Relative effectiveness of pimozide, haloperidol and trifluoperazine on self-stimulation rate-intensity functions

Rats were trained to lever press for 60 Hz sine wave stimulation of the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. Rate intensity functions were determined by stepping down the current intensity by 0.05 log10 units every five min. Haloperidol shifted the function approximately one step to the right at 0.08 mg/kg, with lower doses producing no effect. Pimozide shifted the curve in a dose-dependent manner over the range of 0.06 to 0.24 mg/kg; 0.12 mg/kg produced an approximate one-step shift. Trifluoperazine also produced dose related shifts to the right over the range of 0.08 to 0.32 mg/kg; this agent, unlike the others, appeared to shift the curve down as well as to the right. Less than a one-step shift was produced by 0.08 mg/kg; more than a one-step shift was produced by 0.16 mg/kg. On a molar basis, the order of potency for displacing the curves to the right was haloperidol, pimozide and trifluoperazine. While this order of potency is not predicted from simple in vitro binding affinities for the D2 receptor, this may be due to differences in the penetration of these agents to central D2 receptors in vivo.