Rex Philpot - Academia.edu (original) (raw)
Papers by Rex Philpot
The use of choline supplementation for the prevention of chemotherapy‐related cognitive impairments
The FASEB Journal, May 1, 2022
The majority of patients who report chemotherapy‐related cognitive deficits are women. Many chemo... more The majority of patients who report chemotherapy‐related cognitive deficits are women. Many chemotherapeutic agents suppress ovarian function, decreasing circulating estrogen. Because estrogen regulates high affinity choline uptake (HACU) and HACU is the rate‐limiting step for acetylcholine (ACh) synthesis, chemotherapeutic agents may indirectly impair cholinergic mediated cognitive processes. ACh suppresses cytokine synthesis, inhibits inflammation and prevents tissue damage and cell death by activating α7 nicotinic ACh receptors (nAChRs), thus impaired HACU and ACh synthesis following chemotherapy may exacerbate the adverse effects of neuroinflammation caused by tumors and chemotherapeutic agents. Since increasing available choline can maintain cholinergic function when demand for the precursor is high, and because choline is a full agonist at α7 nAChRs, increasing dietary choline may protect ACh systems from degeneration by attenuating pro‐inflammatory processes.We have demonstrated that one administration of cyclophosphamide (CYP) and doxorubicin (DOX) impairs HACU in the striatum (STR) and hippocampus (HCC) of non tumor‐bearing (M‐) and tumor‐bearing MMTV‐PyVT (M+) female mice. Further, we have shown that the effect of one administration of CYP+DOX on HACU is prevented by placing mice on a 2% choline diet, and a 2% choline diet slows tumor growth in female M+ mice.The present study sought to determine whether a 2% choline diet could: 1) prevent the manifestation of spatial memory deficits resulting from repeated exposure to CYP (66.7mg/kg i.v.; ≍200mg/m2/wk) and DOX (6.7mg/kg i.v.; ≍20mg/m2/wk); 2) maintain HACU in the frontal cortex (CTX), STR and HCC of mice following 4 weekly administrations of CYP+DOX; 3) prevent reductions in circulating E2 consequent to repeated CYP+DOX exposure; 4) attenuate elevations of circulating cytokines induced by repeated CYP+DOX exposure and/or the presence of tumors; and 5) suppress tumor growth and enhance the antineoplastic effects of CYP+DOX treatment in female M+ mice.Results indicate that M‐ and M+ mice exposed to CYP+DOX exhibit deficits in spatial memory 10‐12 days following 4 weekly injections of CYP+DOX and 5 weeks following the final administration. HACU was reduced in the STR and HCC following a single exposure to CYP+DOX and this effect persisted in the STR. However, reduced HACU in the HCC was transient. Supplementation with a 2% choline diet prevented the manifestation of spatial memory deficits in M‐ and M+ mice and HACU in these mice did not differ from controls, suggesting that impaired HACU mediated the deficit in spatial memory. Although we did not observe an anticipated reduction in circulating estradiol due to CYP+DOX exposure, the regular appearance of proestrous was disrupted in groups exposed to either CYP+DOX or 2% choline diet, suggestive of amenorrhea. Circulating concentrations of cytokines, including G‐CSF, IL6, IP10, MCP1 and RANTES, were altered by the presence of tumors as well as the administration of CYP+DOX. 2% choline significantly reduced circulating concentrations of IL‐5, a cytokine associated with poor prognosis and metastasis, and total tumor volume was lower in mice placed on 2% choline diet when compared to tumor bearing mice on standard diet.
Neurotoxicology, 2017
3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotina... more 3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p< 0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior.
The FASEB Journal, Apr 1, 2012
Addictive drugs can activate systems involved in normal reward-related learning, creating long-la... more Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.
