FG-5974

In this study we examined the effects of 5-HT1A ligands in rats trained to discriminate 0.16 mg/kg i.p. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) from saline in a two-lever, fixed ratio (FR)10 schedule of food reinforcement, and in pigeons trained to discriminate 0.31 mg/kg i.m. 8-OH-DPAT from saline in a two-key, FR30 schedule of food reinforcement. In both species, 8-OH-DPAT and a variety of structurally unrelated 5-HT1A ligands occasioned dose-related, relatively high levels of drug-appropriate selection (i.e. > or = 67%). A significant positive correlation was found between estimated ED50 values in both species (r = 0.84, P < .001). Further, 5-HT1A antagonists, NAN-190, penbutolol, (-)-pindolol, tertatolol and WAY-100635, produced dose-related decreases in 8-OH-DPAT-appropriate selection, and their potencies for antagonism in rats and pigeons were highly correlated (r = 0.96, P < .01). The potency of WAY 100635 in rats and pigeons was quantified by Schild analysis (apparent in vivo pA2 values: 7.8 vs. 8.3, rat vs. pigeon respectively). Although most 5-HT1A agonists produced similar 8-OH-DPAT-like discriminative stimulus effects in both species, two compounds, lisuride and eltoprazine, occasioned high levels of drug-appropriate selection in pigeons, but not in rats. In contrast, idazoxan, yohimbine, LEK 8804 and BMY 7378 produced greater effects in rats. Among this latter group of compounds, only BMY 7378 blocked the discriminative stimulus effects of 8-OH-DPAT in pigeons, which suggested that intermediate levels of drug-appropriate selection observed with the remaining compounds are not necessarily the result of low intrinsic activity. Overall, these results demonstrate similarities in the discriminative stimulus effects of 8-OH-DPAT in rats and pigeons despite different training conditions (e.g., training dose and route of administration). Even so, the finding that some 5-HT1A ligands did not produce similar effects in rats and pigeons illustrates the need to examine possible 8-OH-DPAT-like discriminative stimulus effects of compounds in both species.

The present studies sought to elucidate the role of 5‐HT2A receptor antagonists in suppressing alcohol intake by comparing the effects of amperozide and FG 5974 on alcohol, food, and water intake in strains of alcohol‐preferring rats: P, Alko Alcohol (AA), and Fawn‐Hooded (FH). Both amperozide and FG 5974 have 5‐HT2A receptor antagonist properties, but FG 5974 also shows presynaptic 5‐HT1A receptor agonist activity. After establishment of stable baselines for intake measures in a two‐bottle continuous access paradigm, rats (n= 10) were injected with 1 of 5 doses (0, 1.0, 2.5, 5.0, and 10.0 mg/kg, sc) of amperozide or FG 5974 at weekly intervals. Amperozide dose‐dependently reduced alcohol intake, total fluid intake, and alcohol preference in all three strains under continuous access conditions, whereas FG 5974 was less effective. Food intake was also suppressed by amperozide at higher doses, whereas it was increased by FG 5974. Amperozide also dose‐dependently reduced alcohol intake when it was available for only 1 hr/day, but FG 5974 tended to increase it. After oral administration, amperozide was also more effective than FG 5974 in reducing alcohol intake. Despite these differences in efficacy in suppressing alcohol intake, both compounds produced taste aversion to a novel saccharin solution. These complex findings suggest that biochemical properties other than 5‐HT2A receptor antagonism (e.g., 5‐HT1A receptor agonism) may be involved in the effects of amperozide and FG 5974 on alcohol intake and other consummatory behaviors.