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-15s 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.

Differential Effects of Serotonin 5-HT1A Receptor Agonists on the Discriminative Stimulus Effects of the 5-HT2A Receptor Agonist 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane in Rats and Rhesus Monkeys

“…The high efficacy and selective 5-HT 1A receptor agonist F13714 (Koek et al, 2001) also fails to occasion responding on the DOM-associated lever in rats. Second, in the previous study (Khorana et al, 2009) pretreatment with 8-OH-DPAT enhanced the discriminative stimulus effects of DOM, as evidenced by a shift leftward in the DOM dose-response curve; in the current study, neither pretreatment with 8-OH-DPAT nor with F13714 clearly shifts the DOM dose-response curve, leftward or rightward, in rats. Differences obtained with 5-HT 1A receptor agonists in rats, alone and in combination with DOM, might be related to procedural differences between studies including the training dose of DOM (1.0 and 0.56 mg/kg in the previous and current studies, respectively), schedule of reinforcement (variable interval 15 s and FR10, respectively), and reinforcers (sweetened condensed milk and food pellets, respectively).…”

“…There are two notable differences between the results of the previous and current studies. First, in the previous study (Khorana et al, 2009) racemic 8-OH-DPAT (0.3 mg/kg) alone occasioned 37% responding on the DOM-associated lever and R-(ϩ)8-OH-DPAT (0.25 mg/kg) alone occasioned 58% responding on the DOM-associated lever; in the current study, racemic 8-OH-DPAT occasioned responding predominantly on the saline-associated lever (i.e., Ͻ10% on the DOM-associated lever) up to a dose (0.32 mg/kg) that nearly eliminated responding. The high efficacy and selective 5-HT 1A receptor agonist F13714 (Koek et al, 2001) also fails to occasion responding on the DOM-associated lever in rats.…”

“…This study was based, in part, on data showing that the 5-HT 1A receptor agonist 8-OH-DPAT produces partial responding on the DOM-associated lever in rats discriminating DOM and, when administered together with DOM, 8-OH-DPAT enhances the effects of DOM (Glennon, 1991;Khorana et al, 2009). There are two notable differences between the results of the previous and current studies.…”

“…For example, the opioid receptor agonist heroin enhances the discriminative stimulus effects of the cannabinoid receptor agonist ⌬ 9 -tetrahydrocannabinol in rats (Solinas and Goldberg, 2005) but not in rhesus monkeys (Li et al, 2008a). Other data indicate that 5-HT 1A receptor agonists enhance the discriminative stimulus effects of 5-HT 2 receptor agonists in rats (Glennon, 1991;Reissig et al, 2005;Khorana et al, 2009); however, the generality of those observations to other conditions and other species has not been evaluated despite the relevance of such studies to understanding the actions of indirect-acting 5-HT receptor agonists.…”

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

“…Data analysis A determination of complete, partial, or no generalization (or antagonism) was based on previously described criteria (e.g., Khorana et al 2008;Young and Glennon 1986). In this scheme, the results of stimulus generalization (or antagonism) tests are characterized as one of three possible results: (a) complete stimulus generalization resulted when the animals, following a given dose of drug or drug combination, made ≥80% (i.e., group mean) of their responses on the drug-appropriate lever; (b) no generalization (i.e., saline-like responding) occurred when the test agent produced 0-20% drug-appropriate responding; and (c) partial generalization occurred when a test drug produced an intermediate level of responding (i.e., 21% to 79% but usually between 40% and 70%) on the drug-appropriate lever.…”