Sciencemag article re. baclofen

[Ne/Neva Eva]

Ventral Tegmental Area BDNF Induces
an Opiate-Dependent?Like Reward
State in Na?ve Rats
Hector Vargas-Perez,1* Ryan Ting-A Kee,2 Christine H. Walton,3 D. Micah Hansen,3
Rozita Razavi,1 Laura Clarke,2 Mary Rose Bufalino,2 David W. Allison,3
Scott C. Steffensen,3 Derek van der Kooy1,2
The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state
remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor
(BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several
behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found
that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a
dopamine-dependent opiate reward system, identical to that seen when an opiate-na?ve rat becomes
dependent and withdrawn. This shift involves a switch in the g-aminobutyric acid type A (GABAA) receptors
of VTA GABAergic neurons, from inhibitory to excitatory signaling.
The ventral tegmental area (VTA) serves
as an anatomical locus controlling the
switch from an opiate-nondependent to
an opiate-dependent state (1, 2). In nondependent
rats, opiate reward is mediated by a
dopamine-independent neural system, involving
the brainstem tegmental pedunculopontine nucleus
(TPP) (3). Once chronically exposed to opiates
and in a state of withdrawal, opiate reward switches
to a dopamine-dependent system (3). It has been
observed that the switch between the two motivational
systems is due to a switch in g-aminobutyric
acid type A (GABAA) receptor functioning in
VTA GABAergic neurons, from an inhibitory to
an excitatory signaling state (fig. S1) (2).
Brain-derived neurotrophic factor (BDNF) is
capable of producing this change in GABAergic
response, from inhibitory to excitatory, as has
been observed in the hippocampus during epileptic
seizures (4) and in the spinal cord during
neuropathic pain (5). BDNF is present in the
VTA (6), and its TrkB receptors are present on
both GABA (fig. S2) and dopamine VTA
neurons (7, 8). Chronic exposure to drugs of
abuse increase BDNF levels in VTA neurons
1Department of Molecular Genetics, University of Toronto, 160
College Street, Toronto, Ontario M5S 3E1, Canada. 2Institute
of Medical Science, University of Toronto, 160 College Street,
Toronto, Ontario M5S 3E1, Canada. 3Department of Psychology,
Brigham Young University, Provo, UT 84602, USA.
*To whom correspondence should be addressed. E-mail:
vargashector@yahoo.com
1732 26 JUNE 2009 VOL 324 SCIENCE Science

[Ne/Neva Eva]

