Phenylpropanolamine potentiates caffeine neurotoxicity in rats

Numerous case reports have documented that phenylpropanolamine (PPA) stimulates the central nervous system with symptoms ranging from anxiety and hallucinations to grand mal seizures produced by overdoses. Most of these reports have occurred following concomitant use of caffeine which in high doses is known to cause seizures and psychotic episodes. The purpose of this investigation was to determine if PPA could potentiate caffeine-induced seizures in the rat. First, the input rate dependence of caffeine-induced neurotoxicity was determined by infusing rats intravenously with caffeine at one of three different rates (1.65-8.12 mg/min) until the onset of maximal seizure. This occurred after an average of 12 to 60 min of infusion. The PPA concentrations in serum, brain, and cerebrospinal fluid (CSF) at this pharmacologic endpoint were independent of infusion rate. In another experiment, rats were pretreated with an anorexiant dose of PPA (30 mg/kg ip) either acutely or chronically for 6 d, while control animals received saline solution. All groups were then infused with caffeine at a rate of 4.18 mg/min until onset of seizures. Caffeine concentrations at that time in serum, brain, and CSF were significantly lower in the PPA-pretreated animals than in the control group. It is concluded that both acute and chronic pretreatment with PPA increases the sensitivity of rats to the neurotoxic effects of caffeine.