Prenatal exposure to cocaine alters the development of conditioned place-preference to cocaine in adult mice

Abstract

As addiction is increasingly formulated as a developmental disorder, identifying how early developmental exposures influence later responses to drugs of abuse is important to our understanding of substance abuse neurobiology. We have previously identified behavioral changes in adult mice following gestational exposure to cocaine that differ when assessed with methods employing contingent and non-contingent drug administration. We sought to clarify this distinction using a Pavlovian behavioral measure, conditioned place-preference. Adult mice exposed to cocaine in utero (40 or 20 mg/kg/day), vehicle and pair-fed controls were place-conditioned to either cocaine (5 mg/kg or 20 mg/kg, i.p.) or saline injections. The development of conditioned place-preference to cocaine was impaired in mice exposed to cocaine in utero, and was abolished by fetal malnutrition. A context-specific place-aversion to vehicle but not cocaine injection was observed in prenatally cocaine-exposed mice. Locomotor behavior did not differ among prenatal treatment groups. We conclude that early developmental exposure to cocaine may diminish the subsequent rewarding effects of cocaine in adulthood measured with classical conditioning techniques, and that this is not due to changes in locomotor behavior. Sensitivity to acute stress is also altered by prenatal cocaine exposure, consistent with earlier findings in this model.

Models of Intergenerational and Transgenerational Transmission of Risk for Psychopathology in Mice

“…Accompanying this behavioral preference was increased volumes in the olfactory bulbs of the glomeruli that process cherry (M71-expressing olfactory sensory neurons and glomeruli) and mint (M72-expressing cells and glomeruli) (Todrank et al, 2011). In other studies, prenatal exposure to cocaine affected the F1 generation's behavior toward cocaine, as well as dopaminergic neurotransmission and stress responsiveness (Malanga et al, 2007;Wang et al, 2013). Additionally, exposure of pregnant rat dams to a fungicide, Vinclozolin, has been shown to affect reproductive and behavioral endpoints in several generations removed from this F0 exposure (Crews et al, 2007;Skinner et al, 2008;Gillette et al, 2014).…”

Cocaine ExposureIn UteroAlters Synaptic Plasticity in the Medial Prefrontal Cortex of Postnatal Rats

“…Previous animal studies have shown that prenatal cocaine exposure results in changes of cognitive and emotional development of the offspring, including learning and memory (Thompson et al, 2005;Malanga et al, 2007), but cellular and circuit mechanisms underlying these behavioral changes remain unclear. The medial prefrontal cortex (mPFC) is an important part of the reward circuit in the rat brain, with strong reciprocal interactions with the ventral tegmental area (VTA) and nucleus accumbens (NAc)-two regions known to play key functions in the initiation and expression of locomotor sensitization as a result of repeated cocaine exposure (Kalivas et al, 1998;Robinson and Berridge, 2003).…”

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

“…To control for some of these variables we created an animal model of prenatal cocaine exposure which has provided support for the role of cocaine independently contributing to some but not all of the clinical findings (reviewed in (10)). Of note,, rodents exposed to cocaine in utero display an altered response to drugs of abuse when tested as adults including impaired conditioned place preference (11,12), increased acquisition to (13,14) and enhanced reinforcing ability of cocaine (13,14) in self-administration tests, augmented brain stimulation reward following administration of cocaine and D 1 agonists (15), and enhanced stereotypy during cocaine induced behavioral sensitization (16).…”