CPI-1189 prevents apoptosis and reduces glial ®brillary acidic protein immunostaining in a TNF-a
Increasing dietary choline to prevent chemotherapy related cognitive deficits and attenuate tumor growth in MMTV‐PyVT mice
The FASEB Journal, 2020
Alcoholism: Clinical and Experimental Research, 2003
Background: Alcohol abuse levels are very high in adolescents, creating a significant societal is... more Background: Alcohol abuse levels are very high in adolescents, creating a significant societal issue. It has been shown that people who begin alcohol use as adolescents are more likely to become addicts than people who initiate alcohol use as adults. It is important to note that the development of addiction in humans is more rapid with initiation in adolescence than in adulthood.Methods: To determine changes in the reinforcing efficacy of alcohol as a function of adolescent development, we used a place‐conditioning paradigm. In this study, we assessed the ability of ethanol to support a conditioned place preference (CPP) or aversion. Animals [postnatal days (PND) 25, 35, 45, and 60] were tested for alcohol‐induced conditioning in response to a range of ethanol doses (0.2, 0.5, 1.0, and 2.0 g/kg intraperitoneally) or saline.Results: In general, there was a trend for alcohol to produce an aversion to the ethanol‐paired compartment at higher doses. These patterns differed significantly...
The role of the nucleus accumbens septi in the establishment of addiction: An attentional perspective
The FASEB Journal, 2001
Exposing timed pregnant rats to shipping stress during late, but not early gestation, leads to offspring with increased activity in the novel open field
The FASEB Journal, 2012
Differential role of CREB in novelty‐seeking behavior by adolescent and adult rats
The FASEB Journal, 2008
Journal of Psychopharmacology, 2021
Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and hum... more Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. Aim: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). Methods: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. Results: DOX and...
High novelty seeking behavior: A rat model of postpartum depression
Postpartum depression (PPD) is a devastating illness occurring in up to 10-20% of women. Despite ... more Postpartum depression (PPD) is a devastating illness occurring in up to 10-20% of women. Despite this, clinical symptoms are often unrecognized and this illness is frequently undiagnosed and untreated. To better understand PPD, the assessment of postpartum neuroendocrine function in intact animals and its relationship to maternal behavior is critical. Unfortunately, the effects of gestational stress and the postpartum decline of ovarian hormones are typically studied in ovariectomized animals following hormone supplementation and withdrawal, excluding any assessment of maternal behavior and postpartum endocrine function. Research has demonstrated that animals who respond to a novel open field with high activity (HR) exhibit hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and prolonged corticosterone secretion in response to stress when compared with low activity (LR) animals. Interestingly, HR animals exhibit a greater tendency to neglect their young when compared to ...
Neuropharmacology, 2013
Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial sympto... more Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial symptoms in patients with spinocerebellar ataxia type 3, but pharmacological evidence in an animal model of olivocerebellar degeneration has not been demonstrated. This study investigated whether varenicline and nicotine were efficacious for attenuating ataxia in rats induced by chemical destruction of the olivocerebellar pathway. Rats were trained to maintain their balance on a rotating rod and walk across a stationary beam; rod and beam performance, locomotor activity, and gait were assessed prior to and after administration of the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP led to an 85% loss of neurons in the inferior olive at one week after administration without evidence of recovery over the following 4 weeks. The lesion was accompanied by a 72% decrease in rotorod activity, a 3.1-fold increase in the time required to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in both forepaw and hindpaw gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) improved rotorod performance by 50%, an effect apparent following the first week of administration, and which did not improve further over time. Nicotine also normalized the increased hindpaw stride width induced by the lesion. The ability of nicotine to alleviate both rotorod and gait deficits induced by 3-AP were prevented by the administration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg) prior to the daily administration of nicotine. The effects of varenicline were dose-related and doses of 1.0 and 3.0 mg free base/kg daily improved rotorod performance by approximately 50% following the first week of administration. Further, varenicline did not alter
Biochemical Pharmacology, 2011
on sustained attention and reversal of pharmacologically-induced attentional impairment in rats p... more on sustained attention and reversal of pharmacologically-induced attentional impairment in rats produced by the NMDA glutamate antagonist dizocilpine (MK-801). Methods: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats then were injected in a repeated measures, counterbalanced design with saline, AZD3480 (0.01, 0.1, 1 mg/kg), dizocilpine (0.05 mg/kg) or their combinations 15 min before the test. In another experiment, as a positive control the effect of donepezil, on pharmacologically-induced attentional impairment was tested. After training for the sustained attention, rats were injected with donezepil (0.01, 0.1 and 1 mg/kg), dizocilpine (0.05 mg/kg) or their combinations and their sustained attention was assessed. Results: The NMDA glutamate antagonist dizocilpine caused a significant (p < 0.0005) impairment in percent correct. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. There was evidence for an inverted U-shaped doseeffect curve inasmuch as the higher 1.0 mg/kg AZD3480 dose did not effectively reverse the dizocilpine-induced impairment. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also caused a significant (0.005) effect by attenuating the dizocilpine-induced attentional impairment. Conclusions: AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. We have previously shown with this signal detection attentional task that methylphenidate also effectively reversed the attentional impairment caused by dizocilpine. Very low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment. Acknowledgments: This work was supported by AstraZeneca.
