Developmental Exposure to Polychlorinated Biphenyls Prevents Recovery from Noise-Induced Hearing Loss and Disrupts the Functional Organization of the Inferior Colliculus.

Exposure to combinations of environmental toxins is growing in prevalence; and therefore, understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins, polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise, interact to produce dysfunction in central auditory processing. PCBs are well established to impose negative developmental impacts on hearing. However, it is not known whether developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 min of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus (IC) revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.SIGNIFICANCE STATEMENT Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the prenatal and postnatal developmental changes induced by polychlorinated biphenyls (PCBs) could negatively impact the resilience of the brain to noise-induced hearing loss (NIHL) later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.

Developmental exposure to polychlorinated biphenyls prevents recovery from noise-induced hearing loss and disrupts the functional organization of the inferior colliculus.

Exposure to combinations of environmental toxins is growing in prevalence, and therefore understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins - polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise - interact to produce dysfunction in central auditory processing. PCBs are well-established to impose negative developmental impacts on hearing. However, it is not known if developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 minutes of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins. Significance statement: Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.

Impulsive choice in two different rat models of ADHD-Spontaneously hypertensive and Lphn3 knockout rats.

Introduction: Impulsivity is a symptom of attention-deficit/hyperactivity disorder (ADHD) and variants in the Lphn3 (Adgrl3) gene (OMIM 616417) have been linked to ADHD. This project utilized a delay-discounting (DD) task to examine the impact of Lphn3 deletion in rats on impulsive choice. "Positive control" measures were also collected in spontaneously hypertensive rats (SHRs), another animal model of ADHD. Methods: For Experiment I, rats were given the option to press one lever for a delayed reward of 3 food pellets or the other lever for an immediate reward of 1 pellet. Impulsive choice was measured as the tendency to discount the larger, delayed reward. We hypothesized that impulsive choice would be greater in the SHR and Lphn3 knockout (KO) rats relative to their control strains - Wistar-Kyoto (WKY) and Lphn3 wildtype (WT) rats, respectively. Results: The results did not completely support the hypothesis, as only the SHRs (but not the Lphn3 KO rats) demonstrated a decrease in the percent choice for the larger reward. Because subsequent trials did not begin until the end of the delay period regardless of which lever was selected, rats were required to wait for the next trial to start even if they picked the immediate lever. Experiment II examined whether the rate of reinforcement influenced impulsive choice by using a DD task that incorporated a 1 s inter-trial interval (ITI) immediately after delivery of either the immediate (1 pellet) or delayed (3 pellet) reinforcer. The results of Experiment II found no difference in the percent choice for the larger reward between Lphn3 KO and WT rats, demonstrating reinforcement rate did not influence impulsive choice in Lphn3 KO rats. Discussion: Overall, there were impulsivity differences among the ADHD models, as SHRs exhibited deficits in impulsive choice, while the Lphn3 KO rats did not.

An assessment of executive function in two different rat models of attention-deficit hyperactivity disorder: Spontaneously hypertensive versus Lphn3 knockout rats.

Attention-deficit/hyperactivity disorder (ADHD) a common neurodevelopmental disorder of childhood and often comorbid with other externalizing disorders (EDs). There is evidence that externalizing behaviors share a common genetic etiology. Recently, a genome-wide, multigenerational sample linked variants in the Lphn3 gene to ADHD and other externalizing behaviors. Likewise, limited research in animal models has provided converging evidence that Lphn3 plays a role in EDs. This study examined the impact of Lphn3 deletion (i.e., Lphn3-/- ) in rats on measures of behavioral control associated with externalizing behavior. Impulsivity was assessed for 30 days via a differential reinforcement of low rates (DRL) task and working memory evaluated for 25 days using a delayed spatial alternation (DSA) task. Data from both tasks were averaged into 5-day testing blocks. We analyzed overall performance, as well as response patterns in just the first and last blocks to assess acquisition and steady-state performance, respectively. "Positive control" measures on the same tasks were measured in an accepted animal model of ADHD-the spontaneously hypertensive rat (SHR). Compared with wildtype controls, Lphn3-/- rats exhibited deficits on both the DRL and DSA tasks, indicative of deficits in impulsive action and working memory, respectively. These deficits were less severe than those in the SHRs, who were profoundly impaired on both tasks compared with their control strain, Wistar-Kyoto rats. The results provide evidence supporting a role for Lphn3 in modulating inhibitory control and working memory, and suggest additional research evaluating the role of Lphn3 in the manifestation of EDs more broadly is warranted.

