Nicole Schramm-sapyta | Duke University (original) (raw)

Papers by Nicole Schramm-sapyta

Nutrition Research, 2014

Using archival data, we conducted a secondary analysis to examine race-differences in the relatio... more Using archival data, we conducted a secondary analysis to examine race-differences in the relation of serum vitamins A, C, E and β-carotene to insulin resistance (IR), fasting insulin and glucose, high sensitivity C-reactive protein (hsCRP), and leukocyte count in 176 non-smoking, healthy, white and African American (AA) adults aged 18-65 years (48% women, 33% AA). We hypothesized that micronutrient concentrations would be associated with early risk markers of cardiometabolic diseases in a race-dependent manner. Fasting blood samples were analyzed for micronutrients, insulin, glucose, hsCRP, and leukocyte count. Insulin resistance was estimated using the homeostatic model assessment (HOMA). After adjusting for age, body mass index, gender, educational level, use of vitamin supplements, alcohol intake, leisure time physical activity, menopausal status, and total cholesterol, we observed that β-carotene was significantly associated with insulin resistance and fasting insulin in a race-dependent manner. Among AA, lower β-carotene levels were associated with higher estimates of insulin resistance and fasting insulin; whereas, these same associations were not significant for whites. Race also significantly moderated the relation of vitamin C to leukocyte count, with lower vitamin C being associated with higher leukocyte count only in AA but not whites. For all subjects, lower β-carotene was associated with higher hsCRP. In AA, but not whites, lower levels of β-carotene and vitamin C were significantly associated with early risk markers implicated in cardiometabolic conditions and cancer. Whether or not lower levels of micronutrients contribute uniquely to racial health disparities is a worthwhile aim for future research.

Psychopharmacology, Apr 1, 2004

Neurotoxicology and Teratology, Jul 1, 2011

The Journal of Neuroscience, Mar 22, 2006

Criminal Behaviour and Mental Health, Jan 30, 2023

BackgroundA growing body of literature demonstrates strong association between poor mental health... more BackgroundA growing body of literature demonstrates strong association between poor mental health and criminal recidivism, but research from county jails is limited.AimsOur aim was to examine the relationship between re‐arrest and severe mental illnesses—schizophrenia, bipolar disorder and major depressive disorder—together and separately and with substance use disorders, separately and as comorbid conditions, in a mid‐sized county jail cohort in the southeastern United States.MethodsWe examined the full cohort of 8097 individuals who were booked into the County Detention Facility between 31 January 2014 and 31 January 2015. Their incarceration data were merged with data from the local health system to investigate the presence of severe mental illness and substance use disorder diagnoses. Re‐arrest data were tracked for 4 years after the index arrest.ResultsApproximately 60% of the cohort was re‐arrested within 4 years. People with substance use disorders, with or without severe mental illness, had higher re‐arrest rates than those with severe mental illness alone or neither diagnosis. Drug‐associated arrests did not explain this finding.ConclusionsUsing detailed mental illness diagnosis data with a complete cohort of detained arrestees, we have shown the wide range of need among such individuals. By demonstrating that drug‐associated crimes per se do not drive repeated arrest, we underscore a need to examine other factors that promote the cycle of repeated arrest in this population. Each individual requires treatment tailored to their personal psychiatric and criminogenic needs.