Grid Crossing: Inability to Compare Activity Levels between Adolescent and Adult Rats
Annals of the New York Academy of Sciences, 2004
Traditionally, studies measuring behavioral activity have used male adult animals and grid crossi... more Traditionally, studies measuring behavioral activity have used male adult animals and grid crossings (GCs) as a representative measure of activity in lieu of total distance moved (TDM). However, using GCs as the dependent measure may not be effective for comparing the activity of animals during development, as they vary significantly in size. The present study examines the reliability of GCs as opposed to TDM as an indicator of locomotor activity for comparisons during ontogeny using a computerized behavioral tracking system (Noldus). Rats (postnatal day[PND] 35, PND 60) were tracked for a period of 3 minutes inside a closed runway. GCs and TDM were measured for the recorded tracks. It was determined that GCs were positively correlated with TDM in the behavioral apparatus, suggesting that GCs is a reliable measure of an individual animal's activity. Using GCs as the dependent measure, no significant differences in activity were observed across age or sex. However, using TDM indicates adolescent rats are significantly more active than their adult counterparts. These data indicate that although the number of GCs is predictive of total activity, the slope of the relationship varies significantly with age, therefore making it inappropriate to use GCs when comparing across ages. Studies that use animals of differing age must be sensitive to baseline differences in locomotor activity.
Monoamine Vesicular Transporters
xPharm: The Comprehensive Pharmacology Reference, 2007
Sigma Receptors
xPharm: The Comprehensive Pharmacology Reference, 2007
Vecuronium
xPharm: The Comprehensive Pharmacology Reference, 2007
Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits
Neurochemical research, Jan 5, 2015
Over the past several decades, research in both humans and animals has established the existence ... more Over the past several decades, research in both humans and animals has established the existence of persistent cognitive deficits resulting from exposure to chemotherapeutic agents. Nevertheless, there has been very little research addressing the treatment of chemotherapy-induced cognitive deficits and there is currently no approved treatment for this condition, often referred to as 'chemo-brain.' Several drugs that enhance cholinergic function and/or increase nicotinic acetylcholine receptor (nAChR) activity have been demonstrated to improve cognitive performance and/or reverse cognitive deficits in animals, findings that have led to the use of these compounds to treat the cognitive deficits present in a variety of disorders including attention deficit disorder, Alzheimer's disease, Parkinson's disease and schizophrenia. Although nAChR agonists have not been assessed for their efficacy in treating chemotherapy-induced cognitive deficits, these drugs have been shown ...
Pharmacology Biochemistry and Behavior, 1999
Substance abuse is a major issue in today's society, and is an issue of critical importance in th... more Substance abuse is a major issue in today's society, and is an issue of critical importance in the adolescent population. Research indicates that substance use is often initiated during the adolescent period, and that brain reward areas are still undergoing changes during this time. Despite this, little research has investigated the effects of repeated drug use on the reward mechanisms of periadolescent animals. For this reason, the present study examined the effects of repeated cocaine administration on the responsiveness of the nucleus accumbens septi (NAcc) to either cocaine or saline challenge. The data indicate that repeated exposure to cocaine produces temporal shifts in the dopaminergic (DAergic) activity of the NAcc, with peak activity occurring earlier. Importantly, following repeated injections of cocaine, saline injections alone elicit increases followed by a subsequent suppression in DA overflow in the NAcc. These results suggest that the context of cocaine administration produces fundamental changes in the way that neurochemical reinforcement mechanisms respond. The expectancy of the drug alone elicits reward-related activity within the NAcc, which may play a critical role in the development of addiction.