Chronic naltrexone treatment and ethanol responsivity in outbred rats.

BACKGROUND: Acute naltrexone treatment in rats produces significant alterations in ethanol palatability (increase in the aversiveness of the solution) and ethanol consumption during tests of restricted access (decrease in consumption). The effects of chronic naltrexone exposure, accomplished by implantation of osmotic mini-pumps, were examined in the present study. METHODS: Rats were surgically implanted with intraoral fistulae for taste reactivity testing. The animals were given 2 bottles (distilled water and 10% ethanol, v/v) for 3, 2-week phases: Pre-Drug, Drug, and Post-Drug. After the Pre-Drug phase, rats were assigned to groups (counterbalanced based on ethanol intake) and implanted with a mini-pump containing saline, 7.5 mg/kg/d naltrexone, or 15 mg/kg/d naltrexone. The pumps were removed 2 weeks later. During each 2-week phase, taste reactivity tests with 10% ethanol were conducted at 1, 7, and 14 days (a total of 9 reactivity tests). RESULTS: The 7.5 mg/kg/d dose produced only minor effects on 10% ethanol reactivity and consumption during the Drug phase. The 15 mg/kg/d naltrexone dose generally shifted taste reactivity responding to 10% ethanol in a negative direction and produced a transient decrease in ethanol consumption. The 15 mg/kg/d group significantly increased ethanol consumption beyond the level of consumption by the Saline group when the pumps were removed, although the increase was delayed 48 hours. By the end of the Post-Drug period, this naltrexone group returned to control levels of ethanol consumption. CONCLUSIONS: Chronic naltrexone treatment at 15 mg/kg/d significantly decreased the palatability of a 10% ethanol solution, an effect seen even after drug withdrawal. Naltrexone had a minor effect on ethanol consumption during treatment but did decrease overall levels of fluid consumption. The significant increase in ethanol consumption postdrug by the high-dose naltrexone group, presumably due to receptor up-regulation during treatment, is important and understanding this effect and developing means of overcoming it within a clinical practice would be useful goals.

Effects of chronic estradiol treatment on delayed spatial alternation and differential reinforcement of low rates of responding.

Estrogens have been shown to both enhance and impair cognitive function depending on several factors, including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2 +/- 8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol-treated rats showed a lower ratio of reinforced to nonreinforced presses. These data suggest that chronic estrogen exposure may impair rats' abilities on measures of executive function including working memory and response inhibition.

Cocaine self-administration in male and female rats perinatally exposed to PCBs: Evaluating drug use in an animal model of environmental contaminant exposure.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely impact human health. Ortho-substituted PCBs affect the nervous system, including the brain dopaminergic system. The reinforcing effects of psychostimulants are typically modulated via the dopaminergic system, so this study used a preclinical (i.e., rodent) model to evaluate whether developmental contaminant exposure altered intravenous self-administration (IV SA) for the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 6 or 3 mg/kg/day of PCBs throughout gestation and lactation and compared with nonexposed controls. Rats were trained to lever press for a food reinforcer in an operant chamber under a fixed-ratio 5 (FR5) schedule and later underwent jugular catheterization. Food reinforcers were switched for infusions of 250 µg of cocaine, but the response requirement to earn the reinforcer remained. Active lever presses and infusions were higher in males during response acquisition and maintenance. The same sex effect was observed during later sessions which evaluated responding for cocaine doses ranging from 31.25-500 µg. PCB-exposed males (not females) exhibited an increase in cocaine infusions (with a similar trend in active lever presses) during acquisition, but no PCB-related differences were observed during maintenance, examination of the cocaine dose-response relationship, or progressive ratio (PR) sessions. Overall, these results indicated perinatal PCB exposure enhanced early cocaine drug-seeking in this preclinical model of developmental contaminant exposure (particularly the males), but no differences were seen during later cocaine SA sessions. As such, additional questions regarding substance abuse proclivity may be warranted in epidemiological studies evaluating environmental contaminant exposures. (PsycINFO Database Record

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.

Daily patterns of ethanol drinking in peri-adolescent and adult alcohol-preferring (P) rats.

