ROLE OF BRAIN NOREPINEPHRINE IN AUDIOGENIC SEIZURE IN THE RAT

¹ Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona

Treatments which caused severe reduction of brain concentrations of norepinephrine (NE) and dopamine (DA) by interfering with storage or by simultaneously inhibiting synthesis and promoting release of these biogenic amines markedly intensified audiogenic seizure (AGS). These results imply that depletion of brain NE and/or DA is associated with increased severity of AGS. Several observations provide evidence that NE is more important than DA in the modulation of AGS. For example, the benzoquinolizine, Ro 4-1284, markedly intensified AGS and depleted NE and DA one hour after administration; however, four hours later AGS enhancement was no longer apparent and brain NE concentration showed recovery, while DA remained severely reduced. The pronounecd effects of Ro 4-1284 on AGS and brain catecholammes were prolonged by concurrent treatment with l--methyl-p-tyrosine and were still evident 12.75 hours later. In comparison to the combination treatment, l--methyl-p-tyrosine caused an equally severe reduction of brain DA, but it produced significantly less reduction of NE and no enhancement of AGS. Intracerebroventricular injection of reserpine intensified AGS and markedly reduced brain NE, but only moderately lowered DA. Imipramine inhibited AGS and effectively antagonized the NE-depleting and AGS-enhancing effects of Ro 4-1284 without reversing DA depletion. It is proposed that NE exerts all inhibitory effect in the brain which tends to limit spread of seizure discharge. Consequently, depletion of brain NE disrupts inhibitory function, allows more efficient spread of seizure activity in the brain and increases severity of AGS.