Investigating a Novel Neutral Antagonist, 6Beta-Naltrexol, in Alleviating Cocaine Withdrawal...
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Investigating a Novel Neutral Antagonist, 6Beta-Naltrexol, in Alleviating Cocaine Withdrawal Symptoms Timothy DeYoung, Michelle Mueller, and Dr. Boyette-Davis Department of Biological Sciences, York College of Pennsylvania Introduction • Addiction is a debilitating condition which can lead to compulsive behavior, continued abuse of drugs, and persistent changes in the brain’s structure and function. Relapse rates for individuals with a history of drug abuse can be as high as 90%. • Cocaine, a drug known for its addictive properties, is also known to have high relapse rates. A common treatment for cocaine addiction is Naltrexone (NTX), which blocks mu- opioid receptors. However NTX has issues in regards to initially increasing withdrawal symptoms (Guiliano et al. 2013). • 6beta-Naltrexol, a neutral antagonist, has been used in studies relating to decreased alcohol consumption in addicted rats (Stromberg et al. 2002), and has also been found to decrease withdrawal symptoms from opiates in a recent study (Navani et al. 2011). Cohort 1 (n=9) Sep 11-Oct 2 Naltrexone Day 15, 22 6beta- Naltrexol Day 15,22 Vehicle (Saline) Day 15,22 PreSwim FST Day 14 Cocaine Dependence Days 1-14 Baseline Testing Day 1 Cohort 2 (n=9) Sep 28-Oct 19 DV Testing Day 15, 22 Cohort 3 (n=9) Oct 12-Nov 2 Procedure Objectives 1.Determine if 6beta-Naltrexol can help reduce withdraw symptoms in addicted rats. 2.Assess the effectiveness of 6beta- Naltrexol in alleviating withdraw symptoms in addicted rats in comparison to the well known effects of Naltrexone. 3.Observe classic withdrawal symptoms in Sprague Dawley rats utilizing the elevated plus maze (EPM) for anxiety and the forced swim test (FST) for depression. Conclusions 1.6beta-Naltrexol was successful in alleviating the symptoms of cocaine withdrawal showing a statistical significance after adjusting for the high and low responders when compared to the Vehicle group in the FST. 2.Naltrexone was consistent with the literature and unfortunately worked better than 6beta-Naltrexol in reducing both anxiety and depression within the EPM and FST. 3.6beta-Naltrexol could possibly be a suitable alternative for Naltrexone, as it is shown here to decrease depression in addicted rats. 4.With this treatment it may allow an individual to overcome the initial increase in withdraw symptoms due to the inverse agonist actions of Naltrexone. 5.Further research is being conducted on whether or not the Mu-opioid receptors were affected by this treatment, changes will be observed by using immunohistochemistry. Literature Cited Giuliano, C. Robbins, T.W., Wille, D.R. 2013. Attenuation of cocaine and heroin seeking by u-opioid receptor antagonism. Psychopharmacology 227: 137-147 Navani, D.M., Sirohi, S., Madia, P. A., Yoburn, B. C., 2011. The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice. Journal of Pharmacology Biochemistry and Behavior. 99(4):671-675 Stromberg, M.R., Rukstalis, M.R., Mackler, S.A., Volpicelli, J.R., O’Brien, C.P. 2022. A comparison of the effects of 6- β Naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited- access procedure in rats. Journal of Pharmacology Biochemistry and Behavior. 