Alcohol abuse among adolescents continues to be a major health problem for our society. Our laboratory has used the peri-adolescent alcohol-preferring, P, rat as an animal model of adolescent alcohol abuse. Even though peri-adolescent P rats consume more alcohol (g/kg/day) than their adult counterparts, it is uncertain whether their drinking is sufficiently aggregated to result in measurable blood ethanol concentrations (BECs). The objectives of this study were to examine daily alcohol drinking patterns of adolescent and adult, male and female P rats, and to determine whether alcohol drinking episodes were sufficiently aggregated to result in meaningful BECs. Male and female P rats were given 30 days of 24 h free-choice access to alcohol (15%, v/v) and water, with ad lib access to food, starting at the beginning of adolescence (PND 30) or adulthood (PND 90). Water and alcohol drinking patterns were monitored 22 h/day with a "lickometer" set-up. The results indicated that (a) peri-adolescent P rats consumed more water and total fluids than adult P rats, (b) female P rats consumed more water and total fluids than male P rats, (c) there were differences in alcohol, and water, licking patterns between peri-adolescent and adult and female and male P rats, (d) individual licking patterns revealed that alcohol was consumed in bouts often exceeding the amount required to self-administer 1 g/kg of alcohol, and (e) BECs at the end of the dark cycle, on the 30th day of alcohol access, averaged 50 mg%, with alcohol intakes during the last 1 to 2 h averaging 1.2 g/kg. Overall, these findings indicate that alcohol drinking patterns differ across the age and sex of P rats. This suggests that the effectiveness of treatments for reducing excessive alcohol intake may vary depending upon the age and/or sex of the subjects being tested.

Alterations in DRH and DRL performance in rats developmentally exposed to an environmental PCB mixture.

Schedule-controlled responding was examined in offspring of rats exposed to a PCB mixture formulated to mimic the PCB congener profile in fish from the Fox River in Green Bay, WI. Female rats were administered 0, 1, 3, or 6 mg/kg/day of the PCB mixture beginning four weeks prior to breeding until weaning on postnatal day 21. When offspring were approximately 235 days old, they were tested on three different schedules of a differential reinforcement of high rate (DRH) operant task (DRH 2:1, DRH 4:2, and DRH 8:4). DRH testing was followed by testing on the differential reinforcement of low rate (DRL) operant task in which rats had to inhibit responding until 15 s had elapsed (DRL 15) from the previous response in order to obtain a food reinforcer. After completion of DRL 15 testing, 3 days of extinction testing were conducted (DRL EXT) during which no reinforcers were delivered. Developmental exposure to the higher PCB doses resulted in shorter inter-response times (IRTs) and shorter response durations during DRH 8:4, which translated into a greater percentage of reinforced trials. For DRL 15, no significant exposure-related effects were observed on the number of responses or reinforcers earned, or the number or proportion of responses with long or short inter-response times during acquisition or steady state performance. However, during DRL EXT, rats developmentally exposed to the highest PCB dose responded more than controls, produced significantly more short IRT responses, and had a significantly lower proportion of long IRT responses. Overall, exposure to this PCB mixture resulted in increased responding which was suggestive of a deficit in inhibitory control.

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.

Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish.

Each environmental exposure matrix contains a unique mixture of PCB congeners. Since several congener types have multiple and distinct biological actions, it is important to characterize congener profiles in exposure sources. The Fox River Environment and Diet Study (FRIENDS) is assessing the human health effects of consumption of PCB-contaminated fish from the Fox River in northeastern Wisconsin. Concurrent laboratory studies required the formulation of a dosing solution which closely mimicked the human PCB exposure from fish. PCB congener profiles from Fox River walleye were compared to profiles for various theoretical mixtures having different relative percentages of Aroclors by weight. The theoretical mixture which provided the best approximation of the Fox River fish PCB profile contained 35% 1242, 35% 1248, 15% 1254, and 15% 1260. A PCB mixture was formulated to match this theoretical construct, and the congener profile for the mixture of Aroclors was determined by capillary column gas chromatography with electron capture detection (GC/ECD). The relative percent of each congener was compared to the PCB congener profile of the theoretical Aroclor mixture and that for Fox River walleye. The specific congeners differed on average by 17% from the theoretical Aroclor mixture predicted values, and the specific congeners measured in the mixture were on average within 71% of those reported for Fox River fish. The mixture was found to have relatively low AhR activity but high RyR activity. Indirect comparisons suggest that in vivo toxicity was slightly greater than that for Aroclor 1254. This illustrates that Aroclor mixtures are useful for formulating dosing solutions which closely approximate actual environmental exposures.