Sciencemag article re. baclofen

CORRECTED 2 OCTOBER 2009; SEE LAST PAGE
Downloaded from Science on December 12, 2010
(6). Furthermore, BDNF infusions into the VTA
dramatically enhance several behavioral effects
of drugs, including psychomotor sensitization
(6, 9) and drug seeking (6, 10).We hypothesized
that, along with the changes in structural
plasticity induced by BDNF in VTA dopaminergic
neurons (11), increasing BDNF levels in the
VTAwould induce a switch to a drug-dependent
motivational state in drug-nondependent rats due
to the effects of BDNF on GABAergic neurons.
First, we examined whether BDNF protein
and mRNA levels in the VTA were increased in
opiate-dependent rats. Sixteen hours after withdrawal
from repeated daily exposure to heroin
(0.5 mg/kg, subcutaneously) for 8 days [see
supporting online material (SOM)], BDNF protein
(F3,37 = 7.63, P < 0.05) and BDNF mRNA
(F3,19 = 4.04, P < 0.05) levels in the VTA increased
by 150% (P < 0.05) and 193%, respectively,
of the control drug-na?ve rats (P
0.05) or 15 days after withdrawal from
repeated heroin exposure (P > 0.05) (fig. S3).
To explore whether BDNF alone was sufficient
to cause a change in the neurobiological
substrates mediating opiate reward, we next performed
place conditioning procedures on rats
after single bilateral intra-VTA BDNF (0.25 mg
each) infusions (10). Place conditioning procedures
(12) (see SOM) were performed 3 days
after BDNF infusions (10). During training, we
administered four alternating injections of intraperitoneal
morphine (10 mg/kg) and vehicle to
the rats over 8 days. The dopamine receptor
antagonist alpha-flupenthixol (0.8 mg/kg) (or
its saline vehicle) was injected intraperitoneally
2.5 hours before each conditioning trial. Testing
was performed drug-free between 48 and 72
hours after the final conditioning session. After
VTA BDNF (n = 10 animals) [but not the saline
vehicle phosphate-buffered saline (PBS) (n =
20)] infusion, antagonism of the dopaminergic
system blocked the rewarding effects of acute
systemic morphine in drug-nondependent rats
(F1,59 = 5.3, P < 0.05, interaction of morphine
and BDNF treatment). Infusion of BDNF outside
of the VTA (due to cannulae misplaced rostral,
ventral, or lateral to the VTA) (fig. S4) did not
allow the dopamine antagonist to block the
rewarding effects of morphine in nondependent
rats (t10 = 4.65, P < 0.05, n = 11) (Fig. 1A). It is
possible that intra-VTA BDNF modifies the
ability of opiates to produce conditioned place
preferences, making them easier to block. However,
neither BDNF (n = 7) nor PBS (n = 7) alone
had any effect on the sizes of the conditioned
Fig. 1. Motivational effects of a single intra-VTA BDNF infusion in drug-nondependent rats. (A) Blockade
of the dopaminergic system with neuroleptics (alpha-flupenthixol, 0.8 mg/kg) blocked the rewarding
effects of morphine (10 mg/kg) in nondependent rats after a single intra-VTA BDNF (0.25 mg) infusion,
but not after intra-VTA PBS infusion (*P < 0.05). The same treatment failed to block the rewarding effects
of morphine in nondependent rats when BDNF was infused rostral, ventral, or lateral to the VTA because
of missed cannulae placements (*P < 0.05). Error bars indicate SE of the mean. (B) Intra-VTA BDNF alone
did not affect the sizes of the conditioned place preferences produced by acute morphine administration
in drug-nondependent rats (*P < 0.05). (C) BDNF restored the rewarding properties of acute morphine
administration in drug-nondependent TPP-lesioned rats (*P < 0.05). (D) Cresyl violet?stained coronal
section showing one side of a bilateral TPP lesion and (below) a schematic of the anatomical region from

[Ne/Neva Eva]