Journal of Correctional Health Care

Frontiers in behavioral neuroscience, Mar 7, 2024

Alcoholism: Clinical and Experimental Research, May 1, 2008

Background-Alcohol abuse disorders emerge over time with repeated consumption of ethanol, but not... more Background-Alcohol abuse disorders emerge over time with repeated consumption of ethanol, but not all ethanol drinkers develop these disorders. There are pre-existing characteristics that indicate which drinkers are most likely to abuse alcohol. Adolescence, novelty seeking, and high stress reactivity are among the characteristics of the most vulnerable individuals. In addition, an individual's response to his or her first exposure to the drug influences future consumption. We assessed an array of behavioral and hormonal characteristics in adolescent (28-day-old) male rats before exposure to ethanol, and then determined which rats were most prone to high levels of alcohol drinking. Methods-The assessments consisted of measures of anxiety (elevated plus maze), response to novelty (open field locomotion, novel object exploration), and circulating corticosterone levels after mild restraint and after the elevated plus maze task. After this test battery, the rats were placed in lickometer cages nightly (5 PM to 9 AM) for evaluation of fluid consumption. Rats were first habituated to the cages with water in the lickometer bottles, and then given 10% (v/v) ethanol for 3 nights as the only available fluid. After this forced ethanol exposure, the rats were allowed to choose between 8% ethanol and water for 10 consecutive nights. After 2 nights of abstinence, the rats were again placed in the lickometer cages and given a choice between 8% ethanol and water to assess ethanol consumption in response to alcohol deprivation, a measure of relapse-like behavior. Results-Ethanol consumption on the third day of forced consumption was significantly correlated with ethanol consumption on days 8 to 10 of the choice phase, which in turn was significantly correlated to relapse-like consumption. Preference for ethanol was also significantly correlated with early consumption. Novel object exploration, open field activity, open arm time in the elevated plus maze, initial water consumption, and circulating corticosterone levels did not significantly predict deprivation-stimulated consumption. Conclusions-These results suggest that consumption during early exposure to ethanol establishes a pattern leading to development of increased alcohol consumption and preference in adolescent male rats. In addition, they represent an animal model of the well-described observation that humans who consume large quantities of ethanol during early exposure are the most likely to repeat heave drinking behavior. Furthermore, early consumption is distinct from novelty seeking, anxiety, and stress hormone levels which are also thought to contribute to vulnerability to alcoholism.

Behavioural Brain Research, Nov 1, 2013

The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior th... more The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior that is based on an approach/avoidance conflict between the drive to explore novel areas and an aversion to brightly lit, open spaces. We used the LD test to investigate developmental differences in behavior between adolescent (postnatal day (PN) 28-34) and adult (PN67-74) male rats. We investigated whether LD behavioral measures reflect anxiety-like behavior similarly in each age group using factor analysis and multiple regression. These analyses showed that time in the light compartment, percent distance in the light, rearing, and latency to emerge into the light compartment were measures of anxiety-like behavior in each age group, while total distance traveled and distance in the dark compartment provided indices of locomotor activity. We then used these measures to assess developmental differences in baseline LD behavior and the response to anxiogenic drugs. Adolescent rats emerged into the light compartment more quickly than adults and made fewer pokes into the light compartment. These age differences could reflect greater risk taking and less risk assessment in adolescent rats than adults. Adolescent rats were less sensitive than adults to the anxiogenic effects of the benzodiazepine inverse agonist N-methyl-βcarboline-3-carboxamide (FG-7142) and the α 2 adrenergic antagonist yohimbine on anxiety-like behaviors validated by factor analysis, but locomotor variables were similarly affected. These data support the results of the factor analysis and indicate that GABAergic and noradrenergic modulation of LD anxiety-like behavior may be immature during adolescence.

Psychopharmacology, Jun 23, 2009

Background and rationale-Epidemiological evidence suggests that people who begin experimenting wi... more Background and rationale-Epidemiological evidence suggests that people who begin experimenting with drugs of abuse during early adolescence are more likely to develop substance use disorders (SUDs), but this correlation does not guarantee causation. Animal models, in which age of onset can be tightly controlled, offer a platform for testing causality. Many animal models address drug effects that might promote or discourage drug intake and drug-induced neuroplasticity. Methods-We have reviewed the preclinical literature to investigate whether adolescent rodents are differentially sensitive to rewarding, reinforcing, aversive, locomotor, and withdrawal-induced effects of drugs of abuse. Results and conclusions-The rodent model literature consistently suggests that the balance of rewarding and aversive effects of drugs of abuse is tipped toward reward in adolescence. However, increased reward does not consistently lead to increased voluntary intake: age effects on voluntary intake are drug and method specific. On the other hand, adolescents are consistently less sensitive to withdrawal effects, which could protect against compulsive drug seeking. Studies examining neuronal function have revealed several age-related effects but have yet to link these effects to vulnerability to SUDs. Taken together, the findings suggest factors which may promote recreational drug use in adolescents, but evidence relating to pathological drug-seeking behavior is lacking. A call is made for future studies to address this gap using behavioral models of pathological drug seeking and for neurobiologic studies to more directly link age effects to SUD vulnerability.

