Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring

Abstract

Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30–39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA.

Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure

“…Lower levels of morphine self-administration on a FR1 schedule is commonly interpreted as higher drug sensitivity (Arnold and Roberts, 1997; Carroll and Lac, 1997; Doherty et al, 2009; Koob et al, 1984). This is consistent with recent results using this same adolescent exposure regimen that showed increased place conditioning at low doses of morphine in a conditioned place preference paradigm (Vassoler et al, 2015). However, it could also be interpreted as a decrease in motivation to obtain morphine, which is more consistent with the PR, extinction, and reinstatement data.…”

“…The observed reduction in self-administration behaviors, however, should not necessarily be interpreted as a demonstration of a “protective effect” on offspring and grandoffspring with regard to addiction liability. Indeed, other data from our lab suggest additional behavioral and molecular modifications in these animals that would be expected to increase their vulnerability to addiction under various conditions (Byrnes, 2005a, b, 2008; Byrnes et al, 2011; Byrnes et al, 2013; Johnson et al, 2011; Vassoler et al, 2014b; Vassoler et al, 2015). Thus, what we suggest is that maternal exposure to morphine during adolescence alters the neurodevelopment of future offspring that impacts how they respond to drugs of abuse, which may be dependent upon a host of environmental and genetic factors.…”

“…The adolescent exposure is described in Vassoler et al, 2015. Briefly, beginning at PND30 females (n=36) were injected (s.c.) once daily with morphine sulfate (MS) for a total of 10 days using an increasing dosing regimen with doses increased every other day (5, 5, 10, 10, 15, 15, 20, 20, 25, 25 mg/kg).…”

“…For example, inter-generational effects have been documented in animal models following variations in stress, diet, as well as toxin and drug exposures (Skinner, 2015). Following exposure to drugs of abuse animal studies have found both increases and decreases in offspring propensity towards addiction-like behaviors (Szutorisz et al, 2014; Vassoler et al, 2013; Vassoler et al, 2016) that indicate alterations within the reward pathway that may increase vulnerability in certain populations. There remains a paucity of studies examining transgenerational effects following exposure to drugs of abuse.…”

Impaired cocaine‐induced behavioral plasticity in the male offspring of cocaine‐experienced sires

“…A growing body of evidence indicates that ancestral exposure to all of the major classes of abused drugs influences the physiology and behavior of descendants (Finegersh, Rompala, Martin, & Homanics, 2015;Finegersh, Ferguson et al, 2015;Szutorisz et al, 2014;Vassoler, White, Schmidt, Sadri-Vakili, & Pierce, 2013;Vassoler, Wright, & Byrnes, 2016;Vassoler et al, 2017;White, Vassoler, Schmidt, Pierce, & Wimmer, 2015;Yohn, Bartolomei, & Blendy, 2015). Several reports have consistently shown that sire exposure to cocaine influences cocaine-associated behaviors in the next generation.…”