Efavirenz exposure, alone and in combination with known drugs of abuse, engenders addictive-like bio-behavioural changes in rats
Efavirenz is abused in a cannabis-containing mixture known as Nyaope. The addictive-like effects of efavirenz (5, 10 and 20 mg/kg) was explored using conditioned place preference (CPP) in rats following sub-acute exposure vs. methamphetamine (MA; 1 mg/kg) and Δ 9 -tetrahydrocannabinol (THC; 0.75 mg/ kg). The most addictive dose of efavirenz was then compared to THC alone and THC plus efavirenz following sub-chronic exposure using multiple behavioural measures, viz. CPP, sucrose preference test
... SPT) and locomotor activity. Peripheral superoxide dismutase (SOD), regional brain lipid peroxidation and monoamines were also determined. Sub-acute efavirenz (5 mg/kg) had a significant rewarding effect in the CPP comparable to MA and THC. Sub-chronic efavirenz (5 mg/kg) and THC + efavirenz were equally rewarding using CPP, with increased cortico-striatal dopamine (DA), and increased lipid peroxidation and SOD. Sub-chronic THC did not produce CPP but significantly increased SOD and decreased hippocampal DA. Sub-chronic THC + efavirenz was hedonic in the SPT and superior to THC alone regarding cortico-striatal lipid peroxidation and sucrose preference. THC + efavirenz increased cortico-striatal DA and decreased serotonin (5-HT). Concluding, efavirenz has dose-dependent rewarding effects, increases oxidative stress and alters regional brain monoamines. Efavirenz is hedonic when combined with THC, highlighting its abuse potential when combined with THC. More than 56% of people living with human immunodeficiency virus (HIV) receive antiretroviral therapy (ART), which consists primarily of two nucleoside reverse transcriptase inhibitors (NRTI's) such as zidovudine and lamivudine, and one non-nucleoside reverse transcriptase inhibitor (NNRTI) of which efavirenz ((4 S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) is the most popular 1 . Efavirenz is associated with a range of neuropsychiatric side effects (see 2 for review), with manic episodes, euphoria and dissociative effects particularly noteworthy 1,3,4 . Efavirenz is a lipophilic compound 5 , which may underlie its penchant for mediating a diverse range of CNS manifestations 2 . Preclinical studies indicate that efavirenz acts as a weak partial agonist at the serotonin 5-HT 2A receptor 6 , while also presenting with actions at dopamine (DA) and 5-HT transporters, thus in line with other drugs of abuse 7,8 . Crushing and smoking of an efavirenz-cannabis mixture, commonly known as "Nyaope" or "Woonga" 9 , in certain countries like South Africa, has seen the recreational use and abuse of efavirenz escalate to alarming proportions 9 . With other HIV drugs, like dolutegravir 10 , also noted for presenting with a similar neuropsychiatric side-effect profile, there is an urgent need to identify possible mechanisms that might relate to the rewarding effects and addictive-like/abuse potential of these drugs and as such to devise possible treatments. Addictive disorders share a number of common neurobiological substrates critical in reward and reinforcement, in particular the mesocorticolimbic DA pathway 11 , as well as 5-HT and noradrenalin (NA) related processes 12 . In fact, all major classes of drugs of abuse increase the levels of these monoamines in the frontal cortex, striatum and hippocampus, whereby they are purported to mediate euphoria, arousal, reward and relapse in humans 13, 14 . However, drugs such as cocaine and methamphetamine (MA) are pro-oxidants, thereby implicating disordered redox pathways not only in the development of addiction 15 but also mediating neuronal damage so often engendered by the abuse of these drugs 11 .