Tolerance development to a disruptive effect of beta-phenylethylamine (PEA) on a learned behavior in rats

Several doses (8-64 mg/kg) of β-phenylethylamine (PEA), a naturally-occurring sympathomimetic amine structurally related to amphetamine and with similar effects on animal behavior, were administered (IP, daily for ten days) to Fisher 344 rats that were trained to perform a shuttlebox conditioned avoidance response (CAR) at a high, stable rate. PEA 8 mg/kg did not influence avoidance responding after single or multiple injections. Acute administration of PEA 16 mg/kg produced dose-dependent disruptions of the CAR. With repeated administration, complete tolerance to CAR disruption was acquired by the third injection of PEA 16 mg/kg or by the fifth injection of PEA 32 mg/kg and maintained with both doses through ten injections; the use of appropriate controls indicated that tolerance was pharmacological and not behavioral. Over the course of ten injections, tolerance did not develop to shuttlebox disruption caused by 64 mg/kg, and this dose of PEA did not elicit tolerance to stereotyped behavior after 21 injections. These data were interpreted as showing differential tolerance to low vs. high dose effects of PEA: Lower doses produce tolerance to disruption of the CAR, but the highest dose did not because of the presence of incompatible response tendencies (e.g., stereotypy) interfering with the CAR. Our data showing development of tolerance to lower doses of PEA is the first demonstration in the literature that tolerance can develop to a behavioral effect of this compound.