Alcoholism: Clinical and Experimental Research, Sep 22, 2010

Background-Many people experiment with alcohol and other drugs of abuse during their teenage year... more Background-Many people experiment with alcohol and other drugs of abuse during their teenage years. Epidemiological evidence suggests that younger initiates into drug taking are more likely to develop problematic drug seeking behavior, including binge and other high-intake behaviors. The level of drug intake for any individual depends on the balance of rewarding and aversive effects of the drug in that individual. Multiple rodent studies have demonstrated that aversive effects of drugs of abuse are reduced in adolescent compared to adult animals. In the present study we addressed two key questions: First, do reduced aversive effects of ethanol in younger rats correlate with increased ethanol consumption? Second, are the reduced aversive effects in adolescents attributable to reduced sensitivity to ethanol's physiological effects? Methods-Adolescent and adult rats were tested for ethanol conditioned taste aversion followed by a voluntary drinking period, including post-deprivation consumption. Multivariate regression was used to assess correlations. In separate experiments, adolescent and adult rats were tested for their sensitivity to the hypothermic and sedative effects of ethanol, and for blood ethanol concentrations (BECs). Results-We observed that in adolescent rats but not adults, taste aversion was inversely correlated with post-deprivation consumption. Adolescents also exhibited a greater increase in consumption after deprivation than adults. Furthermore, the age difference in ethanol conditioned taste aversion was not attributable to differences in hypothermia, sedation, or BECs. Conclusions-These results suggest that during adolescence, individuals that are insensitive to aversive effects are most likely to develop problem drinking behaviors. These results underscore the importance of the interaction between developmental stage and individual variation in sensitivity to alcohol.

Developmental Cognitive Neuroscience, Oct 1, 2011

Drugs of abuse induce complex motivational states in their users which have been shown to vary de... more Drugs of abuse induce complex motivational states in their users which have been shown to vary developmentally. In addition to developmental variation, interindividual variation in the rewarding and aversive effects of drugs of abuse is an important consideration. A rat model was used to assess whether the conditioned rewarding/aversive effects of cocaine were maintained as individuals matured from adolescence into adulthood. We tested rats in the cocaine conditioned taste aversion task as adolescents and again in adulthood. We observed a wide range of approach/avoidance behaviors in this task, and also observed that the relative interindividual differences in approach/avoidance are remarkably stable across the two developmental stages. Furthermore, we observed that these interindividual differences are not attributable to individual differences in cocaine-induced locomotor effects or individual differences in blood or brain cocaine levels. Taken together, these findings indicate that sensitivity to cocaine's motivational effects is stable across development and part of a unique neurological process.

Pharmacology, Biochemistry and Behavior, Apr 1, 2012

Delay discounting is a key component of many psychiatric disorders, including drug addiction, com... more Delay discounting is a key component of many psychiatric disorders, including drug addiction, compulsive gambling, ADHD, and obesity. However, its underlying mechanisms are not yet fully characterized. One impediment to full characterization of such mechanisms is the fact that rodent models of the task are often complicated and involve extended training of subjects, often requiring more than a month before a stable baseline is obtained. We have therefore characterized a version of the rodent delay discounting task which generates data more quickly than most other published versions. In this version of the task, learning of the operant response is established prior to introduction of the delay component, and delay is tested across subsequent daily sessions with a single delay length per day. We demonstrate here that this version generates a delay discounting curve similar to many published tasks, and is sensitive to changes in reward magnitude and to chronic treatment with cocaine. Furthermore, we present a detailed description of the withinsession patterns of behavior in the task, which provides evidence of within-session learning and establishment of stable response patterns. This faster version of the delay discounting task will facilitate future studies involving pharmacological, electrophysiological, and other mechanistic studies of the underlying basis of this important disease process.

