Possible Interactions Between the Reward Enhancing Effects of Methylphenidate & Nicotine

Eli Grablin and Kyle Fowler Author

04/01/2021 Added

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Our research focused on the possible reward-enhancing effects of methylphenidate and its interactions with nicotine. We also looked to see if chronic adolescent exposure had any effect on reward enhancement

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[00:00:01.130]Hello everyone, I am Eli Grablin
[00:00:04.300]And I am Kyle Fowler.
[00:00:06.140]Our U-CARE project explores the
[00:00:08.468]"Possible Interactions Between the Reward Enhancing Effects
[00:00:10.257]"of Methylphenidate and Nicotine."
[00:00:12.361]Nicotine is the main psychoactive ingredient
[00:00:15.020]in tobacco products.
[00:00:16.100]It is a drug that specifically acts as a stimulant
[00:00:18.650]and is highly addictive
[00:00:19.750]because it can cause changes in your brain chemistry
[00:00:21.940]which leaves the brain craving more.
[00:00:23.890]Nicotine is very dangerous
[00:00:25.160]because it can cause habitual consumption of tobacco.
[00:00:27.780]This is problematic because smoking is the number one cause
[00:00:31.180]of preventable disease disability
[00:00:33.300]and death in the United States.
[00:00:35.180]According to the CDC,
[00:00:36.280]there are currently around 34.1 million adults
[00:00:39.760]who smoke in the U.S.
[00:00:41.130]and 480,000 tobacco related deaths every year.
[00:00:44.782]As said before, a majority of habitual tobacco consumption
[00:00:48.780]can be attributed to nicotine.
[00:00:50.430]This is because the initiation
[00:00:51.860]and maintenance of smoking behavior is mainly established
[00:00:54.570]by the primary reinforcing properties of nicotine.
[00:00:57.640]These properties can also form associations
[00:00:59.306]with other rewards.
[00:01:01.170]Whenever you do things such as eating, relaxing
[00:01:03.210]or even having social interactions,
[00:01:05.780]the pleasure centers of your brain are stimulated
[00:01:07.820]and you get rewarded in the form
[00:01:09.390]of certain neurotransmitters, such as dopamine.
[00:01:12.070]Whenever a person pairs smoking with these rewards
[00:01:14.930]that we get from different activities, they are enhanced
[00:01:18.230]and we get a stronger reward response from our brain.
[00:01:21.210]These associations that are formed
[00:01:22.870]often cause further nicotine consumption.
[00:01:26.308]As you may know, ADHD is one of the
[00:01:28.930]most frequently diagnosed psychiatric disorders.
[00:01:31.600]The most commonly prescribed drug for ADHD
[00:01:33.690]is methylphenidate, also known as Ritalin.
[00:01:35.870]And it is often prescribed in adolescents
[00:01:37.750]because ADHD is a developmental disorder.
[00:01:40.410]This can be problematic because taking substances
[00:01:42.760]such as this one at an early age can have potential
[00:01:45.990]to alter the development of an individual's brain.
[00:01:48.950]Like nicotine, methylphenidate has been shown
[00:01:51.240]to have cognitive enhancement.
[00:01:53.020]Pairing this information with evidence of correlations
[00:01:55.790]between tobacco use and dependence
[00:01:57.870]and ADHD, a few questions arise
[00:02:00.230]which were the ones that we aim to answer
[00:02:01.700]while conducting the study.
[00:02:03.210]The first is, "Does methylphenidate produce
[00:02:05.267]"reward enhancing effects on its own
[00:02:07.247]"and how do those compare
[00:02:08.337]"or interact with those produced by nicotine?"
[00:02:10.500]And the second is, "How does chronic daily exposure
[00:02:12.727]"to methylphenidate during the developmental stage
[00:02:14.787]"of adolescence alter the reward enhancing effects
[00:02:17.037]"of nicotine, methylphenidate or their interactions?"
[00:02:20.420]In order to answer these two questions,
