Helen Sable

Animal models for medications development targeting alcohol abuse using selectively bred rat lines: neurobiological and pharmacological validity.

The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence.

Developmental Exposure to PCBs and/or MeHg: Effects on a Differential Reinforcement of Low Rates (DRL) Operant Task Before and After Amphetamine Drug Challenge

The current study assessed the effects of developmental PCB and/or MeHg exposure on an operant task of timing and inhibitory control and determined if amphetamine (AMPH) drug challenges differentially affected performance. Long-Evans rats were exposed to corn oil (control), PCBs alone (1 or 3 mg/kg), MeHg alone (1.5 or 4.5 ppm), the low combination (1 mg/kg PCBs+1.5 ppm MeHg), or the high combination (3 mg/kg PCBs+4.5 ppm MeHg) throughout gestation and lactation. An environmentally relevant, formulated PCB mixture was used. Male and female offspring were trained to asymptotic performance on a differential reinforcement of low rates (DRL) operant task as adults. PCB-exposed groups had a lower ratio of reinforced to non-reinforced responses than controls. Groups exposed to MeHg alone were not impaired and the deficits observed in PCB-exposed groups were not seen when PCBs were co-administered with MeHg. AMPH was less disruptive to responding in males receiving PCBs alone, MeHg alone, and 1.0 mg/kg PCB+1.5 ppm MeHg. Paradoxically, the disruption in responding by AMPH in males given 3.0 mg/kg PCB+4.5 ppm MeHg did not differ from controls. Exposed females from all treatment groups did not differ from controls in their AMPH response. Overall, the findings suggest that developmental exposure to PCBs can decrease DRL performance. Co-exposure to MeHg seemed to mitigate the detrimental effects of PCBs on performance. The finding that the disruptive effects of AMPH on DRL performance were lessened in some groups of exposed males suggests that alterations in dopaminergic functioning may have a role in behavioral changes seen after perinatal PCB and MeHg exposure.

Developmental exposure to PCBs, MeHg, or both: long-term effects on auditory function.

Background Developmental exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg) can result in a variety of neurotoxic effects, including long-term auditory deficits. However, little is known about the effects of combined exposure to PCBs and MeHg on auditory function. Objective We developmentally exposed rats to PCBs and/or MeHg and assessed auditory function in adulthood to determine the effects of exposure to these contaminants individually and in combination. Methods We exposed female Long-Evans rats to 1 or 3 mg/kg PCB in corn oil, 1.5 or 4.5 ppm MeHg in drinking water, or combined exposure to 1 mg/kg PCB + 1.5 ppm MeHg or 3 mg/kg PCB + 4.5 ppm MeHg. Controls received corn oil vehicle and unadulterated water. Dosing began 28 days before breeding and continued until weaning at postnatal day (PND) 21. Auditory function of the offspring was assessed at approximately PND 200 by measuring distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs). Results Groups exposed to PCBs alone had attenuated DPOAE amplitudes, elevated DPOAE thresholds, and elevated ABR thresholds compared with controls. Groups exposed to MeHg alone did not differ from controls. Unexpectedly, the effects of PCB exposure appeared to be attenuated by coexposure to MeHg. Conclusion Developmental exposure to PCBs can result in permanent hearing deficits, and the changes in DPOAE amplitudes and thresholds suggest a cochlear site of action. Coexposure to MeHg appeared to attenuate the PCB-related deficits, but the mechanism for this unexpected interaction remains to be determined.

Effects of naltrexone on the acquisition of alcohol intake in male and female periadolescent and adult alcohol-preferring (P) rats

