamine, and physostigmine (termed the physostigmine regimen) or HI-6, levetiracetam, and procyclidine (termed the procyclidine regimen) were tested. In Experiment 3, the metabotropic glutamate modulators DCG-IV ((2 ,2' ,3' )-2-(2',3'-dicarboxycyclopropyl)glycine) (4 mg/kg) and MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride) (30 mg/kg) were tested separately or each drug in combination with HI-6 and procyclidine (termed the DCG-IV regimen and the MPEP regimen, respectively). The results showed that the physostigmine and procyclidine regimens both produced severe cognitive impairment (lack of preference for novelty) and reduced locomotor and rearing activities. The DCG-IV and MPEP regimens caused milder deficits on the same behavioral measures. Some relations were seen between prophylactic capacity and degree of behavioral side effects. Only HI-6 or levetiracetam had no adverse effects on behavior. DCG-IV or MPEP produced some impairment, whereas the detrimental effects of scopolamine or procyclidine were pronounced. The relatively high dose of procyclidine (anticholinergic and antiglutamatergic) needed for prophylactic efficacy may have played a major role for the side effects of the regimens in which the drug was used. It was concluded that behavioral side effects are inevitable for potent prophylactic therapies against soman intoxication.