[00:02:22.200]we divided our experiment into many phases.
[00:02:24.561]The first phase was the Adolescent Exposure
[00:02:27.330]and Lever Training period.
[00:02:28.481]The rats arrived to the lab postnatal day 30
[00:02:31.174]and were given four days to acclimate.
[00:02:33.480]After they were done acclimating,
[00:02:35.042]they were randomly assigned into two groups,
[00:02:37.475]the exposure receiving methylphenidate
[00:02:39.457]and the control, which received saline.
[00:02:42.420]This exposure period went on for four weeks.
[00:02:44.351]During the last two weeks of this exposure period,
[00:02:47.504]they were trained to lever press for 2% sucrose.
[00:02:53.050]One hour after their lever training session,
[00:02:55.190]they were given their corresponding drug
[00:02:57.040]based on their group.
[00:02:58.170]This was done in order not build an association
[00:03:00.143]between receiving the drug and the sucrose.
[00:03:05.007]The second phase of our experiment
[00:03:07.179]was the Methylphenidate Enhancement
[00:03:09.080]on a Variable Ratio Schedule.
[00:03:11.395]During this phase,
[00:03:12.493]15 minutes prior to starting their session,
[00:03:15.070]the rats received one of the three doses in red
[00:03:18.977]and five minutes prior to being starting their session,
[00:03:22.664]they received one of the two doses in blue.
[00:03:25.620]They pressed on a variable ratio, three schedule,
[00:03:28.590]meaning that they had depress on average three times
[00:03:31.180]in order to earn sucrose.
[00:03:33.050]Here is the data,
[00:03:34.039]we have active levers on the Y-axis,
[00:03:37.500]methylphenidate on the X,
[00:03:38.990]and they are grouped by either receiving
[00:03:41.370]the methylphenidate dose and saline,
[00:03:43.700]which is an orange or the methylphenidate dose
[00:03:46.810]and nicotine, which is in the teal blue color.
[00:03:49.090]Here, we can see that there is no difference
[00:03:50.900]between the control
[00:03:51.910]and exposure groups, the left and right graph.
[00:03:54.521]So we will no longer be mentioning the control
[00:03:57.210]versus exposure groups as this trend can continue
[00:04:01.720]throughout the experiments.
[00:04:04.370]In order to find reward enhancement effects
[00:04:06.920]of methylphenidate, we switched up the first phase.
[00:04:09.210]We went from a variable ratio to a progressive ratio,
[00:04:12.400]which means that the next reward costs
[00:04:14.590]one more than the previous.
[00:04:16.328]And we changed the doses of methylphenidate,
[00:04:19.110]the doses in red changed.
[00:04:21.070]So they either got saline, three milligrams per kilogram
[00:04:23.720]5.6 or 10, the nicotine doses remained unchanged.
[00:04:27.910]Here we see the active lever presses
[00:04:30.000]and methylphenidate dose graph.
[00:04:32.540]Here, we see enhancement of methylphenidate
[00:04:35.090]especially at that 5.6, so the mid dose.
[00:04:39.080]Here is the locomotor activity.
[00:04:40.580]So the number of times that the infrared beam
[00:04:44.010]inside the operant chamber was broken.
[00:04:46.200]Here, we can see that methylphenidate produces
[00:04:48.250]a dramatic increase in locomotor activity.
[00:04:51.760]So due to the COVID-19 pandemic,
[00:04:53.187]we had a supply chain issue
[00:04:54.790]and ran out of methylphenidate.
[00:04:56.810]So in order to keep their association with the active lever
[00:04:59.770]and sucrose, we have them do,
[00:05:01.490]have the rats do a Nicotine Dose Effect Curve.
[00:05:04.680]So they received one of the five doses in the gray box
[00:05:08.210]and were placed inside the operant chamber
[00:05:10.010]on the same PR schedule they had been operating on.
[00:05:12.610]Here, we see the active lever presses
[00:05:14.330]for this Nicotine Dose Effect Curve
[00:05:16.140]which is a pretty standard curve with nicotine
[00:05:19.030]with the ceiling effect right