The mesolimbic dopamine (DA) system has been implicated in providing the basis of pleasure, guidi... more The mesolimbic dopamine (DA) system has been implicated in providing the basis of pleasure, guiding the general mechanism of reinforcement as well as motivation. Support for these roles have grown from neurochemical research in the field of addiction. It is now well known that DA activity increases in the nucleus accumbens septi (NAcc) with exposure to addictive substances. Moreover, pharmacological manipulation of this system produces predictable changes in the administration of drugs of abuse, as well as natural reinforcers. This system is responsive to natural reinforcers and addiction may be the transference of routine mesolimbic function to environmental stimuli predictive of drug administration. The role of the NAcc in addiction specifically appears to be the facilitation of attention to drug-paired stimuli and addiction may be the behavioral manifestation of conditioned NAcc DA reactivity to the presence of drug-related stimuli. Although these findings have been reported in adults, few stud ies have focused on adolescence, the time when drug use/abuse begins. Adolescents may be particularly susceptible to addiction when considered in the light of this hypothesis. Recent research has revealed that the mesolimbic system of periadolescent animals is undergoing dramatic transition in functional tone. DA receptor and transporter levels are up regulated, synthesis rates are altered, and innervation from prefrontal cortex (PFC), viii involved in regulating tonic and phasic DA activity, is increasing. Consequently, during adolescence there is a dramatic change in tonic DA levels, variations in phasic responses to acute drug administration and alterations in how the system adapts to repeated drug exposure. The present study utilizes the procedures of conditioned place preference, Novelty preference and in vivo microdialysis to determine how this conditioning process changes during the period of adolescence. The results indicate that adolescents are different from adults not only on behavioral measures associated with drug abuse, but in their neurochemical responsiveness to alcohol, and that these differences are related to a general developmental aspect of adolescence that renders them susceptible to addiction.
The use of choline supplementation for the prevention of chemotherapy‐related cognitive impairments
The FASEB Journal, May 1, 2022
The majority of patients who report chemotherapy‐related cognitive deficits are women. Many chemo... more The majority of patients who report chemotherapy‐related cognitive deficits are women. Many chemotherapeutic agents suppress ovarian function, decreasing circulating estrogen. Because estrogen regulates high affinity choline uptake (HACU) and HACU is the rate‐limiting step for acetylcholine (ACh) synthesis, chemotherapeutic agents may indirectly impair cholinergic mediated cognitive processes. ACh suppresses cytokine synthesis, inhibits inflammation and prevents tissue damage and cell death by activating α7 nicotinic ACh receptors (nAChRs), thus impaired HACU and ACh synthesis following chemotherapy may exacerbate the adverse effects of neuroinflammation caused by tumors and chemotherapeutic agents. Since increasing available choline can maintain cholinergic function when demand for the precursor is high, and because choline is a full agonist at α7 nAChRs, increasing dietary choline may protect ACh systems from degeneration by attenuating pro‐inflammatory processes.We have demonstrated that one administration of cyclophosphamide (CYP) and doxorubicin (DOX) impairs HACU in the striatum (STR) and hippocampus (HCC) of non tumor‐bearing (M‐) and tumor‐bearing MMTV‐PyVT (M+) female mice. Further, we have shown that the effect of one administration of CYP+DOX on HACU is prevented by placing mice on a 2% choline diet, and a 2% choline diet slows tumor growth in female M+ mice.The present study sought to determine whether a 2% choline diet could: 1) prevent the manifestation of spatial memory deficits resulting from repeated exposure to CYP (66.7mg/kg i.v.; ≍200mg/m2/wk) and DOX (6.7mg/kg i.v.; ≍20mg/m2/wk); 2) maintain HACU in the frontal cortex (CTX), STR and HCC of mice following 4 weekly administrations of CYP+DOX; 3) prevent reductions in circulating E2 consequent to repeated CYP+DOX exposure; 4) attenuate elevations of circulating cytokines induced by repeated CYP+DOX exposure and/or the presence of tumors; and 5) suppress tumor growth and enhance the antineoplastic effects of CYP+DOX treatment in female M+ mice.Results indicate that M‐ and M+ mice exposed to CYP+DOX exhibit deficits in spatial memory 10‐12 days following 4 weekly injections of CYP+DOX