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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.

October 17, 2013

Oreo cookies, cocaine and final-common mechanisms of reward

Filed under: Neuroscience, SfN Annual Meeting 2013, Society for Neuroscience — mtaffe @ 10:42 am

A poster to be presented at the upcoming 2013 meeting of the Society for Neuroscience (SfN) in San Diego has garnered a bit of play in the popular media this week. The study from Schroeder and colleagues is being described in the media as showing that Oreo cookies are just as addictive as cocaine in rats. For example see the reports in Forbes, The Christian Science Monitor, ABC and the LA Times.

These findings are not particularly astonishing in terms of the science, nor has anything remarkable been demonstrated with this study.

Nevertheless, this provides an excellent opportunity to explain why it is the case that this is not astonishing.

The media reports are a little bit confused because they talk about a “maze” but a hint is provided in the description that animals “spent more time” on the side of the maze associated with the Oreos. This is not a “maze” study but rather a procedure called Conditioned Place Preference (CPP) which is used to assess the pleasurable or rewarding potential of….something. Note that the exact same test can assess unpleasant or aversive feelings and stimuli, when that is expected the test is Conditioned Place Aversion. But really it is the same idea.

The Abstract submitted for the conference is not overly detailed but it was a “8-day biased CPP paradigm”. This indicates the rats were permitted to explore two sides of an enclosed chamber on alternate days (probably 4 days each). One side per day. One group of rats was given Oreos one the days in one side of the maze and rice cakes when in the other side. Additional groups were given an injection of saline before days on one side of the chamber and either cocaine or morphine on the other day. The critical behavioral test day presented the rats with a fully open chamber and tested how much time they spent in each side. If the animals spent more time in the Oreo or cocaine or morphine associated side (versus rice cakes or saline-injection-associated sides, respectively) then this is the demonstration of preference. The SfN Abstract on this study indicates that the magnitude of preference (i.e. the ratio of time spent on one side of the chamber over the other) was similar for all three groups. This is the basis of the media take that Oreos are “just as addictive” as cocaine.

The study went on to assess the expression of c-Fos in the nucleus accumbens region of the rats’ brains and showed that on an individual basis, the magnitude of c-Fos expression correlated positively with the degree of place preference. In other words, the rats that spent the greatest proportion of their time in the Oreo-associated (or drug-associated) side of the chamber had the highest c-Fos levels in the nucleus accumbens.

The c-Fos is a transcription factor which indicates the activation of genetic transcription in a given brain region. For our purposes today, we can just view this as activation of the nucleus accumbens region in response to the conditioning procedure. And to a first approximation the media reports are not far wrong, this indicates triggering of the brain’s “reward” mechanisms.

DiChiara88-amp-DAoverflowThis brings us to the concept of a final-common-pathway of rewarding stimuli. There is a great deal of evidence that things that we humans find to be rewarding and or pleasurable activate the same brain pathways. Similarly, the stimuli that motivate or reinforce the behavior of laboratory rats also have the tendency to activate the same brain pathways. The nucleus accumbens region is one such region. The c-Fos measure of this Oreo cookie study is one way to measure activation of the nucleus accumbens.

Another way to measure it is to examine the extracellular release of the neurotransmitter dopamine.

Di Chiara and Imperato showed in 1988 that amphetamine (shown above) and cocaine, morphine, nicotine or alcohol injected into the rat caused an increase in the concentration of dopamine (DA) in the extracellular space (i.e., outside of the neurons themselves) of both the caudate and nucleus accumbens regions. (DOPAC and HVA are metabolites of dopamine). They used a technique called intra-cerebral microdialysis pioneered by Understedt and his many colleagues. There is a freely-available description of the approach here, including this handy summary picture. We know that stimulant drugs are highly capable of establishing both conditioned place preference and in reinforcing the behavior of laboratory rats. Humans tend to report the experience of them as pleasurable. These authors showed that amphetamine greatly increases the concentration of dopamine on the order of 6 (caudate) to 10 (nucleus accumbens) times the pre-drug level.

Hurd88-Coc-DAYasmin Hurd showed, with Kehr and Ungerstedt, in 1988 that the effect of cocaine to increase caudate dopamine went in temporal register with the levels of cocaine and the effect could be repeated within 90 minutes. In this case dopamine levels only trebled, which was actually similar to the magnitude of effect produced by cocaine, morphine, nicotine and alcohol on accumbens dopamine levels in the Di Chiara and Imperato study. The takeaway points from even this early work were very clear. Recreational drugs of abuse which shared a compulsive use or addictive liability in humans shared the common property of increasing dopamine in the nucleus accumbens of rats. [Later work has verified a similar effect on humans using non-invasive imaging techniques.] The magnitude of the dopamine increase was also shown to be related to the dose of morphine or ethanol that was administered and subsequent investigations have shown similar dose-dependence for many other drugs including cocaine and amphetamine.

Hernandez88-food-DA-nucaccumSure enough, Hernandez and Hoebel showed in 1988 that food likewise increases the extracellular dopamine in nucleus accumbens. As you can see from the figure, the magnitude of increase was smaller, amounting to about a 40% increase, than what has been shown for the drugs. Nevertheless, the final-common-mechanism for rewarding stimuli is supported. Further evidence is supplied by a study showing that dopamine is increased in the nucleus accumbens of male rats on exposure to sexually-receptive (but not nonreceptive) female rats (Wenkstern et al, 1993; Damsma et al, 1992).

Food, drugs and sex. All triggering the same brain mechanism.

Hajnal04-DA-Accumb-sucroseshamIn some cases, the cues that are associated with the rewarding stimulus are sufficient to trigger this reward mechanism. Hajnal and colleagues (2004) showed that oral sucrose solution stimulation (with gastric bypass to eliminate caloric effects) was sufficient to elevate dopamine in the accumbens. This is interesting because it shows that the trigger for reward can be the mere sensation of the sugar water. This ties back to the CPP study with Oreo cookies because on the critical test day, all the animal was exposed to were the cues that had been previously associated with either cookies or rice cakes. It has been shown that environmental cues associated with cocaine are themselves capable of elevating nucleus accumbens dopamine (by about 25% in Gerasimov et al, 2001) and increasing the firing rate of nucleus accumbens neurons (Ghitza et al, 2003). If you pharmacologically block dopamine signalling in the nucleus accumbens it prevents the ability of a cue previously associated with sucrose to stimulate lever pressing in rats (Guy et al, 2011).

I emphasize that I am describing only a little bit of the evidence which supports the idea that both food and drugs produce their rewarding or reinforcing effects through common brain mechanisms. The primary stimulation of systems can be very different. Different drugs of abuse activate dopamine systems directly, or opioid systems, or nicotinic cholinergic systems, etc. Food triggers gustatory sensation pathways as the primary stimulus of the brain. And yet the rewarding part is mediated by the same mechanism(s). Dopamine in the nucleus accumbens is just one aspect of the final-common-reward signalling but it serves to make the case.

There is nothing surprising whatsoever about the fact that Oreo cookies and cocaine both produce CPP and both elevate nucleus accumbens c-Fos.

I was hoping to get on to what this means for “addiction” and trying to compare the relative potential for food, drug, gambling, sex, etc addictions but this post is far too long already.

Additional comment from UCSD Neuroscience Graduate Program student Ashley Juavinett.
Wednesday, Nov 13, 2013, 8:00 AM – 9:00 AM
Nucleus accumbens C-Fos expression is correlated with conditioned place preference to cocaine, morphine and high fat/sugar food consumption
Dept Psychol, Connecticut Coll, NEW LONDON, CT

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