Sciencemag article re. baclofen

which the section displayed was taken. The arrow indicates the TPP lesion area. (E) Cresyl violet?stained
coronal section of a typical bilateral intra-VTA cannula placement.
Fig. 2. Motivational and electrophysiological effects of a single intra-VTA BDNF
infusion in drug-nondependent rats. (A) Blockade of the dopaminergic system
with alpha-flupenthixol blocked the rewarding effects of an intra-VTA?
administered GABAA receptor antagonist bicuculline (50 ng) in nondependent
rats after a single intra-VTA BDNF infusion, but not after intra-VTA PBS infusion
(*P < 0.05). (B and C) Single-unit extracellular recordings of VTA GABAergic
neurons showing the effects of two current applications of muscimol (+50 nA) and
baclofen (+50 nA) on the firing rate of representative VTA GABAergic neurons. In
saline-treated rats, muscimol always decreased the firing rate of the VTA
GABAergic neurons, whereas in BDNF-treated rats, muscimol enhanced the firing
rate. Conversely, in both saline-treated and BDNF-treated rats, baclofen moderately
decreased the firing rate of these VTA GABA neurons, as in this example.
www.sciencemag.org SCIENCE VOL 324 26 JUNE 2009 1733
REPORTS
Downloaded from www.sciencemag.org on December 12, 2010
place preferences produced by morphine [F1,27 =
12.84, P < 0.05, main effect of the morphine
treatment only in both BDNF (P < 0.05) and PBS
(P < 0.05) groups] (Fig. 1B).
To investigate whether BDNF in the
VTA changes opiate reward from a dopamineindependent
(TPP-dependent) to a dopaminedependent
reward system, we examined the
effects of intra-VTA BDNF in TPP-lesioned rats
(13, 14). In drug-nondependent rats, bilateral
TPP (n = 12) [but not sham (n = 14)] lesions
blocked the rewarding properties of morphine
(F1,51 = 14.29, P < 0.05, interaction of lesion and
morphine treatment). However, after BDNF infusion
(n = 12), TPP lesions did not block morphine
reward (P < 0.05) in drug-nondependent
rats, similar to sham-lesioned rats, where morphine
also caused reward (P < 0.05) (F1,51 =
47.87, P < 0.05, main effect of morphine only),
but opposite to TPP-lesioned rats infused with
PBS, where morphine reward was blocked (P
0.05) (F1,37 = 5.88, P n intra-VTA BDNF-infused
rats (n = 8) compared with intra-VTA PBS (n = 8)
infused controls, where 100% (29/29) of the
VTA GABAergic neurons were inhibited by
muscimol (Mann-Whitney U test, P < 0.05)
(Fig. 2, B and C). This shift is very similar to that
seen in a previous study with opiate-dependent
rats, where 44% of VTA GABAergic neurons
switched to excitatory GABAA receptor signaling
(2). In BDNF-treated rats (16.6 T 8.9%,
n = 11), as in control PBS-treated rats (19.5 T
9.26%, n = 7), the GABAB receptor agonist
baclofen was still able to inhibit those GABA
neurons that had been excited by muscimol
(t17 = 0.216, P > 0.05) (Fig. 2, B and C), suggesting
very specific effects of BDNF onGABAA
receptor signaling on the VTA GABAergic neurons
themselves.
The intra-VTA alterations that lead to this
transformation are unclear. BDNF may change
the anion gradient by reducing the level of the
potassium-chloride co-transporter KCC2, so that
the GABAergic neuron intracellular chloride
concentration increases (6, 17). GABAA receptor
activation would then result in anions flooding
out of the neuron, making the neuron?smembrane
potential more positive, or depolarized, relative to
the resting membrane potential. Also, BDNF
might elevate intracellular carbonic anhydrase
levels, favoring HCO3
? efflux and resulting in a
depolarizing response in VTA GABAergic neurons
(fig. S1) (2).
The present work suggests that BDNF in the
VTA induces a transition to a drug-dependent
motivational state, a crucial issue in drug addiction
research. Other studies have found that
BDNF levels within the mesolimbic system progressively
increase after cocaine withdrawal (18).
Intra-VTA BDNF infusion produces long-lasting
enhancement of cocaine seeking (18) and locomotor
stimulation (6, 9), and it increases the rewarding
effects of cocaine itself (9). Conversely,
cocaine-conditioned place preference was reduced
in heterozygous BDNF knockout mice (9), and
inhibiting BDNF activity reduces amphetamineinduced
dopamine release (19). Our findings complement
research in animal and clinical studies
suggesting that VTA BDNF is implicated in the
pathogenesis of drug addiction (20).

[Ne/Neva Eva]