Pharmacology, Biochemistry and Behavior, Jun 1, 2006

In humans, most drug use is initiated during adolescence and adolescent users are more likely to ... more In humans, most drug use is initiated during adolescence and adolescent users are more likely to become drug-dependent than adult users. Repeated, high levels of use are required for the transition from use to addiction. Individual levels of drug use are thought to result from a balance between the pleasant or rewarding and the unpleasant or aversive properties of the drug. Repeated high levels of drug use are required for the transition from drug use to dependence. We hypothesized that diminished aversive effects of drugs of abuse during adolescence might be one reason for higher rates of use and addiction during this phase. We therefore tested adolescent and adult CD rats in single-dose cocaine conditioned taste aversion (CTA) at a range of doses (10-40 mg/kg), and examined whether various behavioral markers of addiction vulnerability were correlated to outcome in cocaine CTA. We found that adolescents are indeed less susceptible to cocaine CTA. In fact, age was the predominant predictor of CTA outcome, predominating over measures of novelty-seeking, anxiety, and stress hormone levels, which are all known to be related to drug intake in other models. Furthermore, we found that adolescent rats are also less susceptible to conditioned taste aversion to a low dose of a non-addictive substance, lithium chloride. These results suggest that one explanation for elevated drug use and addiction among adolescents is reduced aversive or use-limiting effects of the drugs. This contributes to our understanding of why adolescence is a particularly vulnerable period for development of drug abuse.

Psychopharmacology, Oct 26, 2013

Rationale-Vulnerability to alcoholism is determined by many factors, including the balance of ple... more Rationale-Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase drinking, aversive sensations reduce it. Both female sex and adolescent age are associated with fewer uselimiting effects of ethanol and more rapid development of alcohol abuse. Objectives-This study assessed voluntary drinking and the aversive effects of alcohol in adolescent and adult male and female rats, to determine whether these measures are inversely related across the sexes and development. Methods-Voluntary drinking of 20% ethanol in an every-other-day (EOD) availability pattern and the full dose-response relationship of ethanol CTA were assessed in male and female adolescent and adult rats. Results-CTA was sex-specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and interindividual differences in consumption patterns but was not sex-specific. Adolescents initially drank more than adults, exhibited greater day-today variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns. Conclusions-These results show that the evolution of drinking patterns differs in adolescents and adults. While a small cohort of adults establish high consumption patterns quickly, most adolescents drink at high levels initially and show marked deprivation-induced increases, but a significant percentage reduce intake as they become adult. High drinking adolescents do not ramp up like adults, but maintain adolescent drinking patterns into adulthood. Sex differences were not observed in EOD drinking during either adolescence or adulthood.

Neuropsychopharmacology, Oct 5, 2005

Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous rese... more Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.

Neuropsychopharmacology, Oct 5, 2005

Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous rese... more Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.

