Stimulation-evoked dopamine release in the nucleus accumbens following cocaine administration in rats perinatally exposed to polychlorinated biphenyls.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxins that were banned in the late 1970s but remain one of the most frequently identified contaminants in human adipose tissue, serum, and breast milk (Safe, 1993). Ingestion of PCB-contaminated food is the main source of PCB exposure in human populations, whereas breathing contaminated air represents another minor exposure source (ATSDR, 2000). Exposure to mixtures of mostly noncoplanar PCB congeners typically represents the bulk of human exposure (Hansen, 1999). The neurotoxic effects of noncoplanar PCBs may be explained by their ability to alter dopamine (DA) levels in the brain. Adult exposure to commercial Aroclor mixtures consisting of mostly noncoplanar PCB congeners has been shown to decrease DA concentrations in the striatum of rats (Seegal et al., 2002), mice (Richardson and Miller, 2004), and nonhuman primates (Seegal, 1996; Seegal et al., 1990, 1991, 1994). Perinatal exposure to Aroclor 1016 increased DA levels in several brain regions including the substantia nigra, caudate nucleus, and nucleus accumbens (NAc) in rats (Seegal, 1994), whereas exposure to the individual noncoplanar, ortho-substituted congener PCB 47 caused a significant decrease in DA concentration in rat caudate nucleus and frontal cortex (Seegal et al., 1997). Noncoplanar PCBs inhibit the DA transporter (DAT; Mariussen and Fonnum, 2001), leading to increased DA in the synapse. This finding may appear to contradict research demonstrating that PCBs decrease extracellular DA levels, but Seegal et al. (2002) reported that PCB-induced elevations in extracellular DA levels were transient. Basal extracellular DA levels were elevated in adult rat striatum following 3 days of exposure to Aroclor 1254, but after 1 week of exposure, levels were significantly decreased. One explanation for this biphasic response may be because noncoplanar PCBs also inhibit the activity of the vesicular monoamine transporter (VMAT2), which transports monoamines like DA into vesicles in the presynaptic terminal for later release (Mariussen et al., 1999). The increase in cytosolic DA may lead to end-product inhibition of tyrosine hydroxylase (TH), the rate-limiting enzyme of intraneuronal DA synthesis (Cooper et al., 1996). Bemis and Seegal (2004) demonstrated that PCB inhibition of VMAT2 seemed to play a greater role than the inhibition of DAT on decreasing tissue DA. They observed a weak (nonsignificant) relationship between PCB-induced elevations in media DA and reductions in synaptosomal DA. Known DAT inhibitors elevated media DA significantly more than PCBs while having similar effects on tissue DA content. Known VMAT inhibitors, however, elevated 3,4-dihydroxyphenylacetic acid (the intraneuronal metabolite of DA) and decreased tissue DA to the same degree that PCBs did. Fewer DATs and VMATs are expressed within the striatum of PCB-exposed adult laboratory animals (Caudle et al., 2006; Richardson and Miller, 2004) and in synaptosomes during in vitro exposure (Fonnum et al., 2006). There is also evidence to suggest that DA autoreceptor (DAR) activity can influence DAT and VMAT2 function, but the effects of PCB exposure on DAR sensitivity have not been investigated. With respect to DAT, in vitro and in vivo evidence has suggested that pharmacological blockade of DAR activity or reduction in DAR expression results in a decrease in DAT efficiency. Increased extracellular DA levels that accompany reductions in DAR activity lead to a compensatory increase in DAT velocity, but this is insufficient to overcome the reduction in DAT efficiency (Dickinson et al., 1999; Mayfield et al., 2001; Wu et al., 2002; Zahniser et al., 1999). Thus, stimulation of DARs increased DAT function, whereas blockade of DARs by DA D2 antagonists decreased DAT function, and DAR sensitivity has been shown to be positively coupled to DAT function (Gulley & Zahniser, 2003). Likewise for VMAT2, it has been shown that increased extracellular DA caused by the uptake blockers cocaine and methylphenidate cause the redistribution of VMAT2-containing vesicles from a plasmalemmal membrane fraction to a presumably cytosolic fraction. This cocaine-induced vesicular trafficking is blocked with DA D2 receptor antagonists, suggesting a potential involvement with presynaptic D2 DARs. Moreover, administration of D2 agonists has been shown to cause vesicle trafficking in a manner similar to uptake blockers, suggesting that increased extracellular concentrations of DA in response to DAT blockade may stimulate DARs causing vesicles to move into the cytosol, thus facilitating release (Riddle et al., 2005). Because DA levels within the mesolimbic dopaminergic pathway influence psychostimulant reinforcement and addiction (Pierce and Kumaresan, 2006), the relationship between drug addiction and PCB exposure warrants further investigation. Animals that have been exposed to PCBs exhibit behaviors that suggest that they may have a higher risk of developing drug addiction (Jones and Miller, 2008). For example, deficits on inhibitory control tasks in rats (Holene et al., 1998, 1999; Sable et al., 2006, 2009), monkeys (Mele et al., 1986; Rice, 1997, 1998), and humans (Jacobson et al., 1992; Stewart et al., 2003, 2005, 2006) perinatally exposed to PCBs have been demonstrated. Likewise, interoceptive cues following administration of cocaine and amphetamine (Sable et al., 2011) and locomotor activation and behavioral sensitization following amphetamine administration (Poon et al., 2013) have all been reported to be altered in rats perinatally exposed to PCBs. The aim of this study was to examine the relationship between developmental exposure to PCBs and mesolimbic DA functioning associated with psychostimulant administration. In vivo fixed potential amperometry (FPA) was used in anesthetized adult offspring to determine whether perinatal PCB exposure altered (1) presynaptic DAR sensitivity, (2) electrically evoked NAc DA release following administration of cocaine, and (3) the rate of depletion of presynaptic DA stores. The hypotheses were that relative to non–PCB exposed rats, those perinatally exposed to PCBs would exhibit (1) enhanced DAR sensitivity, (2) elevated levels of stimulated DA release in the NAc (relative to baseline) following cocaine administration, and (3) greater stimulation-induced depletion of DA vesicular stores. These predictions were made based on the ability of PCBs to (1) decrease basal DA levels thereby resulting in greater DAR sensitivity, (2) decrease DAT expression thereby causing greater DAT occupancy by cocaine, and (3) decrease VMAT2 expression thereby resulting in decreased sequestration of DA into synaptic vesicles for later release.