TL neuro

November 8, 2013

Taffe Lab SFN2013 Poster on MDPV

Filed under: Cathinones, MDPV, SfN Annual Meeting 2013 — mtaffe @ 10:14 am

Saturday 11/9, 1-5pm

Board: 62.15/EE3

Rapid devaluation of running wheel activity coincident with the rapid, binge-like acquisition of 3,4-methylenedioxypyrovalerone self-administration

CNAD and Dept. of Chem., The Scripps Res. Inst., La Jolla, CA

One proposed risk factor for drug abuse/addiction is impoverishment of access to non-drug rewards/reinforcers. It is also hypothesized that engagement with non-drug reinforcers will prevent or treat drug abuse/addiction but for some individuals the drug maintains a relative advantage over natural rewards. In preclinical models, it has been shown that access to a running wheel can reduce drug intravenous self-administration (IVSA) in rats under some conditions but also that drug access decreases wheel activity. This study examined the effects of access to a running wheel and to the high efficacy stimulant reinforcer 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”) on IVSA and wheel activity. Male Wistar rats were given concurrent access to MDPV (0.05 mg/kg/inf, i.v.) and a running wheel that was either locked (LW) or unlocked (UW) in 60-min operant sessions. Mean MDPV intake increased across 20 sessions, but was equivalent for LW and UW groups. Mean wheel activity decreased across 20 sessions in the UW group. Inspection of individuals’ data showed that ~2/3 of the UW rats exhibited apparent “crossovers” wherein wheel activity plummeted within the same session that MDPV IVSA increased. Follow-up analyses confirmed a negative relationship between wheel activity and drug intake and confirmed that rats with crossovers earned more infusions than those without such crossovers. Also, regardless of wheel condition, the rapid acquisition of MDPV IVSA often began with a binge-like pattern of drug intake wherein post-reinforcement pauses decreased to the limit imposed by a 20 second post-infusion timeout. Analysis of post-acquisition MDPV intake confirmed that rats exhibiting binging had higher drug intakes than those that didn’t show the pattern (even after excluding the initial binge from the analysis). These results indicate that the coincident introduction of running-wheel access during access to MDPV IVSA is without effect on that IVSA, unlike a prior finding for methamphetamine (MA) IVSA. And, these results indicate that acquisition of MDPV IVSA rapidly decreases wheel activity in a devaluation similar to prior effects of MA IVSA. Lastly, acquisition of MDPV IVSA was often associated with an initial binge that predicted greater subsequent drug intake. Thus, it appears that MDPV rapidly diminishes the value of non-drug reinforcers, that initial drug intake levels are capped only by physically imposed limits and that a binge-like acquisition pattern has consequences for subsequent drug consumption. Together, these results strengthen the prediction that MDPV has an abuse/addiction liability much greater than that of MA.

SFN2013: Notes 1

Filed under: SfN Annual Meeting 2013 — mtaffe @ 10:08 am

OASIS Planner link

Saturday NanoSymposia
Nanosymposium.013.Mood Disorders: Human Biomarkers, Treatment, and Post Mortem Studies 30B
-two exercise talks at the start

Nanosymposium.014.Cocaine: Neural Mechanisms of Addiction I 33C
Saturday Drug Posters

  • 62.03 Schenk 11/9/2013 13:00 11/9/2013 16:00 62 DD9 Role of the serotonin 1b receptor in MDMA self-administration
  • 62.15 Aarde 11/9/2013 13:00 11/9/2013 16:00 62 EE3 Rapid devaluation of running wheel activity coincident with the rapid, binge-like acquisition of 3,4-methylenedioxypyrovalerone self-administration
  • 93.14 Gruene 11/9/2013 13:00 11/9/2013 15:00 93 HHH30 Sex-specific individual differences in fear behavior in large cohorts of rats: Neuroanatomical markers of vulnerability and resilience
  • 103.06 Cha 11/9/2013 13:00 11/9/2013 15:00 103 KKK58 Psychological dependence of tetrahydrocannabinol and synthetic cannabinoids JWH-073, JWH-081 and JWH-210
  • 73.05 Smith 11/9/2013 13:00 11/9/2013 14:00 73 PP19 The interaction between ecstasy user status and sense of affective touch

Saturday “Amphetamines and related drugs” poster sessions

032. Board C34 starts Cholinergic Modulation of the Dopaminergic System. Poster session

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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