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.

Working memory and hippocampal expression of BDNF, ARC, and P-STAT3 in rats: effects of diet and exercise.

OBJECTIVES: Mounting evidence suggests diet and exercise influence learning and memory (LM). We compared a high-fat, high-sucrose Western diet (WD) to a plant-based, amylose/amylopectin blend, lower-fat diet known as the Daniel Fast (DF) in rats with and without regular aerobic exercise on a task of spatial working memory (WM). METHODS: Rats were randomly assigned to the WD or DF at 6 weeks of age. Exercised rats (WD-E, DF-E) ran on a treadmill 3 times/week for 30 min while the sedentary rats did not (WD-S, DF-S). Rats adhered to these assignments for 12 weeks, inclusive of ab libitum food intake, after which mild food restriction was implemented to encourage responding during WM testing. For nine months, WM performance was assessed once daily, six days per week, after which hippocampal sections were collected for subsequent analysis of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal protein (ARC), and signal transducer and activator of transcription 3 (P-STAT3, Tyr705). RESULTS: DF-E rats exhibited the best DSA performance. Surprisingly, the WD-S group outperformed the WD-E group, but had significantly lower BDNF and ARC relative to the DF-S group, with a similar trend from the WD-E group. P-STAT3 expression was also significantly elevated in the WD-S group compared to both the DF-S and WD-E groups. DISCUSSION: These results support previous research demonstrating negative effects of the WD on spatial LM, demonstrate the plant-based DF regimen combined with chronic aerobic exercise produces measurable WM and neuroprotective benefits, and suggest the need to carefully design exercise prescriptions to avoid over-stressing individuals making concurrent dietary changes.

Cerebellar Modulation of Mesolimbic Dopamine Transmission Is Functionally Asymmetrical.

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed potential amperometry with carbon fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.

Comparing phasic dopamine dynamics in the striatum, nucleus accumbens, amygdala, and medial prefrontal cortex.

Midbrain dopaminergic neurons project to and modulate multiple highly interconnected modules of the basal ganglia, limbic system, and frontal cortex. Dopamine regulates behaviors associated with action selection in the striatum, reward in the nucleus accumbens (NAc), emotional processing in the amygdala, and executive functioning in the medial prefrontal cortex (mPFC). The multifunctionality of dopamine likely occurs at the individual synapses, with varied levels of phasic dopamine release acting on different receptor populations. This study aimed to characterize specific aspects of stimulation-evoked phasic dopamine transmission, beyond simple dopamine release, using in vivo fixed potential amperometry with carbon fiber recording microelectrodes positioned in either the dorsal striatum, NAc, amygdala, or mPFC of anesthetized mice. To summarize results, the present study found that the striatum and NAc had increased stimulation-evoked phasic dopamine release, faster dopamine uptake (leading to restricted dopamine diffusion), weaker autoreceptor functioning, greater supply levels of available dopamine, and increased dopaminergic responses to DAT blockade compared to the amygdala and mPFC. Overall, these findings indicate that phasic dopamine may have different modes of communication between striatal and corticolimbic regions, with the first being profuse in concentration, rapid, and synaptically confined and the second being more limited in concentration but longer lasting and spatially dispersed. An improved understanding of regional differences in dopamine transmission can lead to more efficient treatments for disorders related to dopamine dysfunction.

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.

Indirect and direct cannabinoid agonists differentially affect mesolimbic dopamine release and related behaviors.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

Sex Differences and Effects of Predictive Cues on Delayed Punishment Discounting.

The majority of the research studying punishment has focused on an aversive stimulus delivered immediately after an action. However, in real-world decision-making, negative consequences often occur long after a decision has been made. This can engender myopic decisions that fail to appropriately respond to consequences. Whereas discounting of delayed rewards has been well studied in both human and animal models, systematic discounting of delayed consequences remains largely unexplored. To address this gap in the literature, we developed the delayed punishment decision-making task. Rats chose between a small, single-pellet reinforcer and a large, three-pellet reinforcer accompanied by a mild foot shock. The shock was preceded by a delay, which systematically increased throughout the session (0, 4, 8, 12, 16 s). On average, rats discounted the negative value of delayed punishment, as indicated by increased choice of the large, punished reward as the delay preceding the shock lengthened. Female rats discounted delayed punishment less than males, and this behavior was not influenced by estrous cycling. The addition of a cue light significantly decreased the undervaluation of delayed consequences for both sexes. Finally, there was no correlation between the discounting of delayed punishments and a traditional reward delay discounting task for either sex. These data indicate that the ability of punishment to regulate decision-making is attenuated when punishment occurs later in time. This task provides an avenue for exploration of the neural circuitry underlying the devaluation of delayed punishment and may assist in developing treatments for substance use disorders.

