TL neuro

October 16, 2017

High ambient temperature facilitates MDMA self-administration

Filed under: IVSA, MDMA, Thermoregulation — mtaffe @ 1:02 pm

The following has recently been accepted for publication:

Aarde, S.M., Huang, P-K  and Taffe, M.A. High Ambient Temperature Facilitates The Acquisition Of 3,4-Methylenedioxymethamphetamine (MDMA) Self-Administration. Pharmacol Biochem Behav, 2017, in press. 

This study was motivated by a finding from Cornish and colleagues in 2003 where they showed that rats trained to self-administer MDMA at 21 °C ambient temperature will significantly increase their drug intake when placed in a 30 °C ambient temperature. This finding was of interest to our lab because of our longstanding interest in the role of the body temperature response to MDMA. In brief, the effect of a given dose of MDMA at ~21-24 °C is generally to lower a rat’s body temperature whereas the same dose given at ~27-30 °C elevates body temperature. The typical laboratory ambient temperature of about 21-24 °C is actually somewhat cold for a rat since their point of thermoneutrality is up around 30 °C.  This led us to think that perhaps one of the reasons why MDMA is a poor reinforcer in the intravenous self-administration (IVSA) paradigm is because it lowers body temperature. If this effect is aversive to the rat, this may oppose the rewarding properties of the drug. Consequently, the Cornish finding may have illustrated increased IVSA due to a blunted hypothermia (but that study didn’t measure it). This rationale formed the basis for an entire Aim of a grant proposal which was submitted in original form in 2007 and eventually funded in 2011 (R01 DA024105-01A2).

In this figure from the paper we present the number of MDMA infusions (1.0 mg/kg/infusion) obtained by the groups of rats trained to self-administer under Cold (20 °C; N=12) or Hot (30 °C; N=11) ambient conditions in two-hour sessions. The schedule of reinforcement was FR5 for these studies meaning that each infusion required that the rat make five lever presses. As is obvious from the figure, the Hot group obtained more infusions of MDMA than did the Cold group. On session 16 only the drug-free vehicle was available and the increased responding (“saline bursting”) can be interpreted as a sign of drug-seeking behavior. This is particularly important for the Cold group given their very low (but consistent) numbers of infusions obtained. So to this point of the study, the behavior replicates and extends the work of Cornish and colleagues in 2003. They trained their rats in a lower ambient condition and then did post-acquisition tests at a higher ambient temperature and so the effect of ongoing experience in cold versus hot conditions could not be assessed. Interestingly, however, Feduccia and colleagues (2010) did a study much more like ours in design and failed to find any difference in the acquisition of IVSA in cold versus hot ambient conditions. There are a few procedural differences which may explain the difference in outcome but additional experiments would be required for firm conclusions. One potential difference is the selection of FR1 reward contingency which led to similar behavior in the MDMA groups and the groups allowed to self-administer saline only in that study. Although we did not have saline-only controls, our lever discrimination remained over 80% in both groups. In Aarde et al (2013) we ran a saline-only control group, pretrained to lever press for food at FR5, at normal laboratory ambient temperature (24 °C) and showed that lever discrimination breaks down significantly within the first 10 sessions of saline IVSA.

As outlined above, we were interested in the nature of the body temperature response during self-administration and how this might be changed by different ambient temperature conditions. Feduccia and colleagues had found no change in body temperature induced by MDMA IVSA at all, but their monitoring was via pre- and post-session rectal sampling. The temperature response to MDMA in rats is transient and it was likely that the sampling at 2 hours after the start of the session missed the dynamic response. This technique also requires handling the rats which can cause a stress response which may increase the body temperature. Our study used implanted radiotelemetry to observe the temperature response during the session. This adaptation of a figure from the paper presents 30 min averages (data collected every 5 minutes) of body temperature across the self-administration session and for one hour after the drug was no longer available. The daily responses are collapsed across blocks of 5-6 sequential training days. The takeaway here is that body temperature decreased in both Hot and Cold groups during the initial hour of the self-administration session and this response was gradually blunted in the Hot group across the self-administration training. The similar degree of hypothermia early in the acquisition phase and the course of tolerance versus drug intake in the Hot group was not consistent with our original hypothesis. It looked much more as though MDMA caused hypothermia under all training conditions and any attenuation of that response followed, rather than caused, increased drug intake over time.

