Melanin-concentrating Hormone Receptor Antagonism Attenuates the Expression of Nicotine Psychomotor Sensitization in Rats
Youxi Liu
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04/02/2021
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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
- [00:00:05.820]antagonism
- [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 nicotine addiction.
- [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 pharmacology.
- [00:01:37.020]Our hypothesis is systemic
- [00:01:41.880]MCH receptor (MCHR1)
- [00:01:43.440]antagonism
- [00:01:48.270]attenuates the nicotine psychomotor sensitization.
- [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 timeline overview.
- [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
- [00:04:14.700]travelled.
- [00:04:17.990]The dose response results show
- [00:04:19.950]there was no significant difference between the acute and the
- [00:04:23.430]post-treatment session,
- [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
- [00:04:44.730]curve,
- [00:04:45.450]suggesting that locomotion increases with the dose of nicotine until a dose
- [00:04:50.460]where the locomotion decreases again.
- [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 of sensitization.
- [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,
- [00:06:44.260]and Josh.
- [00:06:47.080]Thank you.
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