Effect of 8-hydroxy-2-(N,N-di-n-propylamino)tetralin and MDMA on the discriminative stimulus effects of the classical hallucinogen DOM in rats

Abstract

Co-administration of the 5-HT1A serotonin receptor agonist (+/-)8-hydroxy-2-(N,N-di-n-propylamino)tetralin [(+/-)8-OH DPAT] enhances the discriminative stimulus effects of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. In the present investigation, using Sprague-Dawley rats trained to discriminate DOM (1.0 mg/kg) from saline vehicle under a VI-15 s schedule of reinforcement, it was shown that the stimulus-enhancing actions of 8-OH DPAT are related more to its R(+)-isomer than to its S(-)-enantiomer, and that the (+/-)- and R(+)8-OH DPAT-induced effects are antagonized by the 5-HT1A receptor antagonist NAN-190. (+/-)8-OH DPAT and its isomers substitute in rats trained to discriminate the designer drug N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; methylenedioxymethamphetamine) from vehicle indicating some similarity of effect. On this basis, it was hypothesized that MDMA might be capable of enhancing the DOM stimulus. Co-administration of MDMA with low (i.e., 0.1 and 0.3 mg/kg) doses of DOM resulted in greater DOM-appropriate responding than engendered by administration of DOM alone. As such, the present findings are the first to demonstrate an MDMA-induced enhancing effect on the discriminative stimulus actions of a classical hallucinogen. The results also suggest that a 5-HT1A serotonin receptor mechanism might contribute to this phenomenon.

Fig. 1

Results (group mean ±SEM) of stimulus generalization studies conducted with DOM, (±)8-OH DPAT, and MDMA in rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 2

Results (group mean ±SEM) of stimulus generalization studies with the optical isomers of 8-OH DPAT in rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel), and animals’ response rates (lower panel). DOM = responses following 1.0 mg/kg of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 3

Results (group mean ±SEM) of (±)8-OH DPAT doses given in combination with the ED₅₀ dose of DOM to rats (n=5) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). One asterisk indicates a statistically significant difference from the response of saline vehicle. The animals’ response rates are shown in the lower panel. DOM = responses following 1.0 mg/kg of DOM, ED50 = responses following administration of the ED₅₀ dose (i.e., 0.3 mg/kg) of DOM, and S = responses following administration of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 4

Results (group mean ±SEM) of selected R(+)- and S(−)8-OH DPAT doses given in combination with the ED₅₀ dose of DOM to rats (n=5) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. DOM = responses following 1.0 mg/kg of DOM, ED50 = responses following administration of the ED₅₀ dose (i.e., 0.3 mg/kg) of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 5

Results (group mean ±SEM) of NAN-190 doses given alone (open squares) or in combination with 1.0 mg/kg of DOM (open circles) to rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. DOM = responses following 1.0 mg/kg of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg).

Fig. 6

Results (group mean ±SEM) of NAN-190 doses (0.1 and 0.3 mg/kg) administered to animals receiving a combination of the ED₅₀ dose of DOM plus either 0.5 mg/kg of (±)8-OH DPAT or 0.25 mg/kg of R(+)8-OH DPAT to rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. ED50 = responses following administration of the ED₅₀ dose (i.e., 0.3 mg/kg) of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg; control percent = 98% (±1); responses/min = 5.3 (±0.8). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 7

Results (group mean ±SEM) of MDMA doses given in combination with the ED₅₀ dose of DOM to rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. DOM = responses following 1.0 mg/kg of DOM, ED50 = responses following administration of the ED₅₀ dose (i.e., 0.3 mg/kg) of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).

Fig. 8

Results (group mean ±SEM) of MDMA doses given in combination with a very low dose (i.e., 0.1 mg/kg) of DOM to rats (n=6) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (upper panel). The animals’ response rates are shown in the lower panel. DOM = responses following 1.0 mg/kg of DOM, and S = responses following administration of saline vehicle. One asterisk indicates a statistically significant difference from the response of saline vehicle. Two asterisks indicate a statistically significant difference from the response of DOM (1.0 mg/kg). Three asterisks indicate a statistically significant difference from the response of saline vehicle and DOM (1.0 mg/kg).