72: 483-490 Future Studies • Evaluate and determine if varying the dosage has any effect on withdrawal symptoms. Methods/Materials • Male SD rats, aged 60 days • Housing- 3 per cage • Free access to food and water • 12:12 light dark cycle • Cocaine: 15mg/kg • 6beta-Naltrexol: 15mg/kg • Naltrexone: 1mg/kg • Vehicle: Saline Acknowledgements I would like to thank both the Biology and Psychology department of York College of Pennsylvania for the use of their laboratories and equipment. I would also like to thank Michelle Mueller for the assistance in conducting the experiment. Finally I would like to extend my gratitude to Dr. Boyette-Davis and Dr. Thompson for their guidance and support throughout my research. http://www.abcam.com/mu-opioid-receptor- antibody-ab10275.html http://www.janvier-labs.com/rodent-research-models- services/research-models/per-species/outbred-rats/ product/sprague-dawley.html * Results Elevated Plus Maze Forced Swim Test * * * * 6beta N TX Vehicle 0 50 100 150 200 250 300 M ean Im m obile Tim e (s) Figure 3.M ean im m obile tim e (s) com pared in the FST across all treatm entgroups including 6beta (n=10),N TX (n=8),and the Vehicle (n=8).Errorbars representSEM .A significantdifference w as found betw een the N TX and vehicle group using an uncorrected FisherLSD m ultiple com parisons test (p=0.034). High R esponder Low R esponder Vehicle 0 25 50 75 100 125 150 Tim e in O pen A rm s (s) Figure 2.M ean tim e (s)spentin open arm s across H igh (n=5),Low (n=5) responders to 6beta-Naltrexol,and the Vehicle group (n=8).Errorbars representSEM .No significant difference w as found betw een the high responderand vehicle group. Low R esponder H igh R esponder Vehicle 0 50 100 150 200 250 300 M ean Im m obile Tim e (s) Figure 4.M ean im m obile tim e (s) com pared in the FST across the Vehicle (n=8),H igh (n=5),and Low (n=5)respondergroups.Errorbars representSEM .A significant difference w as found am ong the high responders w hen com pared to both the low responderand vehicle groups w hen using a Posthoc Bonferroni test (p=0.003). 6beta N TX V ehicle 0 25 50 75 100 125 150 175 200 Tim e in O pen A rm s (s) Figure 1.M ean tim e spentin open arm s across all treatm entgroups including 6beta (n=10),N TX (n=8),and Vehicle (n=8).ErrorBars representSEM .The am ountoftim e spentin the open arm s w as statistically differentforthe N TX group w hen com pared to both treatm ents based on a O ne-w ay ANO VA (p=0.0138).
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Transcript of Investigating a Novel Neutral Antagonist, 6Beta-Naltrexol, in Alleviating Cocaine Withdrawal...
Investigating a Novel Neutral Antagonist, 6Beta-Naltrexol,in Alleviating Cocaine Withdrawal Symptoms
Timothy DeYoung, Michelle Mueller, and Dr. Boyette-DavisDepartment of Biological Sciences, York College of Pennsylvania
Introduction• Addiction is a debilitating condition which can lead to
compulsive behavior, continued abuse of drugs, and persistent changes in the brain’s structure and function. Relapse rates for individuals with a history of drug abuse can be as high as 90%.
• Cocaine, a drug known for its addictive properties, is also known to have high relapse rates. A common treatment for cocaine addiction is Naltrexone (NTX), which blocks mu-opioid receptors. However NTX has issues in regards to initially increasing withdrawal symptoms (Guiliano et al. 2013).
• 6beta-Naltrexol, a neutral antagonist, has been used in studies relating to decreased alcohol consumption in addicted rats (Stromberg et al. 2002), and has also been found to decrease withdrawal symptoms from opiates in a recent study (Navani et al. 2011).
Cohort 1 (n=9)Sep 11-Oct 2
NaltrexoneDay 15, 22
6beta-NaltrexolDay 15,22
Vehicle (Saline)Day 15,22
PreSwim FSTDay 14
Cocaine DependenceDays 1-14
Baseline TestingDay 1
Cohort 2 (n=9)Sep 28-Oct 19
DV TestingDay 15, 22
Cohort 3 (n=9)Oct 12-Nov 2
Procedure
Objectives1. Determine if 6beta-Naltrexol can help reduce withdraw
symptoms in addicted rats.
2. Assess the effectiveness of 6beta-Naltrexol in alleviating withdraw symptoms in addicted rats in comparison to the well known effects of Naltrexone.
3. Observe classic withdrawal symptoms in Sprague Dawley rats utilizing the elevated plus maze (EPM) for anxiety and the forced swim test (FST) for depression.
