The 5-HT1A receptor and the stimulus effects of LSD in the rat

Abstract

Rationale: It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD).

Objective: The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD.

Methods: Twelve male Fischer 344 rats were trained in a two-lever, fixed-ratio (FR) 10, and food-reinforced task with LSD (0.1 mg/kg, i.p.; 15-min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT(1A) agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg, s.c.; 30-min pretreatment).

Results: In combination tests, stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635.

Conclusion: These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD.

Fig. 1

Effects of 8-OH-DPAT, the selective 5-HT_1A antagonist WAY-100,635, and their combination in rats trained to discriminate LSD (0.1 mg/kg) from saline. The diamond represents the effects of water administered IP 15 min before testing. Circles represent the effects of 8-OH-DPAT administered IP 15 min. before testing. The Square represents the effects of 8-OH-DPAT in the presence of WAY-100,635 (0.3 mg/kg, SC, 30 min pretreatment). The Triangle represents the training dose of LSD. The Inverted Triangle represents the effects of the training dose of LSD given in the presence of WAY-100,635. Each point represents the mean of one determination in each of 12 rats. Standard errors of the mean are shown. * Significantly different from both training conditions. # Significantly different from 8-OH-DPAT (1.0 mg/kg). Ordinate: upper panel: percent LSD-appropriate responding; lower panel: rate expressed as responses per minute. Abscissa: dose plotted on a log scale.

Fig. 2

Dose-response relationship for LSD alone and in combination with 8-OH-DPAT. Circles represent the effects of LSD alone in rats trained with LSD as a discriminative stimulus (0.1 mg/kg). Triangles represent the effects of LSD in combination with 8-OH-DPAT (0.05 mg/kg). Squares represent the effects of LSD following treatment with 8-OH-DPAT and WAY-100,635 (0.3 mg/kg). LSD was administered IP 15 min. before testing. 8-OH-DPAT and WAY-100,635 were administered SC 15 min and 30 min respectively, before testing. Each point represents the mean of one determination in 12 rats. Standard errors of the means are indicated. * Significantly different from LSD given alone. Ordinate: upper panel: percent LSD-appropriate responding; lower panel: rate expressed as responses per minute. Abscissa: dose plotted on a log scale.

Fig. 3

Dose-response relationship for LSD alone and in combination with buspirone. Circles represent the effects of LSD alone in rats trained with LSD as a discriminative stimulus (0.1 mg/kg). Triangles represent the effects of LSD in combination with buspirone (0.3 mg/kg). Squares represent the effects of LSD in combination with buspirone and WAY- 100,635. Number of subjects completing each session are indicated. Other details are as described in figure 2.

Fig 4

Dose-response relationship for LSD alone and in combination with gepirone. Circles represent the effects of LSD alone in rats trained with LSD as a discriminative stimulus (0.1 mg/kg). Triangles represent the effects of LSD given in combination with gepirone (0.3 mg/kg). Squares represent the effects of LSD in combination with gepirone and WAY-100,635. Other details are as described in figure 2.

Fig 5

Dose-response relationship for LSD alone and in combination with ipsapirone. Circles represent the effects of LSD alone in rats trained with LSD as a discriminative stimulus (0.1mg/kg). Triangles represent the effects of LSD given in combination with ipsapirone (0.3 mg/kg). Squares represent the effects of LSD in combination with ipsapirone and WAY-100,635. Other details are as described in figure 2.