and 5 weeks following the final administration. HACU was reduced in the STR and HCC following a single exposure to CYP+DOX and this effect persisted in the STR. However, reduced HACU in the HCC was transient. Supplementation with a 2% choline diet prevented the manifestation of spatial memory deficits in M‐ and M+ mice and HACU in these mice did not differ from controls, suggesting that impaired HACU mediated the deficit in spatial memory. Although we did not observe an anticipated reduction in circulating estradiol due to CYP+DOX exposure, the regular appearance of proestrous was disrupted in groups exposed to either CYP+DOX or 2% choline diet, suggestive of amenorrhea. Circulating concentrations of cytokines, including G‐CSF, IL6, IP10, MCP1 and RANTES, were altered by the presence of tumors as well as the administration of CYP+DOX. 2% choline significantly reduced circulating concentrations of IL‐5, a cytokine associated with poor prognosis and metastasis, and total tumor volume was lower in mice placed on 2% choline diet when compared to tumor bearing mice on standard diet.
Neurotoxicology, 2017
3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotina... more 3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p< 0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior.
The FASEB Journal, Apr 1, 2012
Addictive drugs can activate systems involved in normal reward-related learning, creating long-la... more Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.
CPI-1189 prevents apoptosis and reduces glial ®brillary acidic protein immunostaining in a TNF-a
Increasing dietary choline to prevent chemotherapy related cognitive deficits and attenuate tumor growth in MMTV‐PyVT mice
The FASEB Journal, 2020
Alcoholism: Clinical and Experimental Research, 2003
Background: Alcohol abuse levels are very high in adolescents, creating a significant societal is... more Background: Alcohol abuse levels are very high in adolescents, creating a significant societal issue. It has been shown that people who begin alcohol use as adolescents are more likely to become addicts than people who initiate alcohol use as adults. It is important to note that the development of addiction in humans is more rapid with initiation in adolescence than in adulthood.Methods: To determine changes in the reinforcing efficacy of alcohol as a function of adolescent development, we used a place‐conditioning paradigm. In this study, we assessed the ability of ethanol to support a conditioned place preference (CPP) or aversion. Animals [postnatal days (PND) 25, 35, 45, and 60] were tested for alcohol‐induced conditioning in response to a range of ethanol doses (0.2, 0.5, 1.0, and 2.0 g/kg intraperitoneally) or saline.Results: In general, there was a trend for alcohol to produce an aversion to the ethanol‐paired compartment at higher doses. These patterns differed significantly...
The role of the nucleus accumbens septi in the establishment of addiction: An attentional perspective
The FASEB Journal, 2001
Exposing timed pregnant rats to shipping stress during late, but not early gestation, leads to offspring with increased activity in the novel open field
The FASEB Journal, 2012
Differential role of CREB in novelty‐seeking behavior by adolescent and adult rats
The FASEB Journal, 2008
Journal of Psychopharmacology, 2021
Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and hum... more Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. Aim: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). Methods: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. Results: DOX and...
High novelty seeking behavior: A rat model of postpartum depression
Postpartum depression (PPD) is a devastating illness occurring in up to 10-20% of women. Despite ... more Postpartum depression (PPD) is a devastating illness occurring in up to 10-20% of women. Despite this, clinical symptoms are often unrecognized and this illness is frequently undiagnosed and untreated. To better understand PPD, the assessment of postpartum neuroendocrine function in intact animals and its relationship to maternal behavior is critical. Unfortunately, the effects of gestational stress and the postpartum decline of ovarian hormones are typically studied in ovariectomized animals following hormone supplementation and withdrawal, excluding any assessment of maternal behavior and postpartum endocrine function. Research has demonstrated that animals who respond to a novel open field with high activity (HR) exhibit hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and prolonged corticosterone secretion in response to stress when compared with low activity (LR) animals. Interestingly, HR animals exhibit a greater tendency to neglect their young when compared to ...
