Evaluation of efavirenz alone or in combination with tetrahydrocannabinol (THC) on addictive-like bio-behavioral alterations in rats

[Speaker] Marisa Moller:1
[Co-author] Jaco Fourie:1, Brian H Harvey:2
1:Pharmacology, Nort-West University, Potchefstroom, South Africa, 2:Center of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa

Background: Recently, the abuse of the antiretroviral drug efavirenz has surfaced reporting people crushing and smoking or injecting it with marijuana in a mixture known as "Nyope". Patients treated with efavirenz have been observed to experience neuropsychiatric symptoms which could be linked to the abuse potential of the drug. This study assesses the addictive-like properties of efavirenz after sub-acute and -chronic exposure alone and in combination with tetrahydrocannabinol (THC) (the psychoactive constituent of marijuana) in rats.
Methods: This study (ethics: NWU-00267-16-S5) used a total of 120 male Sprague Dawley rats (12 per group). A sub-acute study (n=72) exposed rats to 5, 10 and 20 mg/kg efavirenz, 1 mg/kg methamphetamine (MA) and 0.75 mg/kg THC (used as positive controls and as adjunctive exposure) as well as vehicle for 6 days using the biased study design of the conditioned place preference (CPP) paradigm. The sub-chronic study (n=48) exposed rats to a vehicle, the most rewarding dosage of efavirenz (established in the sub-acute study), 0.75 mg/kg THC and the combination thereof (efavirenz+THC) for 14 days. CPP as well as cortical and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were assessed in the sub-chronic study. One-way ANOVA with Bonferroni post hoc test was used for statistical analysis.
Results: The sub-acute study observed that 5 mg/kg efavirenz induced a significant increase in the time spent in the drug-paired chamber in the CPP, comparable to the rewarding effects of MA and THC as positive control. Efavirenz at 10 mg/kg showed no preference for the drug-paired chamber while 20 mg/kg showed a significant decrease in CPP in comparison to the control group. The sub-chronic study indicated a significant CPP, increased frontal cortical DA, DOPAC and striatal DA in rats exposed to efavirenz and efavirenz+THC. Efavirenz+THC bolstered the effect on CPP and frontal cortical DOPAC levels compared to efavirenz exposure alone. Sub-chronic efavirenz, THC and efavirenz+THC exposure significantly reduced striatal DOPAC levels.
Conclusion: The findings in the sub-acute and -chronic studies show a dose dependant rewarding effect of efavirenz with lower doses showing significant rewarding properties augmented with the addition of THC, highlighting its abuse potential.

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