Psychopharmacological distinction between novel full-efficacy "D1-like" dopamine receptor agonists

The search for full-efficacy agonists selective for the "D1-like" family of dopamine receptor subtypes has recently generated two novel series of compounds: the isochromans, typified by A 68930, and the phenanthridines, typified by dihydrexidine. This study was undertaken to compare systematically the effects of these two agents on the spectrum of unconditioned motor behaviour (i.e., construction of their drug ethograms) in the intact adult rat and to determine the sensitivity of these responses to selective antagonists of "D1-like" (SCH 23390) vs. "D2-like" (YM 09151-2) receptors. A 68930 (0.0625-4.0 mg/kg) readily induced grooming, including intense grooming, the most widely accepted behavioural model of "D1-like" receptor stimulation; it also induced vacuous chewing, a more controversial model thereof, and sniffing. Conversely, dihydrexidine (0.25-16.0 mg/kg) induced grooming, but little intense grooming was evident; it failed to induce vacuous chewing but did induce sniffing. Grooming and sniffing responses to A 68930 were readily blocked by SCH 23390 (0.01-1.0 mg/kg) but were only attenuated or spared by YM 09151-2 (0.005-0.5 mg/kg). Conversely, the grooming and sniffing responses to dihydrexidine were readily blocked both by SCH 23390 and by YM 09151-2. A 68930 and dihydrexidine do not show identical psychopharmacological profiles; they appear to differ in the specificity of their effects on "D1-like" vs. "D2-like" function and may interact differentially with putative subtypes of "D1-like" receptors that are indicated behaviourally.