1. Rats were anesthetized with urethane (1.5 mg/kg IP) and placed into a stereotaxic apparatus (Kopf).
A concentric bipolar stimulating electrode was implanted into the left medial forebrain bundle (MFB;
coordinates from bregma in mm: AP -4.2, ML -1.8 and DV -7.8 from dura) of each rat. A carbon-fiber
microelectrode (250 μm in length by 10 µm o.d.) was implanted into the left NAc core (coordinates
from bregma in mm: AP 1.60, ML +1.5, and DV -7.4 from dura) [7]. A Ag/AgCl reference/auxiliary
electrode was positioned in contact with contralateral cortical tissue. A fixed positive potential (+0.8 V)
was applied via the auxiliary electrode to induce oxidation of DA at the recording electrode. The
analog current (e-), constituting DA oxidation, was converted (A/D converter) to a digital signal that
was monitored in real time (10K samples/sec) on an electrometer 60 Hz line-filtered and 10 Hz low-
pass filtered.
Thus, increases in DA oxidation corresponded to proportional increases in DA release in the NAc
core as a result of brief electrical stimulation of DA axons in the MFB. Stimulation parameters (15
cathodic monophasic 0.5 msec pulses at 50 Hz and 800 µA intensity every 30 sec) were applied to the
MFB to one male and female/litter beforeand after a single acute administration of cocaine (20 mg/kg,
Perinatal exposure to polychlorinated biphenyls in rats alters
cocaine-induced dopamine efflux in the nucleus accumbens
Jenna R. Fielding, Tiffany D. Rogers, Abby E. Meyer, Mellessa M. Miller, Jenna L. Nelms, Melissa A. Ward,
Guy Mittleman, Charles D. Blaha, and Helen J. K. Sable
[1] Erickson M. (1986). Analytical chemistry of PCBs. Boston: Butterworth Publishers. [2] Jacobson, J., Fein, G., et al. (1984). Am J Public Health 74: 378-9; Sable, H., Schantz, S. (2006). In Animal Models of Cognitive Impairment
(Frontiers in Neuroscience). E. D. Levin and J. J. Buccafusco (eds). New York, CRC Press: 147-67. [3] Angus, W., Contreras, M. L. (1996). Toxicol Lett, 89, 191-9; Bemis, J., Seegal, R. (2004). Toxicol Sci, 80, 288-95; Choksi, N.,
Kodavanti, P., et al.(1997). Fund Appl Toxicol, 39, 76-80. Seegal R., Brosch, et al. (1989). Neurotoxicol, 10, 757-64. [4] Bemis , J., Seegal, R. (2000), Neurotoxicol, 21, 1123-34. [5] Wise, R. (1984). NIDA Res Monogr, 50, 15-33. [6]
Kostyniak, P., Hansen, L. et al. (2005). Toxicol Sci, 88, 400-11. [7] Paxinos, G., Franklin, K. (2001) The Mouse Brain in Stereotaxic Coordinates (2nd ed.). San Diego, CA: Academic Press.
Introduction
Subjects and Exposure
Polychlorinated Biphenyls (PCBs) are a ubiquitous environmental
toxin that were widely used in industry for commercial needs until
they were banned in the late 1970s [1]. Over time, PCBs have been
dispersed into rivers, lakes, air and soil and have bioaccumulated
within the ecosystem. A major health concern is that PCBs readily
cross the placenta and can accumulate in breastmilk [2] thereby
exposing the developing fetus/infant to potentially irreversible
neuroteratogenic effects during gestation and lactation.
Using a variety of experimental designs, researchers have found that
PCB exposure reduces brain dopamine (DA) content [3], resulting in
reduced extracellular DA concentrations in medial prefrontal cortex
and striatum that lasts into adulthood [4]. These alterations suggest
the reinforcing properties of drugs of abuse that act on the dopamine
system may be affected by developmental PCB exposure. For example,
the reinforcing properties of cocaine have been related to increased
extracellular concentrations of dopamine in the nucleus accumbens
(NAc) [5]. Thus, the current study was conducted to determine if
electrically evoked NAc DA efflux following both acute and chronic
daily injections of cocaine (20 mg/kg IP) differed between adult rats
exposed to an environmentally relevant mixture of PCBs throughout
gestation and lactation and non-exposed controls.
Amperometry Testing
Results and Conclusions
ReferencesFemale Long-Evans rats were dosed with the Fox River PCB Mixture
[6] beginning 28 days prior to breeding and continuing until weaning
(n=8 litters/exposure group). At weaning two males and females from
each litter were kept for later amperometry testing.
Department of Psychology
Memphis, TN 38152 USA
Gestation
21 days
Lactation
21 days
PND -57 -29 -21 0 21 60
Pups
Born
Weaning
Breeding
Dosing began Fixed
Potential
Amperometry
began
Gestation
PCB Exposure
Developmental PCB Exposure
In a Rat Model
0, 3, or 6 mg/kg PCBs dissolved in corn oil and pipetted
onto half of a vanilla wafer; volume based on body weight
IP). These parameters were repeated in a second male and female/litter who had received six prior daily cocaine injections of the same dose. Changes in
stimulation-evoked DA oxidation current were recorded for 60 min post-injection. Peak increases in DA oxidation current evoked by MFB stimulation after cocaine
injection were expressed as percentage change with respect to pre-injection baseline responses (100%). Percentage changes were subsequently averaged across
animals for each condition. Sixty min post-injection, continuous stimulation (100 Hz) was administered with the intention of depleting presynaptic NAc DA stores.
The total current measured was summed across the period beginning 30 sec and terminating 90 sec after the start of continuous stimulation.
There was a significant PCB exposure group x injection schedule
interaction [F(2,21)=10.76, p=.001]. Exposure dose-dependently
increased peak DA release following the acute injection of cocaine
(+p=.055, ***p=.001 from 0 mg/kg group) but attenuated release
following chronic injections of cocaine (*p=.019 from 0 mg/kg
group). PCB-exposure attenuated the typical DA sensitization seen
in non-exposed rats following chronic cocaine exposure (**p=.005).
There was a marginally significant main effect of exposure group
[F(2,21)=3.10, p=.066]. PCB exposure dose-dependently attenuated
DA release following continuous, MFB stimulation (*p=.047).
Supported by R00 ES015428
PCB-exposed rats exhibited enhanced stimulated DA release following acute administration of cocaine. Non-exposed rats exhibited
typical DA sensitization following the chronic cocaine injections, but this effect was attenuated in PCB-exposed rats. Continuous
stimulation suggested a reduction in pre-synaptic DA stores in PCB-exposed animals. No differences in the time-course of peak DA release
were found. These results indicate that developmental PCB exposure can modify DA synaptic transmission and pharmacology in the NAc
in a manner previously shown to alter the reinforcing properties of cocaine.
There were no significant main effects or interactions found on the
time course of peak DA release following cocaine administration.