Neuropharmacology, 2013
Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial sympto... more Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial symptoms in patients with spinocerebellar ataxia type 3, but pharmacological evidence in an animal model of olivocerebellar degeneration has not been demonstrated. This study investigated whether varenicline and nicotine were efficacious for attenuating ataxia in rats induced by chemical destruction of the olivocerebellar pathway. Rats were trained to maintain their balance on a rotating rod and walk across a stationary beam; rod and beam performance, locomotor activity, and gait were assessed prior to and after administration of the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP led to an 85% loss of neurons in the inferior olive at one week after administration without evidence of recovery over the following 4 weeks. The lesion was accompanied by a 72% decrease in rotorod activity, a 3.1-fold increase in the time required to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in both forepaw and hindpaw gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) improved rotorod performance by 50%, an effect apparent following the first week of administration, and which did not improve further over time. Nicotine also normalized the increased hindpaw stride width induced by the lesion. The ability of nicotine to alleviate both rotorod and gait deficits induced by 3-AP were prevented by the administration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg) prior to the daily administration of nicotine. The effects of varenicline were dose-related and doses of 1.0 and 3.0 mg free base/kg daily improved rotorod performance by approximately 50% following the first week of administration. Further, varenicline did not alter
Biochemical Pharmacology, 2011
on sustained attention and reversal of pharmacologically-induced attentional impairment in rats p... more on sustained attention and reversal of pharmacologically-induced attentional impairment in rats produced by the NMDA glutamate antagonist dizocilpine (MK-801). Methods: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats then were injected in a repeated measures, counterbalanced design with saline, AZD3480 (0.01, 0.1, 1 mg/kg), dizocilpine (0.05 mg/kg) or their combinations 15 min before the test. In another experiment, as a positive control the effect of donepezil, on pharmacologically-induced attentional impairment was tested. After training for the sustained attention, rats were injected with donezepil (0.01, 0.1 and 1 mg/kg), dizocilpine (0.05 mg/kg) or their combinations and their sustained attention was assessed. Results: The NMDA glutamate antagonist dizocilpine caused a significant (p < 0.0005) impairment in percent correct. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. There was evidence for an inverted U-shaped doseeffect curve inasmuch as the higher 1.0 mg/kg AZD3480 dose did not effectively reverse the dizocilpine-induced impairment. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also caused a significant (0.005) effect by attenuating the dizocilpine-induced attentional impairment. Conclusions: AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. We have previously shown with this signal detection attentional task that methylphenidate also effectively reversed the attentional impairment caused by dizocilpine. Very low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment. Acknowledgments: This work was supported by AstraZeneca.
Grid Crossing: Inability to Compare Activity Levels between Adolescent and Adult Rats
Annals of the New York Academy of Sciences, 2004
Traditionally, studies measuring behavioral activity have used male adult animals and grid crossi... more Traditionally, studies measuring behavioral activity have used male adult animals and grid crossings (GCs) as a representative measure of activity in lieu of total distance moved (TDM). However, using GCs as the dependent measure may not be effective for comparing the activity of animals during development, as they vary significantly in size. The present study examines the reliability of GCs as opposed to TDM as an indicator of locomotor activity for comparisons during ontogeny using a computerized behavioral tracking system (Noldus). Rats (postnatal day[PND] 35, PND 60) were tracked for a period of 3 minutes inside a closed runway. GCs and TDM were measured for the recorded tracks. It was determined that GCs were positively correlated with TDM in the behavioral apparatus, suggesting that GCs is a reliable measure of an individual animal's activity. Using GCs as the dependent measure, no significant differences in activity were observed across age or sex. However, using TDM indicates adolescent rats are significantly more active than their adult counterparts. These data indicate that although the number of GCs is predictive of total activity, the slope of the relationship varies significantly with age, therefore making it inappropriate to use GCs when comparing across ages. Studies that use animals of differing age must be sensitive to baseline differences in locomotor activity.