To further probe the role of ambient temperature we next switched the temperature conditions and found that MDMA IVSA was unchanged within the groups. As if they’d been set on a preference trajectory. The failure to increase drug intake in the Cold group when placed in higher ambient temperature conditions was discordant with the original Cornish finding and we do not know why this might be the case. Most importantly, the Hot-trained group self-administered more drug in Cold ambient then did the Cold-trained group in Hot ambient and developed a more pronounced drop in body temperature. This showed that the ongoing self-administration training did not categorically alter the temperature response to MDMA in these animals.

The last study in the self-administering groups examined the effect of non-contingent administration of a range of MDMA doses (1-5 mg/kg, i.v.) on the body temperature response under Hot and Cold ambient temperature conditions. Up to this point, the animals self-selected their doses and so the interaction of dose with the temperature responses could not be easily disentangled. This last study found that hypothermia depended on dose, ambient temperature and the prior MDMA intake of the rat. Those individuals who self-administered very low amounts across the study (regardless of ambient temperature condition) were most sensitive to MDMA-induced hypothermia. Hypothermia was produced in both subgroups under Cold ambient, albeit to a greater degree in the animals with less cumulative MDMA intake. The takeaway from this part of the study is less clear cut. Clearly the hypothermic response to  MDMA under low ambient temperature conditions was only quantitatively, not categorically, altered in rats that self-administered more MDMA. Temperature responses under higher ambient temperature conditions were blunted- to the point that 3-5 mg/kg MDMA, i.v., did not change body temperature from baseline in the higher preference subgroup and while 2-3 mg/kg lowered body temperature in the lower-preference subgroup, 4-5 mg/kg did not.  [In general, the dose-effect relationship for MDMA-induced hypothermia does not reflect across Cold and Hot ambient temperatures. A high MDMA dose produces both less hypothermia under Cold conditions and increased hyperthermia under Hot conditions. Likewise, a moderate dose produces less hyperthermia in Hot conditions and more hypothermia in Cold ambient temperature conditions.] Thus, these data allow for the possibility that incremental blunting of the hypothermic response to MDMA may have some effect on sustaining IVSA behavior. Still, the overall thrust of this study suggests that the body temperature response is not a primary driver of self-administration of MDMA.

An additional study examined the effect of MDMA on intracranial self-stimulation (ICSS) reward in a different group of animals with no MDMA self-administration history. In ICSS the animal makes behavioral responses in response to small amounts of electrical current delivered to a specific region of the brain. We used a thresholding procedure in which the amount of current required for the animal to feel a rewarding effect can be determined from day to day. This procedure has been used by many laboratories over decades to show that treatments that make the animal feel good (such as an injection of methamphetamine) lower reward thresholds whereas conditions that make the animal feel bad (such as drug withdrawal in a dependent rat) lead to increased reward thresholds. Our study found that thresholds were increased merely by being placed in a hot environment (these data are all relative to individual thresholds from a 24 °C uninjected test session). Under Cold conditions, a 2.5 mg/kg MDMA, i.p., injection reduced reward thresholds in a manner consistent with the effects of methamphetamine, MDPV or mephedrone (Nguyen et al, 2016). Under Hot conditions, the same MDMA dose only returned reward thresholds to a baseline established under 24 °C without producing a pro-reward effect.

 

This ICSS experiment supports an interpretation of increased MDMA self-administration under high ambient temperature conditions as a normalization of negative affect, rather than an enhancement of the positive, feel-good subjective effects of MDMA.

