Melanin-concentrating Hormone Receptor Antagonism Attenuates the Expression of Nicotine Psychomotor Sensitization in Rats
Nicotine in tobacco is the main cause of smoking addiction and can induce neurobiological changes in the brain. One population of neurons that may undergo this change is Melanin-concentrating Hormone (MCH) neurons. This research tested the hypothesis that systemic MCH receptor antagonism will attenuate nicotine psychomotor sensitization, and specifically tested whether MCH antagonism with the compound GW803430 blocks the expression of nicotine sensitization in male Wistar rats. These results demonstrate that systemic administration of the MCH receptor antagonist attenuates the expression of nicotine sensitization, possibly implicating MCH in nicotine use and abuse. Pharmacological treatments of MCH receptor antagonists could be effective in treating nicotine addiction.
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[00:00:00.900]Hello, our research topic is melanin
concentrating hormone receptor
[00:00:06.690]attenuates the expression of nicotine
psychomotor sensitization in rats.
[00:00:11.130]There is overview of the presentation.
[00:00:13.950]Smoking is a major cause
of a preventable disease
[00:00:16.650]and death in the United States.
[00:00:19.380]Nicotine is the main cause of smoking
addiction that makes people cannot quit
[00:00:23.580]smoking even though they know is harmful.
[00:00:25.920]Nicotine psychomotor sensitization
is an experience-dependent,
[00:00:29.670]progressive increase in the behaviorally
activation effects of the same
[00:00:34.350]doses of nicotine. It was
hypothesized to underlie
[00:00:38.580]the pathological motivation
[00:00:40.680]characteristic of addiction.
Melaning concentrating hormone,
[00:00:44.940]abbreviated MCH, is a neuropeptide
that projects widely
[00:00:49.860]from the lateral hypothalamus and the
[00:00:52.300]incertohypothalamic area. MCH
circuit regulates the energy
[00:00:56.880]balance, feeding and the behavior
associated with some psychostimulants
[00:01:01.320]and alcohol. Studies
showed only MCH1 receptor found
[00:01:06.150]in rats and that blocking MCHR1
reduce the self administration of alcohol
[00:01:11.100]and the cocaine.
[00:01:12.270]So change in MCH receptor function may
underlie nicotine psychomotor
[00:01:16.650]sensitization that underlies
[00:01:20.190]So, this study was designed
to determine the role of MCHR1
[00:01:24.810]in the expression of nicotine
[00:01:27.450]psychomotor sensitization using
a rat animal model
[00:01:32.310]and MCH receptor
[00:01:37.020]Our hypothesis is systemic
[00:01:41.880]MCH receptor (MCHR1)
[00:01:48.270]attenuates the nicotine
[00:01:53.090]Now looking at the methods, the
animals we used were male Wistar rats.
[00:01:58.160]We had 10 rats for the GW
compound condition and seven
rats for the vehicle.
[00:02:03.560]The light cycle went from 3:00 PM to
3:00 AM and we weighted the rats every
[00:02:07.910]other day during experiments, just
to make sure we get the right doses.
[00:02:11.870]The drugs we used were nicotine
tartrate and the doses are reported
[00:02:16.790]as a nicotine base. And the other
drug is what we call the GW compound,
[00:02:21.590]which is a MCHR1 antagonist.
[00:02:25.760]The locomotor monitoring. We
used an open field chamber,
[00:02:29.660]as you can see here to the right,
[00:02:32.360]where the rats are just
allowed to move freely.
[00:02:35.930]And we use the software ANY-maze
in order to track the rat's
[00:02:40.760]locomotion or the distance
traveled by each rat.
[00:02:47.120]This is the experimental
[00:02:51.950]First, the animals arrived to the
facility and for three to five days,
[00:02:56.480]we handled them just to make sure that
they get used to being picked up,
[00:03:00.490]interacting with the
researchers. Then we have
[00:03:04.330]two habituation days where
we just put the rats
[00:03:08.320]in the chambers.
[00:03:09.970]And then they're allowed to
explore, getting used to the
[00:03:14.290]experimental setting. We don't
inject them with anything this day.
[00:03:19.930]We moved to the acute dose response
curve, where the rats are first
[00:03:24.430]exposed to nicotine.
And we do this by
[00:03:29.290]using a cumulative dose of nicotine.
[00:03:33.730]And we inject them intraperitoneally,
or IP injection.
[00:03:39.430]Then we have six days of pre-treatment
where rats just receive one dose
[00:03:44.380]of nicotine each day. After this,
[00:03:47.020]we have the post-treatment
dose response curve.
[00:03:50.020]Then the rats are going to
be drug-free for six days.
[00:03:55.300]And finally, we have the
chronic dose response curve.
[00:03:58.060]This is where half of the rats are going
to be pretreated with the GW compound
[00:04:02.320]and the other half with the vehicle.
[00:04:05.430]These two graphs show the data
for the results. X-axis shows the doses of
[00:04:10.110]nicotine and the saline and the Y
axis shows the distance of the rat
[00:04:17.990]The dose response results show
[00:04:19.950]there was no significant
difference between the acute and the
[00:04:25.020]but there was a trend towards an
increase during the post-treatment,
[00:04:29.930]suggesting the development of
nicotine psychomotor sensitization.
[00:04:33.540]The graph of the chronic dose
[00:04:35.310]response shows that both vehicle
and GW compound pre-treated
[00:04:40.050]rats exhibited and inverted
U-shaped dose response
[00:04:45.450]suggesting that locomotion increases
with the dose of nicotine until a dose
[00:04:50.460]where the locomotion
[00:04:53.610]The GW reduces the expression of
nicotine psychomotor sensitization.
[00:04:58.740]There was a significant reduction
in nicotine psychomotor sensitization at a
[00:05:03.630]0.1 milligram per kilogram
dose of nicotine.
[00:05:09.600]And as a summary,
[00:05:11.430]the systemic administration
of an MCH receptor antagonist,
[00:05:16.020]that is the GW compound, attenuates the
expression of nicotine sensitization.
[00:05:21.780]We saw that cumulative dose response
curves show more complete information
[00:05:25.800]than a single dose of a drug,
in this case, nicotine.
[00:05:29.850]We could also conclude that MCH
receptor antagonists could be effective
[00:05:34.830]in treating nicotine addiction
as a it implicates MCH
[00:05:39.720]action in the brain.
[00:05:43.050]The future directions this study is going
to take is complete the lower dose of
[00:05:47.520]the GW compound, which is 10
milligrams per kilograms.
[00:05:52.320]Also replicating these with females,
in order to test for sex differences.
[00:05:57.950]Also, assess FOS expression
to see MCH neurons
[00:06:02.270]activation in the brain
during the experiment.
[00:06:05.420]And finally the induction
[00:06:08.150]So, pre-treating the rats with the GW
compound during the pre-treatment days,
[00:06:13.220]instead of just the last day.
[00:06:19.660]Finally, I want to thank everyone
that made this project possible.
[00:06:25.030]The Rural Drug Addiction Research
center, the Nebraska Tobacco Settlement
[00:06:29.800]Biochemical Research and UCARE at
the University of Nebraska-Lincoln.
[00:06:34.870]And I want to thank our PI, Dr. Ken
Wakabayashi, and the other members in the
[00:06:39.790]lab who have helped a lot in
this project. Isabel, Noah, Raaga,
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