High ambient temperature facilitates the acquisition of 3,4-methylenedioxymethamphetamine (MDMA) self-administration

Abstract

Rationale MDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict. Objective To determine how body temperature responses under high and low TA influence MDMA IVSA. Methods Male Sprague-Dawley rats were trained to IVSA MDMA (1.0 mg/kg/infusion; 2-hr sessions; FR5 schedule of reinforcement) under TA 20°C or 30°C. Radiotelemetry transmitters recorded body temperature and activity during IVSA. Results MDMA intake increased under both TA during acquisition, but to a greater extent in the 30°C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30°C group. Within-session activity was initially lower in the 30° C group, but by the end of acquisition and maintenance, activity was similar for both groups. When TA conditions were swapped, the hot-trained group increased MDMA IVSA under 20 °C TA and a modest decrease in drug intake was observed in the cold-trained group under 30 °C TA. Subsequent non-contingent MDMA (1.0–5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High TA increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, TA. Conclusions High TA appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.

Distinguishing the behavioral potencies of α-pyrrolidino-phenone cathinone stimulants

“…The temperature response to all three drugs was small (Figure 5, 6), consistent with prior reports for α-PVP and MDPV (Aarde et al, 2015a;Aarde et al, 2013), as well as for other non-pyrrolidinophenone cathinones with mostly monoamine transporter inhibitor activity (Javadi-Paydar et al, 2018b). This stands in substantial contrast with the larger temperature effects produced by some of the monoamine transporter substate/releaser cathinones (Miller et al, 2013a;Wright et al, 2012) and the substrate/releaser amphetamines (Aarde et al, 2017;Malberg and Seiden, 1998;Miller et al, 2013a). These results contrast slightly with one prior report of thermoregulatory effects of α-PVP in male and female Sprague-Dawley rats, however those studies were conducted in the light part of the cycle and relative elevations of temperature were most pronounced several hours after injection when temperature declined in the vehicle condition (Nelson et al, 2019).…”

“…in a counterbalanced order across the group. MA was included as a positive control, since this reliably reduces thresholds in male rats in our hands (Nguyen et al, 2016;Nguyen et al, 2019), similar to the effects of 3,4-methylenedioxymethamphetamine (Aarde et al, 2017). The rats (N=10 completed all conditions) were next injected 15 minutes prior to the session with saline or one of two doses (0.5, 1.0 mg/kg, i.p.)…”

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats

“…For single time point studies blood samples were collected ( ~500-1000 ul) via jugular needle insertion under anesthesia with an isoflurane/oxygen vapor mixture (isoflurane 5% induction, 1-3% maintenance). For serial blood sampling (200 ul; 35, 60, 120 and 240 minutes after vapor initiation) rats were prepared with chronic intravenous catheters as previously described (Aarde et al 2017). Catheter function was assessed prior to starting a series of experiments and only animals with a functional catheter were used; a two week recovery interval was imposed prior to any further experimentation for multiple-sampling procedures.…”

“…The first group of male (N=8) and female (N=8) Wistar rats were 20 weeks of age at the start of this study. These rats arrived in the lab as a cohort and were previously implanted with jugular catheters, for methods see (Aarde et al 2017); one male and one female rat did not survive catheter surgery. Intact rats with patent catheters at 20 weeks of age (2 out of 7 male and 3 out of 7 female rats) were used for serial plasma collection at 35, 60, 120 and 240 minutes after the start of inhalation of THC Vapor (100 mg/mL, 30 min).…”

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…The sexes were treated identically up until PND 86 and thereafter there were some slight differences; the order and details of studies are outlined in Table 1. Intravenous Catheterization. Rats (N=16 female; N= 24 male) were anesthetized with an isoflurane/oxygen vapor mixture (isoflurane 5% induction, 1-3% maintenance) and prepared with chronic indwelling intravenous catheters as described previously (Aarde et al, 2017;Miller et al, 2015;Nguyen et al, 2017) on PND 84-87, i.e. after adolescent vapor exposure (see below).…”