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November 13, 2014

SfN 2014 Presentation: Vape drug delivery

We will present a poster describing our efforts to develop technologies for the intrapulmonary (inhaled) delivery of psychoactive drugs at the 2004 meeting of the Society for Neuroscience.

Abstract 810.04 on Board AA05: Development and validation of a device for the intrapulmonary delivery of cannabinoids and stimulants to rats .
Authors: M. A. TAFFE, S. M. AARDE, M. COLE;
Cmte Neurobio. of Addictive Disorders, The Scripps Res. Inst., LA JOLLA, CA;

The presentation time is Wednesday, Nov 19, 2014, 1:00 PM – 5:00 PM.

Abstract Text:

The recent popularization of non-combustible methods for intrapulmonary delivery of psychoactive drugs to humans (Vape, Volcano, e-cigarette, etc) has stimulated interest in the intrapulmonary administration models for rodent studies. We have designed a sealed rodent chamber, with a well regulated air flow, that is suitable for the controlled exposure of rats to psychoactive substances. Use of e-cigarette type delivery systems was found to afford excellent dosing control for this purpose. Studies were conducted in male rats to verify the in vivo efficacy of drug delivery. Implantable radiotelemetry methods were used to demonstrate that a 20 min exposure to [[unable to display character: ∆]]9-tetrahydrocannabinol (THC), or the CB1 receptor full agonist JWH-018, produces a robust hypothermia. The temperature nadir was reached within 40 min of exposure, was of comparable magnitude to that found after 30 mg/kg THC or 1.1 mg/kg JWH-018, i.p. and had resolved within 3 hours compared with a 6 hour time course following injection. Studies also demonstrated that 30 min of intrapulmonary exposure to methamphetamine (MA) significantly increased home cage locomotor behavior for up to 2 hrs. A final study showed that a 30 min intrapulmonary exposure to MA reduced drug intake during the loading phase of intravenous self-administration of MA. Finally, it is shown that rats will nosepoke for the delivery of MA vapor. These studies show that an electronic cigarette type delivery system can be successfully used to model intrapulmonary drug delivery in rats. These techniques will be of increasing utility as recreational users continue to adopt “vaping” for the administration of psychtropic drugs.

SrN2014-teaserFigureDisclosures: M.A. Taffe: None. S.M. Aarde: None. M. Cole: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); La Jolla Alcohol Research, Inc..

This work was supported by NIH grants DA035281 and DA024105.

This figure is small preview of the data that we will be presenting. The figure depicts body temperature responses to 20 minutes of Vape-exposure to THC and the synthetic cannabinoid JWH-018 (upper panel) and locomotor activity responses to 30 minutes of Vape-exposure to methamphetamine (lower panel) in a group (N=7) male rats. In both panels there are comparison data for a session in which animals were just in normal cages with no drug intervention (No Chamber) and another session in the inhalation chamber in which animals were exposed to the Vape delivery vehicle without any drug in it (Vehicle). As you can see, we were successful in delivering active doses of the drugs, each of which had class-specific effects, i.e. cannabinoid hypothermia and stimulant hyperlocomotion.

December 20, 2012

Functional efficacy of an anti-methamphetamine vaccine

Filed under: Methamphetamine, Thermoregulation, Vaccines — mtaffe @ 9:31 am

An early study which attempted to generate active vaccination against methamphetamine (METH) found no significant differences between vaccinated and control rats in a locomotor response to METH (Byrnes-Blake et al. 2001), however the vaccine led to a monoclonal antibody which was effective as a passive vaccine in a range of pharmacological studies including pharmacokinetic, animal models of drug overdose, locomotor activity, self-administration, and drug discrimination (Byrnes-Blake et al. 2003; McMillan et al. 2002). Passive vaccines are considered to be less ideal because they require the infusion of large quantities of drug-specific antibodies which must be manufactured and stored for use. In many cases active vaccine can be manufactured more cheaply and the antibodies are then generated by the immune system. Typically, or perhaps ideally, the duration of protection for passive vaccination is not as long as with active vaccination. Thus there continues to be interest if determining if active vaccination can work.