The objective of this study was to compare the effects of naltrexone (NTX) on the acquisition of alcohol drinking, during periadolescence and adulthood in rats using a rodent model of alcoholism. Periadolescent and adult alcohol-preferring (P) rats of both sexes were given access to water and 15% (v/v) alcohol 24-hr/day for 45 days. Alcohol access started at 1200 hr on post-natal day (PND) 30 for the periadolescent rats and approximately PND 90 for the adult rats. Subcutaneous (SC) injections of NTX (0, 5, 10, 20, and 30 mg/kg) were administered daily between 1600-1700 hr to separate groups of animals during the first 10 days of alcohol access. During the treatment period, differential effects on alcohol intake were seen between periadolescent and adult animals: (a) lower doses of NTX were more effective in the periadolescent than the adult P rats, and (b) greater tolerance to repeated dosing was displayed by adult, compared with periadolescent, rats. By the 20h day of alcohol access there were no significant differences between the NTX dose groups. Additionally, there were no sex of animal differences at the ages tested. These findings indicate that the endogenous opioid system(s) mediating alcohol intake are developmentally present in periadolescent P rats, such that NTX not only interfered with the acquisition of alcohol intake by adolescent P rats but appeared to also have a greater effect than that observed in adult P rats. Therefore, NTX may serve as an effective treatment in reducing alcohol abuse and dependence in genetically, and perhaps environmentally, at-risk youth.

Parenteral Nutrition Compromises Neurodevelopment of Preterm Pigs

BACKGROUND Despite advances in nutritional support and intensive care, preterm infants are at higher risk of compromised neurodevelopment. OBJECTIVE This study evaluated the contribution of total parenteral nutrition (PN) to compromised neurodevelopment after preterm birth. METHODS Preterm pigs were provided PN or enteral nutrition (EN) for 10 d. Neurodevelopment was assessed by observations of motor activity and evaluation of sensory/motor reflexes, brain weight, MRI, and cerebellar histology. RESULTS Despite similar gains in body weight, PN pigs had smaller brains (32 ± 0.4 vs. 35 ± 0.6 g; P = 0.0002) including the cerebellum, as well as reduced motor activity (P = 0.005), which corresponded to underdeveloped myelination (P = 0.004) measured by diffusion tensor imaging. PN resulted in lower serum triglycerides (17 ± 5.9 vs. 27 ± 3.1 mg/dL; P = 0.05), total cholesterol (31 ± 9.6 vs. 85 ± 8.1 mg/dL; P = 0.04), VLDL cholesterol (3.7 ± 1.2 vs. 5.7 ± 0.7 mg/dL; P = 0.04), and HDL cholesterol (16 ± 4.6 vs. 57 ± 7.3 mg/dL; P = 0.03) and nonsignificantly lower LDL cholesterol (10.7 ± 4.4 vs. 22.7 ± 2.9 mg/dL; P = 0.09). CONCLUSIONS The compromised neurodevelopment caused by total PN is a novel finding, was independent of confounding variables (disease, inconsistent gestational ages, diverse genetics, extrauterine growth retardation, and inconsistent neonatal intensive care unit protocols), and highlights a need to improve current PN solutions. The preterm pig is a translational animal model for improving nutrition support to enhance neurodevelopment of preterm infants requiring PN.

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting that the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest that developmental PCB exposure can alter the interoceptive cues of psychostimulants.

Developmental exposure to polychlorinated biphenyls reduces amphetamine behavioral sensitization in Long–Evans rats

PCBs have long been known to affect dopamine (DA) function in the brain. The current study used an amphetamine behavioral sensitization paradigm in rats developmentally exposed to PCBs. Long-Evans rats were given perinatal exposure to 0, 3, or 6mg/kg/day PCBs and behavioral sensitization to d-amphetamine (AMPH) was assessed in one adult male and female/litter. Non-exposed (control) males showed increasing locomotor activity to repeated injections of 0.5mg/kg AMPH, typical of behavioral sensitization. PCB-exposed males showed greater activation to the initial acute AMPH injection, but sensitization occurred later and was blunted relative to controls. Sensitization in control females took longer to develop than in the males, but no exposure-related differences were observed. Analysis of whole brain and serum AMPH content following a final IP injection of 0.5mg/kg revealed no differences among the exposure groups. Overall, these results indicated developmental PCB exposure can alter the motor-stimulating effects of repeated AMPH injections. Males developmentally exposed to PCBs appeared to be pre-sensitized to AMPH, but quickly showed behavioral tolerance to the same drug dose. Results also revealed the behavioral effect was not due to exposure-induced alterations in AMPH metabolism following PCB exposure.