Criminal Behaviour and Mental Health, Jan 30, 2023

Psychopharmacology, 2011

Rationale-Early-onset drug taking is associated with increased likelihood of addiction, but it is... more Rationale-Early-onset drug taking is associated with increased likelihood of addiction, but it is unclear whether early onset is causal in development of addiction. Many other factors are associated with increased risk of addiction and also promote early intake. Here, a rodent model is used to explore the causality of early onset in development of self-administration and addictionlike behavior and to examine factors that promote self-administration. Methods-We used cocaine self-administration to examine drug taking and addiction-like behavior in adolescent and adult rats a priori characterized for their locomotor responses to novelty and cocaine and behavior in the light-dark task. Results-Adolescent animals initially sought more cocaine than adults. However, as the adolescents matured, their intake fell and they did not differ from adults in terms of unreinforced lever-pressing, extinction or reinstatement behavior. For both age groups, self-administration was positively correlated with the locomotor response to novelty, the locomotor response to cocaine, and with time in light in the light-dark task. The rats that were insensitive to cocaine's locomotor effects and that spent the least time in light in the light-dark task sought the least cocaine, appearing to be "protected" from the reinforcing effects of cocaine. There was no difference between the two age groups in appearance of this "protected" phenotype.

Nutrition Research, 2014

Using archival data, we conducted a secondary analysis to examine race-differences in the relatio... more Using archival data, we conducted a secondary analysis to examine race-differences in the relation of serum vitamins A, C, E and β-carotene to insulin resistance (IR), fasting insulin and glucose, high sensitivity C-reactive protein (hsCRP), and leukocyte count in 176 non-smoking, healthy, white and African American (AA) adults aged 18-65 years (48% women, 33% AA). We hypothesized that micronutrient concentrations would be associated with early risk markers of cardiometabolic diseases in a race-dependent manner. Fasting blood samples were analyzed for micronutrients, insulin, glucose, hsCRP, and leukocyte count. Insulin resistance was estimated using the homeostatic model assessment (HOMA). After adjusting for age, body mass index, gender, educational level, use of vitamin supplements, alcohol intake, leisure time physical activity, menopausal status, and total cholesterol, we observed that β-carotene was significantly associated with insulin resistance and fasting insulin in a race-dependent manner. Among AA, lower β-carotene levels were associated with higher estimates of insulin resistance and fasting insulin; whereas, these same associations were not significant for whites. Race also significantly moderated the relation of vitamin C to leukocyte count, with lower vitamin C being associated with higher leukocyte count only in AA but not whites. For all subjects, lower β-carotene was associated with higher hsCRP. In AA, but not whites, lower levels of β-carotene and vitamin C were significantly associated with early risk markers implicated in cardiometabolic conditions and cancer. Whether or not lower levels of micronutrients contribute uniquely to racial health disparities is a worthwhile aim for future research.

Psychopharmacology, Apr 1, 2004

Neurotoxicology and Teratology, Jul 1, 2011

The Journal of Neuroscience, Mar 22, 2006

Criminal Behaviour and Mental Health, Jan 30, 2023

BackgroundA growing body of literature demonstrates strong association between poor mental health... more BackgroundA growing body of literature demonstrates strong association between poor mental health and criminal recidivism, but research from county jails is limited.AimsOur aim was to examine the relationship between re‐arrest and severe mental illnesses—schizophrenia, bipolar disorder and major depressive disorder—together and separately and with substance use disorders, separately and as comorbid conditions, in a mid‐sized county jail cohort in the southeastern United States.MethodsWe examined the full cohort of 8097 individuals who were booked into the County Detention Facility between 31 January 2014 and 31 January 2015. Their incarceration data were merged with data from the local health system to investigate the presence of severe mental illness and substance use disorder diagnoses. Re‐arrest data were tracked for 4 years after the index arrest.ResultsApproximately 60% of the cohort was re‐arrested within 4 years. People with substance use disorders, with or without severe mental illness, had higher re‐arrest rates than those with severe mental illness alone or neither diagnosis. Drug‐associated arrests did not explain this finding.ConclusionsUsing detailed mental illness diagnosis data with a complete cohort of detained arrestees, we have shown the wide range of need among such individuals. By demonstrating that drug‐associated crimes per se do not drive repeated arrest, we underscore a need to examine other factors that promote the cycle of repeated arrest in this population. Each individual requires treatment tailored to their personal psychiatric and criminogenic needs.