Another group found that active vaccination with the same hapten published by Byrnes-Blake (2001), coupled to a “molecular adjuvant” with a tetanus toxin T-cell epitope in place of the traditional keyhole limpet hemocyanin (KLH), resulted in an intial increase in methamphetamine self-administration in rats, followed by a decrease to levels indistinguishable from controls over 15 sessions (Duryee et al. 2009). This enhances confidence that it would be possible to develop active vaccines against methamphetamine.

The following paper is now in press at Biological Psychiatry.

Miller ML, Moreno AY, Aarde SM, Creehan KM, Vandewater SA, Vaillancourt BD, Wright MJ Jr, Janda KD, Taffe MA. A Methamphetamine Vaccine Attenuates Methamphetamine-Induced Disruptions in Thermoregulation and Activity in Rats.Biol Psychiatry. 2012 Oct 22. pii: S0006-3223(12)00803-7. doi: 10.1016/j.biopsych.2012.09.010. [Epub ahead of print] [PubMed][DOI]

VaccineTelem-Fig2In this paper we have shown that active vaccination can protect against the effects of METH. This figure is reproduced from the paper and the data show that METH causes an elevation of body temperature and an increase in wheel activity in the control animals vaccinated with the carrier protein (KLH). These effects are blocked in the animals vaccinated with the MH6-KLH conjugate vaccine. These data show the potential for active vaccination to oppose effects of methamphetamine.

Another paper from a competing group (Shen et al, 2012) appeared at nearly the same time as ours, demonstrating efficacy of active vaccination against METH stimulated locomotor activity in mice. It is to be hoped that these three successful demonstrations of efficacy of anti-METH vaccines will overcome the apparent failure of the early Byrnes-Blake et al (2001) finding and stimulate additional research.

This project was supported by NIH/NIDA grant R01 DA024705.

A NIDA generated brief animation video on the basic idea of anti-drug vaccination can be found in this post.
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Additional Reading:

Byrnes-Blake KA, Carroll FI, Abraham P, Owens SM. Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats. Int Immunopharmacol. 2001 Feb;1(2):329-38. [PubMed]

Duryee MJ, Bevins RA, Reichel CM, Murray JE, Dong Y, Thiele GM, Sanderson SD. Immune responses to methamphetamine by active immunization with peptide-based, molecular adjuvant-containing vaccines. Vaccine. 2009 May 14;27(22):2981-8. doi: 10.1016/j.vaccine.2009.02.105. Epub 2009 Mar 10. [PubMed]

Shen XY, Kosten TA, Lopez AY, Kinsey BM, Kosten TR, Orson FM. A vaccine against methamphetamine attenuates its behavioral effects in mice. Drug Alcohol Depend. 2012 Sep 27. doi: 10.1016/j.drugalcdep.2012.09.007. [Epub ahead of print] [PubMed]

July 6, 2011

Wheel activity and MDMA hyperthermia

Filed under: MDMA, Methamphetamine, Thermoregulation — mtaffe @ 2:18 pm

The following has been assigned an issue in Pharmacology, Biochemistry & Behavior

Gilpin NW, Wright MJ Jr, Dickinson G, Vandewater SA, Price JU, Taffe MA. Influences of activity wheel access on the body temperature response to MDMA and methamphetamine., Pharmacol Biochem Behav. 2011 Sep;99(3):295-300. Epub 2011 May 13. DOI PubMed

In this paper we report that while the opportunity to run on an activity wheel does not increase the mean body temperature increase associated with 10 mg/kg MDMA in rats, the two correlate across individuals. Also, the individuals who ran most / increased their temperature most were at increased risk of 24-hr mortality, despite having stable body temperature 6 hrs post dosing.

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