Conclusions1. 6beta-Naltrexol was successful in alleviating the
symptoms of cocaine withdrawal showing a statistical significance after adjusting for the high and low responders when compared to the Vehicle group in the FST.
2. Naltrexone was consistent with the literature and unfortunately worked better than 6beta-Naltrexol in reducing both anxiety and depression within the EPM and FST.
3. 6beta-Naltrexol could possibly be a suitable alternative for Naltrexone, as it is shown here to decrease depression in addicted rats.
4. With this treatment it may allow an individual to overcome the initial increase in withdraw symptoms due to the inverse agonist actions of Naltrexone.
5. Further research is being conducted on whether or not the Mu-opioid receptors were affected by this treatment, changes will be observed by using immunohistochemistry.
Literature CitedGiuliano, C. Robbins, T.W., Wille, D.R. 2013. Attenuation ofcocaine and heroin seeking by u-opioid receptor antagonism. Psychopharmacology 227: 137-147
Navani, D.M., Sirohi, S., Madia, P. A., Yoburn, B. C., 2011. The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice. Journal of Pharmacology Biochemistry and Behavior. 99(4):671-675
Stromberg, M.R., Rukstalis, M.R., Mackler, S.A., Volpicelli, J.R., O’Brien, C.P. 2022. A comparison of the effects of 6- β Naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats. Journal of Pharmacology Biochemistry and Behavior. 72: 483-490
Future Studies• Evaluate and determine if varying the dosage has any effect
on withdrawal symptoms.
Methods/Materials• Male SD rats, aged 60 days
• Housing- 3 per cage• Free access to food and water
• 12:12 light dark cycle• Cocaine: 15mg/kg
• 6beta-Naltrexol: 15mg/kg• Naltrexone: 1mg/kg
• Vehicle: Saline
AcknowledgementsI would like to thank both the Biology and Psychology department of York College of Pennsylvania for the use of their laboratories and equipment. I would also like to thank Michelle Mueller for the assistance in conducting the experiment. Finally I would like to extend my gratitude to Dr. Boyette-Davis and Dr. Thompson for their guidance and support throughout my research.
http://www.abcam.com/mu-opioid-receptor-antibody-ab10275.htmlhttp://www.janvier-labs.com/rodent-research-models-services/research-models/per-species/outbred-rats/product/sprague-dawley.html
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6beta NTX Vehicle 0
50
100
150
200
250
300
Mea
n Im
mo
bile
Tim
e (s
)
Figure 3. Mean immobile time (s)compared in the FST across alltreatment groups including 6beta(n=10), NTX (n=8), and the Vehicle(n=8). Error bars represent SEM. Asignificant difference was foundbetween the NTX and vehicle groupusing an uncorrected Fisher LSDmultiple comparisons test(p=0.034).
ResultsElevated Plus Maze
Forced Swim Test
HighResponder
LowResponder
Vehicle 0
25
50
75
100
125
150
Tim
e in
Op
en
Arm
s (
s)
Figure 2. Mean time (s) spent in openarms across High (n=5), Low (n=5)responders to 6beta-Naltrexol, andthe Vehicle group (n=8). Error barsrepresent SEM. No significantdifference was found between thehigh responder and vehicle group.
* *
LowResponder
HighResponder
Vehicle 0
50
100
150
200
250
300
Mea
n Im
mo
bile
Tim
e (s
)
Figure 4. Mean immobile time (s)compared in the FST across theVehicle (n=8), High (n=5), and Low(n=5) responder groups. Error barsrepresent SEM. A significantdifference was found among the highresponders when compared to boththe low responder and vehicle groupswhen using a Post hoc Bonferroni test(p=0.003).
*
6beta NTX Vehicle0
25
50
75
100
125
150
175
200T
ime
in O
pen
Arm
s (s
)
Figure 1. Mean time spent in open armsacross all treatment groups including6beta (n=10), NTX (n=8), and Vehicle(n=8). Error Bars represent SEM. Theamount of time spent in the open armswas statistically different for the NTXgroup when compared to bothtreatments based on a One-wayANOVA (p=0.0138).
*
