Differences in the locomotor-activating effects of indirect serotonin agonists in habituated and non-habituated rats

Abstract

The indirect serotonin (5-HT) agonist 3,4-methylenedioxymethamphetamine (MDMA) produces a distinct behavioral profile in rats consisting of locomotor hyperactivity, thigmotaxis, and decreased exploration. The indirect 5-HT agonist α-ethyltryptamine (AET) produces a similar behavioral profile. Using the Behavioral Pattern Monitor (BPM), the present investigation examined whether the effects of MDMA and AET are dependent on the novelty of the testing environment. These experiments were conducted in Sprague-Dawley rats housed on a reversed light cycle and tested during the dark phase of the light/dark cycle. We found that racemic MDMA (RS-MDMA; 3 mg/kg, SC) increased locomotor activity in rats tested in novel BPM chambers, but had no effect on locomotor activity in rats habituated to the BPM chambers immediately prior to testing. Likewise, AET (5 mg/kg, SC) increased locomotor activity in non-habituated animals but not in animals habituated to the test chambers. These results were unexpected because previous reports indicate that MDMA has robust locomotor-activating effects in habituated animals. To further examine the influence of habituation on MDMA-induced locomotor activity, we conducted parametric studies with S-(+)-MDMA (the more active enantiomer) in habituated and non-habituated rats housed on a standard or reversed light cycle. Light cycle was included as a variable due to reported differences in sensitivity to serotonergic ligands during the dark and light phases. In confirmation of our initial studies, rats tested during the dark phase and habituated to the BPM did not show an S-(+)-MDMA (3 mg/kg, SC)-induced increase in locomotor activity, whereas non-habituated rats did. By contrast, in rats tested during the light phase, S-(+)-MDMA increased locomotor activity in both non-habituated and habituated rats, although the response in habituated animals was attenuated. The finding that habituation and light cycle interact to influence MDMA- and AET-induced hyperactivity demonstrates that there are previously unrecognized complexities associated with the behavioral effects of these drugs.

Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice

“…The lack of a significant effect could in part be due to the extra habituation to the chambers during the 30 min after WAY100635, but before agonist administration. Habituation to the testing chamber has been previously shown to impact locomotor effects of serotonergic drugs and psychedelics. , Pretreatment with 3 mg/kg s.c. WAY100635 prior to agonist administration appeared to rescue the reduced distance traveled seen in the vehicle/4-PrO-DMT group (Figure S2C), but this effect was not statistically significant, also likely due to habituation differences between dose–response and antagonist study designs.…”

“…Habituation to the testing chamber has been previously shown to impact locomotor effects of serotonergic drugs and psychedelics. 53,54 Pretreatment with 3 mg/kg s.c. WAY100635 prior to agonist administration appeared to rescue the reduced distance traveled seen in the vehicle/4-PrO-DMT group (Figure S2C), but this effect was not statistically significant, also likely due to habituation differences between dose−response and antagonist study designs. WAY100635 pretreatment also modulated the HTR activity induced by high dose 4-PrO-DMT (10 mg/kg s.c.) (Figure 4C).…”

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

“…Stereotypy was defined as the repeated interruption of the same photocell beam within 2 s. Rats were placed in the activity monitor every weekday for 1 h, at the same time each day, for 7 days before drug testing to allow for habituation to the monitor and to stabilize activity levels. This procedure was carried out to minimize the effects of novelty and light cycle on the results obtained (Halberstadt et al, 2012). Rats were then tested with subcutaneous (s.c.) injections of saline, MDPV (0.1-3.0 mg/kg), or cocaine (3-17 mg/kg) given 5 min before being placed in the activity monitor.…”

α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant

“…47,54,55 Yet, it was shown that habituation to the apparatus employed (i.e., a Behavioral Pattern Monitor) and light-cycle interact to influence MDMA-and AET-induced hyperactivity somewhat differently. 56 According to the DEA, AET was being clandestinely marketed as an MDMA-like substance, 27 and it has been reported that oral doses of AET (100 and 160 mg) produced MDMA-like effects in (an unspecified number of) human subjects. 33 Taken together, this evidence suggests that AET can produce at least some behavioral effects reminiscent of MDMA.…”

“…More will be said about the optical isomers of AET in the AET isomers section below. Geyer and colleagues examined a number of behavioral properties of AET (e.g., rat locomotor activity and multiple components of the startle reflex) and concluded that AET produces an MDMA-like profile of behavioral changes. ,, Yet, it was shown that habituation to the apparatus employed (i.e., a Behavioral Pattern Monitor) and light-cycle interact to influence MDMA- and AET-induced hyperactivity somewhat differently …”