MDMA [KLH]

Rodents exhibit natural exploratory behaviors, which can be measured by the spontaneous alternation behavior (SAB) test. Perseverance in this test induced by the 5-hydroxytryptamine 1A receptor (5-HT1AR) agonist, 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), resembles compulsive behaviors observed in humans and manifests as reduced alternation ratio. This study characterized 8-OH-DPAT-induced perseverance in the SAB test in C57BL/6JOlaHsd male mice by coadministration of WAY100635, citalopram and the 5-HT releasing agent, 3,4-methylenedioxymethamphetamine (MDMA), to deepen the understanding of 5-HT-dependent mechanisms. The 5-HT1AR mechanism of 8-OH-DPAT (1.0 mg/kg, p < 0.01) on perseverance was confirmed by coadministration of the 5-HT1AR antagonist, WAY100635 (2.0 mg/kg, p < 0.05), which attenuated the effects of 8-OH-DPAT. Such effects could also be reversed by MDMA (1.0 mg/kg, p < 0.05; 10.0 mg/kg, p < 0.001) but not citalopram. These findings confirm the importance of 5-HT in regulating perseverative behavior. Future investigations are required to determine the predictive validity of the 8-OH-DPAT-disrupted SAB test as an inducible mouse model of compulsivity.

Background: Drugs of abuse affect both central nervous system (CNS) and peripheral immune function. Besides the involvement of dopamine and glutamate systems, chronic exposure to drugs of abuse alters immune homeostasis, promoting a pro-inflammatory status. At the same time, impaired peripheral immunity leads to an increased susceptibility to infections in drug abusers. Discussion: There is evidence that certain drugs, such as opioids, activate microglial cells and astrocytes which, in turn, provoke central neuroinflammation. Particularly, opioids bind the Toll-like receptor (TLR)-4 with increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and release of pro-inflammatory cytokines. Peripheral mediators released by immune cells also contribute to aggravate central neuroinflammation. Conclusion: These are based either on the inhibition of TLR-4 activation by drugs of abuse or on the correction of dopamine and glutamate pathways. Finally, a hypothetic nutraceutical intervention with polyphenols in view of their anti-inflammatory and anti-oxidant properties will be outlined as an adjuvant treatment for drugs of abuse-related disorders.