Sciencemag article re. baclofen

References and Notes
1. S. R. Laviolette, D. van der Kooy, Eur. J. Neurosci. 13,
1009 (2001).
2. S. R. Laviolette, R. A. Gallegos, S. J. Henriksen, D. van der
Kooy, Nat. Neurosci. 7, 160 (2004).
3. S. R. Laviolette, K. Nader, D. van der Kooy, Behav. Brain
Res. 129, 17 (2002).
4. C. Rivera et al., J. Cell Biol. 159, 747 (2002).
5. J. A. Coull et al., Nature 438, 1017 (2005).
6. C. A. Bola?os, E. J. Nestler, Neuromol. Med. 5, 69 (2004).
7. S. Numan, K. B. Seroogy, J. Comp. Neurol. 403, 295
(1999).
8. C. Hyman et al., J. Neurosci. 14, 335 (1994).
9. B. A. Horger et al., J. Neurosci. 19, 4110 (1999).
10. L. Lu, J. Dempsey, S. Y. Liu, J. M. Bossert, Y. Shaham,
J. Neurosci. 24, 1604 (2004).
11. S. E. Hyman, R. C. Malenka, E. J. Nestler, Annu. Rev.
Neurosci. 29, 565 (2006).
12. A. Bechara, D. van der Kooy, Behav. Neurosci. 106, 351
(1992).
13. T. E. Kippin, D. van der Kooy, Eur. J. Neurosci. 18, 2581
(2003).
14. H. Vargas-Perez et al., Eur. J. Neurosci. 25, 3713 (2007).
15. S. R. Laviolette, D. van der Kooy, Eur. J. Neurosci. 20,
2179 (2004).
16. S. C. Steffensen, R. S. Lee, S. H. Stobbs, S. J. Henriksen,
Brain Res. 906, 190 (2001).
17. H. Wake et al., J. Neurosci. 27, 1642 (2007).
18. J. W. Grimm et al., J. Neurosci. 23, 742 (2003).
19. M. Narita, K. Aoki, M. Takagi, Y. Yajima, T. Suzuki,
Neuroscience 119, 767 (2003).
20. S. J. Tsai, Med. Hypotheses 68, 410 (2007).
21. This work was funded by the Canadian Institutes of
Health Research. S.C.S. received funding from NIH
(grant AA13666).
Supporting Online Material
Ventral Tegmental Area BDNF Induces an Opiate-Dependent–Like Reward State in Naïve Rats — Supporting Online Material | Science/AAAS
SOM Text
Figs. S1 to S4
References
13 November 2008; accepted 14 May 2009
Published online 28 May 2009;
10.1126/science.1168501
Include this information when citing this paper.
1734

[Seethepony]

Sciencemag article re. baclofen

Doesn't really slip off the tongue, does it?

[ignominous]

Sciencemag article re. baclofen

Hmmm Thanks Ne, hmm

My take is that there is an actual physical quantifiable switch:

From: inhibitory to excitable

From: Take this stuff carefully, slowly to Oh great another party

From: Getting nauseous (for some of us) the first time taking a drink, cigarette, heroin to knowing this is going to be fun

From: pre addiction to post addiction

I think Dr. Levin was saying that once you reach this you need to maintain it while the rest of your brain wiring gets itself in line with this new response. i.e. don't titrate down too fast.

Any one else got comments or a better transcription of the article? TerryK, Publius, Loop et al.

[guardian]

Sciencemag article re. baclofen

Unfortunately, this study doesn't tell us much if anything about baclofen. Alcohol is a different creature entirely from opiates. Opiate addiction and alcohol addiction are very different animals. Anybody is capable of becoming physiologically addicted to alcohol or opiates, but some of us are predisposed to psychological dependence, especially with alcohol (MWO). The BDNF-GABAergic neuron link is probably a path worth following, but something tells me it isn't relevant for genetic alcoholic, non-naive-humans (or geneti-calcoholic, non-naive-rats). 37 Degrees, Loop?

neva eva, thank you so much for posting a study. When I came to MWO, people talking about a cure was enough. I was seriously fucked up and grasping at straws at that point. I'm a different person now, and I'm unwilling to accept that some people, many of whom are in the last days of their lives are turned away from baclofen because we haven't presented enough of an argument for it. Again, thank you. If you decide to post studies in the future, please just post the abstract portion along with the studies conclusion. If you feel like adding a few personal comments, great. If it has anything to do with baclofen, rest assured that I will.

[Topsy-Turvy-Tracy]

Sciencemag article re. baclofen

This study is about addiction. Baclofen was part of the study, just as baclofen is PART of the flurry of activity happening around addiction. Also, I think it is smart (to say nothing of honest) to post honestly about baclofen experience rather than taking the "savior," decidedly evangelical approach (always hidden agendas there), of endeavoring to send an appealing message to the suffering masses rather than just posting the truth. It's perfectly fine to be honest, and anyone who doesn't think so has an agenda, IMO. It also really irks me that one self-decided "authority" tells - literally orders - other people how and what to post.

Thanks for posting it in it's entirety, Neva. I think that it's valuable, and I can think of no good reason not to make such posts.

Sounds like you are doing well. Good on you!