[00:05:20.120]around 0.2 milligrams per kilogram.
[00:05:22.980]The second to last phase of our experiments was the nicotine
[00:05:26.410]and methylphenidate interaction.
[00:05:27.929]So 15 minutes prior to the session,
[00:05:30.153]the rats received one of the three doses in red
[00:05:33.450]and five minutes prior to insertion into the chamber,
[00:05:36.586]the rats received one of these six doses in blue.
[00:05:39.861]Here, we have the active lever presses
[00:05:42.230]for this phase of our experiment.
[00:05:43.430]We can see that the nicotine
[00:05:45.220]and methylphenidate are not interacting.
[00:05:48.123]They seem to be doing their own thing.
[00:05:50.160]We also see enhancement at that high dose
[00:05:52.250]which was the 1.0 milligrams per kilogram.
[00:05:54.942]Here is the locomotor activity, same general concept.
[00:05:58.770]We see increases in locomotor activity
[00:06:00.920]with the methylphenidate.
[00:06:02.270]The large error bars were likely due
[00:06:04.070]to one of the activity beams breaking
[00:06:06.940]or having malfunctions during the experiment phase.
[00:06:10.679]The final phase of our experiment
[00:06:13.835]was the Methylphenidate Dose Effect Testing.
[00:06:16.290]This was done in order to see if there is a difference
[00:06:18.610]in the dose effects of reward enhancement.
[00:06:22.990]So the different, if a different dose affected
[00:06:25.500]how much the reward was enhanced.
[00:06:27.150]So the rats received one of the five doses
[00:06:29.688]in the gray box and were placed on the same PR schedule.
[00:06:33.640]Here is the active lever presses with general increases
[00:06:37.430]in reward enhancement as methylphenidate dose increases.
[00:06:40.174]With dose dependencies only between the 0.5
[00:06:43.170]and one milligrams per kilogram methylphenidate
[00:06:46.410]and the one and two milligrams per kilogram methylphenidate.
[00:06:50.250]Here's the locomotor activity with general increases
[00:06:52.810]as the methylphenidate dose increases.
[00:06:55.830]So the main results we can draw from this experiment
[00:06:57.707]is that methylphenidate does indeed
[00:07:00.380]have reward enhancing effects.
[00:07:02.300]There is a small dose dependence
[00:07:03.680]at the beginning of the dose curve,
[00:07:05.800]with a ceiling at around 5.6 milligrams per kilogram
[00:07:08.850]and nicotine and methylphenidate do not interact
[00:07:11.030]and cause any additive
[00:07:12.300]or attenuated effects on reward enhancement.
[00:07:15.370]In conclusion, the mechanisms for methylphenidate
[00:07:17.850]and nicotine likely involve different receptors
[00:07:20.310]which could explain the lack of evidence
[00:07:22.150]for an interaction between the two.
[00:07:24.040]It was also found that there are no sex differences
[00:07:26.102]in regards to methylphenidate reward enhancement
[00:07:28.700]and that there is a ceiling effect
[00:07:30.310]for methylphenidates reward enhancing effects
[00:07:32.480]at around 5.6 milligrams per kilogram.
[00:07:35.700]Future studies could look into other stimuli
[00:07:37.636]to observe possible enhancement differences
[00:07:40.050]when paired with methylphenidate.
[00:07:41.840]Other ADHD drugs could also be studied in the same manner.
[00:07:45.010]Finally, you could include receptor antagonists
[00:07:47.450]to determine the receptors utilized
[00:07:49.240]in methylphenidate its mechanism.
[00:07:51.640]We would like to thank Dr. Rick Bevins
[00:07:53.300]and Dr. Scott Barrett for all their help.
[00:07:54.870]We would also like to thank Tyler Neeley, Patrick White
[00:07:57.060]and Alyssa Flynn for other help working on this project.

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Possible Interactions Between the Reward Enhancing Effects of Methylphenidate & Nicotine

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