Development of sensitization to methamphetamine in offspring prenatally exposed to morphine, methadone and buprenorphine

Abstract

Heroin use among young women of reproductive age has drawn much attention around the world. However, there is lack of information on the long-term effects of prenatal exposure to opioids on their offspring. Our previous study demonstrated that prenatally buprenorphine-exposed offspring showed a marked change in the cross-tolerance to morphine compared with other groups. In the current study, this animal model was used to study effects of methamphetamine (METH)-induced behavioral sensitization in the offspring at their adulthood. The results showed no differences in either basal or acute METH-induced locomotor activity in any of the groups of animals tested. When male offspring received METH injections of 2 mg/kg, i.p., once a day for 5 days, behavioral sensitization was induced, as determined by motor activity. Furthermore, the distance and rate of development (slope) of locomotor activity and conditioned place preference induced by METH were significantly increased in the prenatally buprenorphine-exposed animals compared with those in other groups. The dopamine D1 R in the nucleus accumbens of the prenatally buprenorphine-exposed offspring had lower mRNA expression; but no significant changes in the μ-, κ-opioid, nociceptin, D2 R and D3 R receptors were noted. Furthermore, significant alterations were observed in the basal level of cAMP and the D1 R agonist enhanced adenylyl cyclase activity in the prenatally buprenorphine-exposed group. Overall, the study demonstrates that D1 R and its downregulated cAMP signals are involved in enhancing METH-induced behavioral sensitization in prenatally buprenorphine-exposed offspring. The study reveals that prenatal exposure to buprenorphine caused long-term effects on offspring and affected the dopaminergic system-related reward mechanism.

Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats

“…The current findings suggest that buprenorphine treatment during pregnancy reduced the potential risk for development of certain aspects of psychiatric illness as compared with treatment using morphine or methadone. Lines of evidence have shown enhancement of tolerance to morphine, reduction in nerve growth factor (NGF) contents, deficits of myelination development and oligodendrocyte maturation, and development of sensitization to methamphetamine in the prenatally buprenorphine-exposed offspring 20,21,59–61. These findings indicate that it may be necessary to consider whether higher buprenorphine is a really safe therapeutic agent for treating pregnant women.…”

“…The dose of opioids used in pregnant rats was selected based on the studies reported previously 19–21,34. The dosage was selected to produce overt toxicity, but not overdose deaths.…”

“…Therefore, it is warranted to compare the behavioral manifestations associated with prenatal exposure to methadone or buprenorphine in animals. Previous studies have shown that prenatal exposure to methadone and buprenorphine induced the tolerance of antinociceptive effects to morphine in the tail-flick test,19,20 whereas methamphetamine-induced behavioral sensitization was only significantly increased in prenatally buprenorphine-exposed offspring at their adulthood 21. It remains unclear whether offsprings prenatally exposed to these two therapeutic opioids are prone to develop cognitive dysfunction and mood disorders in the same manner.…”

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

“…Like other opiates, perinatal buprenorphine produces morphine tolerance (Chiang et al, 2010;Robinson and Wallace, 2001), delayed acquisition of developmentally timed behaviors (Robinson and Wallace, 2001), and increased sensitization to METH (Chiang et al, 2013). Chiang et al (2013) also found decreased D1 receptor mRNA, basal cyclic AMP, and D1 receptor induced adenylyl cyclase activity in the NAc of buprenorphine-exposed offspring, suggesting disrupted signal transduction may underlie the increased METH sensitization.…”

Effects of Electroacupuncture on Methamphetamine‐Induced Behavioral Changes in Mice

“…CPP, based on Pavlovian conditioning, is widely used for identifying the addictive liability of compounds in animals [21–23]. EA at KI9–LR3 affected CPP considerably and improved the extinction, indicating that EA at KI9–LR3 may also regulate the brain reward learning system.…”