Effects of ethanol drinking on central nervous system functional activity of alcohol-preferring rats.

The [(14)C]-2-deoxyglucose (2-DG) technique was used to assess the rates of local cerebral glucose utilization (LCGU) in key limbic, cerebral cortical, hippocampal, basal ganglionic, and subcortical regions of alcohol-preferring (P) rats following chronic 24-h free-choice ethanol drinking. Adult male P rats were submitted to (1) 8 continuous weeks of two-bottle access to 15% ethanol and water (E-C group); (2) 8 weeks of identical two-bottle access followed by 2 weeks of ethanol deprivation (E-D group); (3) cycles of 2 weeks of two-bottle ethanol access and 2 weeks of deprivation, repeated for four cycles (E-RD group); or (4) water only treatment [ethanol-naive group (E-N group)]. A single pulse of [(14)C]-2-DG (125 microCi/kg) was administered via a venous catheter, and timed arterial blood samples were collected over 45 min and later assayed for plasma glucose and [(14)C]-2-DG concentrations. Quantitative autoradiography was used to determine [(14)C] densities, and LCGU values were calculated. With the exception of a few small differences in the hippocampus, no significant differences were found in any of the central nervous system (CNS) regions examined among the four experimental groups of P rats. Animals in the E-D group had lower LCGU rates in the anterior hippocampal CA1 subregion than animals in the E-N, E-C, and E-RD groups. In the anterior hippocampal CA3 subregion and the anterior hippocampal dentate gyrus, the E-D group had significantly lower LCGU rates than the E-RD group. Overall, the results of this study indicate that 24-h ethanol-drinking experience has little effect on CNS functional neuronal activity in P rats.

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.

Recent advances in animal models of alcohol craving and relapse.

Animal models designed to examine different facets of alcohol-related behaviors have been developed to study genetic and neurobiological factors underlying alcoholism and alcohol abuse. One goal has been to develop valid, congruent, complementary animal models of alcohol craving and relapse, with the ultimate objective of assessing the effectiveness of pharmacological agents with these models. Animal models of alcohol craving include drug-induced responding (drug reinstatement), cue-induced responding, Pavlovian Spontaneous Recovery (PSR), and appetitive/consummatory responding. A primary experimental approach to study alcohol relapse has been through expression of the Alcohol Deprivation Effect (ADE) following a single deprivation or multiple deprivations. To date, five selectively bred lines of rats have been developed to study alcohol-drinking behavior. These are the ALKO/Alcohol (AA), alcohol-preferring (P), high alcohol-drinking (HAD-1 and HAD-2 replicates), and the Sardinian alcohol-preferring (sP) lines of rats. Findings thus far indicate that only the P line of rats meets all the criteria established for a valid animal model of alcoholism, with progress having been made in characterizing the AA, HAD and sP lines of rats. The focus of the current review will be to analyze the various models of alcohol craving, emphasizing the use of the Indiana University selected rat lines (P and HADs). Overall, the findings indicate substantial progress has been made in developing animal models of alcohol abuse, relapse and craving using these selectively bred rat lines, as well as outbred rats.

Effects of chronic naltrexone treatment in rats on place preference and locomotor activation after acute administration of cocaethylene or ethanol plus cocaine.

When cocaine and ethanol are taken together a cocaine metabolite called cocaethylene is produced. Investigators have determined that cocaine, ethanol, and cocaethylene all produce a conditioned place preference when administered intraperitoneally. On the basis of the moderate success of naltrexone at attenuating the rewarding effects of ethanol and cocaine administered independently, we examined the ability of chronic naltrexone treatment (administered by means of subcutaneous implant across 6 days) to reduce the preference and motor-stimulating effects resulting from intraperitoneal administration of cocaethylene (Experiment 1) and the co-administration of ethanol with cocaine (Experiment 2) in outbred rats. Results demonstrated naltrexone modestly reduced conditioned place preference for cocaethylene but had no effect on the locomotor stimulation resulting from cocaethylene administration. Naltrexone failed to decrease the preference for the chamber paired with co-administration of ethanol and cocaine and did not change the degree of locomotor activation produced by these drugs. These results support the suggestion that naltrexone as a pharmacotherapy to treat co-abuse of ethanol and cocaine in human beings may have limited benefits.

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.

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.