Monoamine Vesicular Transporters
xPharm: The Comprehensive Pharmacology Reference, 2007
Sigma Receptors
xPharm: The Comprehensive Pharmacology Reference, 2007
Vecuronium
xPharm: The Comprehensive Pharmacology Reference, 2007
Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits
Neurochemical research, Jan 5, 2015
Over the past several decades, research in both humans and animals has established the existence ... more Over the past several decades, research in both humans and animals has established the existence of persistent cognitive deficits resulting from exposure to chemotherapeutic agents. Nevertheless, there has been very little research addressing the treatment of chemotherapy-induced cognitive deficits and there is currently no approved treatment for this condition, often referred to as 'chemo-brain.' Several drugs that enhance cholinergic function and/or increase nicotinic acetylcholine receptor (nAChR) activity have been demonstrated to improve cognitive performance and/or reverse cognitive deficits in animals, findings that have led to the use of these compounds to treat the cognitive deficits present in a variety of disorders including attention deficit disorder, Alzheimer's disease, Parkinson's disease and schizophrenia. Although nAChR agonists have not been assessed for their efficacy in treating chemotherapy-induced cognitive deficits, these drugs have been shown ...
Pharmacology Biochemistry and Behavior, 1999
Substance abuse is a major issue in today's society, and is an issue of critical importance in th... more Substance abuse is a major issue in today's society, and is an issue of critical importance in the adolescent population. Research indicates that substance use is often initiated during the adolescent period, and that brain reward areas are still undergoing changes during this time. Despite this, little research has investigated the effects of repeated drug use on the reward mechanisms of periadolescent animals. For this reason, the present study examined the effects of repeated cocaine administration on the responsiveness of the nucleus accumbens septi (NAcc) to either cocaine or saline challenge. The data indicate that repeated exposure to cocaine produces temporal shifts in the dopaminergic (DAergic) activity of the NAcc, with peak activity occurring earlier. Importantly, following repeated injections of cocaine, saline injections alone elicit increases followed by a subsequent suppression in DA overflow in the NAcc. These results suggest that the context of cocaine administration produces fundamental changes in the way that neurochemical reinforcement mechanisms respond. The expectancy of the drug alone elicits reward-related activity within the NAcc, which may play a critical role in the development of addiction.
The mesolimbic dopamine (DA) system has been implicated in providing the basis of pleasure, guidi... more The mesolimbic dopamine (DA) system has been implicated in providing the basis of pleasure, guiding the general mechanism of reinforcement as well as motivation. Support for these roles have grown from neurochemical research in the field of addiction. It is now well known that DA activity increases in the nucleus accumbens septi (NAcc) with exposure to addictive substances. Moreover, pharmacological manipulation of this system produces predictable changes in the administration of drugs of abuse, as well as natural reinforcers. This system is responsive to natural reinforcers and addiction may be the transference of routine mesolimbic function to environmental stimuli predictive of drug administration. The role of the NAcc in addiction specifically appears to be the facilitation of attention to drug-paired stimuli and addiction may be the behavioral manifestation of conditioned NAcc DA reactivity to the presence of drug-related stimuli. Although these findings have been reported in adults, few stud ies have focused on adolescence, the time when drug use/abuse begins. Adolescents may be particularly susceptible to addiction when considered in the light of this hypothesis. Recent research has revealed that the mesolimbic system of periadolescent animals is undergoing dramatic transition in functional tone. DA receptor and transporter levels are up regulated, synthesis rates are altered, and innervation from prefrontal cortex (PFC), viii involved in regulating tonic and phasic DA activity, is increasing. Consequently, during adolescence there is a dramatic change in tonic DA levels, variations in phasic responses to acute drug administration and alterations in how the system adapts to repeated drug exposure. The present study utilizes the procedures of conditioned place preference, Novelty preference and in vivo microdialysis to determine how this conditioning process changes during the period of adolescence. The results indicate that adolescents are different from adults not only on behavioral measures associated with drug abuse, but in their neurochemical responsiveness to alcohol, and that these differences are related to a general developmental aspect of adolescence that renders them susceptible to addiction.