Stimulation-Evoked Dopamine Release in the Nucleus Accumbens Following Cocaine Administration in Rats Perinatally Exposed to Polychlorinated Biphenyls

Exposure to polychlorinated biphenyls (PCBs) alters brain dopamine (DA) concentrations and DA receptor/transporter function, suggesting the reinforcing properties of drugs of abuse acting on the DA system may be affected by PCB exposure. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day PCBs from 4 weeks prior to breeding until litters were weaned on postnatal day 21. In vivo fixed potential amperometry (FPA) was used in adult anesthetized offspring to determine whether perinatal PCB exposure altered (1) presynaptic DA autoreceptor (DAR) sensitivity, (2) electrically evoked nucleus accumbens (NAc) DA efflux following administration of cocaine, and (3) the rate of depletion of presynaptic DA stores. One adult male and female littermate were tested using FPA following a single injection of cocaine (20 mg/kg ip), whereas a second adult male and female littermate were tested following the last of seven daily cocaine injections of the same dose. The carbon fiber recording microelectrode was positioned in the NAc core, and DA oxidation currents (i.e., DA release) evoked by brief stimulation of the medial forebrain bundle (MFB) were quantified before and after administration of cocaine. PCB-exposed rats exhibited enhanced stimulation-evoked DA release (relative to baseline) following a single injection of cocaine. Although nonexposed controls exhibited typical DA sensitization following repeated cocaine administration, this effect was attenuated in PCB-exposed rats. In addition, DAR sensitivity was higher (males only), and the rate of depletion of presynaptic DA stores was greater in PCB-exposed animals relative to nonexposed controls. These results indicate that perinatal PCB exposure can modify DA synaptic transmission in the NAc in a manner previously shown to alter the reinforcing properties of cocaine.

A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

Polychlorinated Biphenyls (PCBs) are very stable environmental contaminants whose exposure induces a number of health and cognitive concerns. Currently, it is well known that PCB exposure leads to poor performance on inhibitory control tasks. It is also well known that dopamine (DA) depletion within medial prefrontal cortex (mPFC) leads to poor performance on inhibitory control tasks. However, what is not well established is whether or not the inhibitory control problems found following PCB exposure are mediated by DA depletion in mPFC. This study was an investigation into the link between perinatal exposure to PCBs, the effect of this exposure on DA neurotransmission in the mPFC, and inhibitory-control problems during adulthood using a rodent model. The current study served to determine if microinjections of different DA agonists (the presynaptic DA transporter inhibitor and vesicular monoamine transporter agonist bupropion, the postsynaptic DA receptor 2 (DAD2) agonist quinpirole, and the postsynaptic DA receptor 1 (DAD1) agonist SKF81297) directly into the mPFC would differentially improve performance on an inhibitory control task in rats perinatally exposed to an environmentally relevant PCB mixture. Findings suggest several significant sex-based differences on differential reinforcement of low rates (DRL) 15 performance as well as some evidence of differential effectiveness of the DA agonists based on PCB exposure group.

Cocaine sensitization in adult Long-Evans rats perinatally exposed to polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely affect the nervous system and more specifically the dopamine system. Developmental PCB exposure in rats has been shown to produce alterations in dopaminergic signaling that persist into adulthood. The reinforcing properties of psychostimulants are typically modulated via the dopaminergic system, so this project used a behavioral sensitization paradigm to evaluate whether perinatal PCB exposure altered sensitization to the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 0, 3 or 6mg/kg/day of PCBs throughout gestation and lactation. One male and female pup from each litter was retained for behavioral testing. Both horizontal and vertical activity were used to measure cocaine sensitization following repeated injections of 10mg/kg cocaine (IP) on post-natal day (PND) 91-96 and again after a week in the home cage on PND 103. A final locomotor activity session following a challenge injection of 20mg/kg was given on PND 110 to further evaluate the availability of presynaptic dopamine stores. The PCB-exposed rats appeared to be pre-sensitized to cocaine as they exhibited a greater degree of cocaine-induced locomotor activation to the initial injections of cocaine and therefore demonstrated a more rapid onset of cocaine behavioral sensitization compared to non-exposed controls. These results add to the literature detailing how perinatal exposure to dopamine-disrupting contaminants can change the developing brain, thereby producing permanent changes in the neurobehavioral response to psychostimulants later in life.