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.

Nutrient Intake and Physical Exercise Significantly Impact Physical Performance, Body Composition, Blood Lipids, Oxidative Stress, and Inflammation in Male Rats.

BACKGROUND: Humans consuming a purified vegan diet known as the "Daniel Fast" realize favorable changes in blood lipids, oxidative stress, and inflammatory biomarkers, with subjective reports of improved physical capacity. OBJECTIVE: We sought to determine if this purified vegan diet was synergistic with exercise in male rats. METHODS: Long⁻Evans rats (n = 56) were assigned to be exercise trained (+E) by running on a treadmill three days per week at a moderate intensity or to act as sedentary controls with normal activity. After the baseline physical performance was evaluated by recording run time to exhaustion, half of the animals in each group were fed ad libitum for three months a purified diet formulated to mimic the Daniel Fast (DF) or a Western Diet (WD). Physical performance was evaluated again at the end of month 3, and body composition was assessed using dual-energy x-ray absorptiometry. Blood was collected for measurements of lipids, oxidative stress, and inflammatory biomarkers. RESULTS: Physical performance at the end of month 3 was higher compared to baseline for both exercise groups (p < 0.05), with a greater percent increase in the DF + E group (99%) than in the WD + E group (51%). Body fat was lower in DF than in WD groups at the end of month 3 (p < 0.05). Blood triglycerides, cholesterol, malondialdehyde, and advanced oxidation protein products were significantly lower in the DF groups than in the WD groups (p < 0.05). No significant differences were noted in cytokines levels between the groups (p > 0.05), although IL-1ß and IL-10 were elevated three-fold and two-fold in the rats fed the WD compared to the DF rats, respectively. CONCLUSIONS: Compared to a WD, a purified diet that mimics the vegan Daniel Fast provides significant anthropometric and metabolic benefits to rats, while possibly acting synergistically with exercise training to improve physical performance. These findings highlight the importance of macronutrient composition and quality in the presence of ad libitum food intake.

A Phosphatidylserine Source of Docosahexanoic Acid Improves Neurodevelopment and Survival of Preterm Pigs.

The amount, composition, and sources of nutrition support provided to preterm infants is critical for normal growth and development, and particularly for structural and functional neurodevelopment. Although omega-3 long chain polyunsaturated fatty acids (LC-PUFA), and particularly docosahexanoic acid (DHA), are considered of particular importance, results from clinical trials with preterm infants have been inconclusive because of ethical limitations and confounding variables. A translational large animal model is needed to understand the structural and functional responses to DHA. Neurodevelopment of preterm pigs was evaluated in response to feeding formulas to term-equivalent age supplemented with DHA attached to phosphatidylserine (PS-DHA) or sunflower oil as the placebo. Newborn term pigs were used as a control for normal in utero neurodevelopment. Supplementing formula with PS-DHA increased weight of the brain, and particularly the cerebellum, at term-equivalent age compared with placebo preterm pigs (P's < 0.10 and 0.05 respectively), with a higher degree of myelination in all regions of the brain examined (all p < 0.06). Brains of pigs provided PS-DHA were similar in weight to newborn term pigs. Event-related brain potentials and performance in a novel object recognition test indicated the PS-DHA supplement accelerated development of sensory pathways and recognition memory compared with placebo preterm pigs. The PS-DHA did not increase weight gain, but was associated with higher survival. The benefits of PS-DHA include improving neurodevelopment and possibly improvement of survival, and justify further studies to define dose-response relations, compare benefits associated with other sources of DHA, and understand the mechanisms underlying the benefits and influences on the development of other tissues and organ systems.

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.