[terryk]

Sciencemag article re. baclofen

guardian;1021813 wrote: Unfortunately, this study doesn't tell us much if anything about baclofen. Alcohol is a different creature entirely from opiates. Opiate addiction and alcohol addiction are very different animals. Anybody is capable of becoming physiologically addicted to alcohol or opiates, but some of us are predisposed to psychological dependence, especially with alcohol (MWO). The BDNF-GABAergic neuron link is probably a path worth following, but something tells me it isn't relevant for genetic alcoholic, non-naive-humans (or geneti-calcoholic, non-naive-rats). 37 Degrees, Loop?
.

Use of Naltrexone to curb alcohol use is based on the premise that alcohol releases natural opiates in drinker's bodies and that that is a factor in causing addiction. So, somewhere, somehow, somebody has made a connection between the two. I just wanted to throw that out there. -terryk still at 250mg/day "switched" since Sept. 26th 2010.

[guardian]

Sciencemag article re. baclofen

Yes, but the difference between how alcohol and opiates act in the brain is exactly the reason why opiate blockade is only slightly more effective than placebo for controlling alcoholism. I just don't see how the study in question is relevant to alcoholism or baclofen.

[Topsy-Turvy-Tracy]

Sciencemag article re. baclofen

guardian;1022199 wrote: Yes, but the difference between how alcohol and opiates act in the brain is exactly the reason why opiate blockade is only slightly more effective than placebo for controlling alcoholism. I just don't see how the study in question is relevant to alcoholism or baclofen.

The issue is not alcoholism per se but addiction itself. Is Nal amazingly effective for opiate users? I haven't read that - in fact, it would be all over the news if that was the case. It is not terribly effective for opiate addicts, as it is not terribly effective with alcoholics. What it is - what it does - what this study filled in - is another piece of the puzzle, a big puzzle, and baclofen is a small piece of that puzzle. Whether or not you, personally, see the relevance is rather irrelevant to the subject at hand. It's not relevant to the initial post either.

[Ne/Neva Eva]

Sciencemag article re. baclofen

sigh.
I posted the article in it's entirety because ig asked to see it on his thread and no-one else had. Also because Otter brought up on another thread that he was curious about opiates and bac. And finally because I figured that someone else would decipher it if it had any relevance.
I am hopelessly inept at reading this stuff. I'll reserve my opinions for places where I can have a (relatively) thoughtful one.
My thought initially, was, "poor rats." ha.
Tracy, I worship at that alter at the moment. But thanks. And I agree. Lots of silence when it doesn't work out is not such a good thing. I appreciate the debates. Wish they could be reasonable, but presumably we're all drunks and sobriety doesn't sit well... Nor does the struggle to get there. I've seen better brawls in AA meetings, not to mention clubs.
Guardian, you've posted some interesting stuff recently re. bac/genes/alcoholism. If you've got time I'd love the 101 version. Glad you're sticking around for the long haul
Yes, Tracy, I'm doing well. Woohoo. Hope you are too.
Peace out.

[Sunnyvalenting]

Sciencemag article re. baclofen

Best general compendium I have seen of late for lay and scientific types is a book called Rethinking Substance Abuse. I got a copy from ABE books. It was published in the last few years and includes some limited references to bac but covers a lot of the scientific studies and observations of both people and animal models for addiction and recovery. It was very helpful for me to understand the why and how of both my addiction and possible opportunities for recovery.
All the best
Sunny

[guardian]

Sciencemag article re. baclofen

Topsy-Turvy-Tracy;1022205 wrote: The issue is not alcoholism per se but addiction itself. Is Nal amazingly effective for opiate users? I haven't read that - in fact, it would be all over the news if that was the case. It is not terribly effective for opiate addicts, as it is not terribly effective with alcoholics. What it is - what it does - what this study filled in - is another piece of the puzzle, a big puzzle, and baclofen is a small piece of that puzzle. Whether or not you, personally, see the relevance is rather irrelevant to the subject at hand. It's not relevant to the initial post either.

Yes, naltrexone is effective for opiate users.

Here, news:

NIDA - Publications - NIDA Notes - Vol. 21, No. 3 - Research Findings

Tracy, please help a brain-fog having moron with a God-complex and ulterior motives understand. How exactly does this "piece of the puzzle" fit in with the big puzzle of alcoholism?