Journal of Correctional Health Care

Frontiers in behavioral neuroscience, Mar 7, 2024

Alcoholism: Clinical and Experimental Research, May 1, 2008

Background-Alcohol abuse disorders emerge over time with repeated consumption of ethanol, but not... more Background-Alcohol abuse disorders emerge over time with repeated consumption of ethanol, but not all ethanol drinkers develop these disorders. There are pre-existing characteristics that indicate which drinkers are most likely to abuse alcohol. Adolescence, novelty seeking, and high stress reactivity are among the characteristics of the most vulnerable individuals. In addition, an individual's response to his or her first exposure to the drug influences future consumption. We assessed an array of behavioral and hormonal characteristics in adolescent (28-day-old) male rats before exposure to ethanol, and then determined which rats were most prone to high levels of alcohol drinking. Methods-The assessments consisted of measures of anxiety (elevated plus maze), response to novelty (open field locomotion, novel object exploration), and circulating corticosterone levels after mild restraint and after the elevated plus maze task. After this test battery, the rats were placed in lickometer cages nightly (5 PM to 9 AM) for evaluation of fluid consumption. Rats were first habituated to the cages with water in the lickometer bottles, and then given 10% (v/v) ethanol for 3 nights as the only available fluid. After this forced ethanol exposure, the rats were allowed to choose between 8% ethanol and water for 10 consecutive nights. After 2 nights of abstinence, the rats were again placed in the lickometer cages and given a choice between 8% ethanol and water to assess ethanol consumption in response to alcohol deprivation, a measure of relapse-like behavior. Results-Ethanol consumption on the third day of forced consumption was significantly correlated with ethanol consumption on days 8 to 10 of the choice phase, which in turn was significantly correlated to relapse-like consumption. Preference for ethanol was also significantly correlated with early consumption. Novel object exploration, open field activity, open arm time in the elevated plus maze, initial water consumption, and circulating corticosterone levels did not significantly predict deprivation-stimulated consumption. Conclusions-These results suggest that consumption during early exposure to ethanol establishes a pattern leading to development of increased alcohol consumption and preference in adolescent male rats. In addition, they represent an animal model of the well-described observation that humans who consume large quantities of ethanol during early exposure are the most likely to repeat heave drinking behavior. Furthermore, early consumption is distinct from novelty seeking, anxiety, and stress hormone levels which are also thought to contribute to vulnerability to alcoholism.

Behavioural Brain Research, Nov 1, 2013

The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior th... more The light/dark (LD) test is a commonly used rodent test of unconditioned anxiety-like behavior that is based on an approach/avoidance conflict between the drive to explore novel areas and an aversion to brightly lit, open spaces. We used the LD test to investigate developmental differences in behavior between adolescent (postnatal day (PN) 28-34) and adult (PN67-74) male rats. We investigated whether LD behavioral measures reflect anxiety-like behavior similarly in each age group using factor analysis and multiple regression. These analyses showed that time in the light compartment, percent distance in the light, rearing, and latency to emerge into the light compartment were measures of anxiety-like behavior in each age group, while total distance traveled and distance in the dark compartment provided indices of locomotor activity. We then used these measures to assess developmental differences in baseline LD behavior and the response to anxiogenic drugs. Adolescent rats emerged into the light compartment more quickly than adults and made fewer pokes into the light compartment. These age differences could reflect greater risk taking and less risk assessment in adolescent rats than adults. Adolescent rats were less sensitive than adults to the anxiogenic effects of the benzodiazepine inverse agonist N-methyl-βcarboline-3-carboxamide (FG-7142) and the α 2 adrenergic antagonist yohimbine on anxiety-like behaviors validated by factor analysis, but locomotor variables were similarly affected. These data support the results of the factor analysis and indicate that GABAergic and noradrenergic modulation of LD anxiety-like behavior may be immature during adolescence.

Psychopharmacology, Jun 23, 2009

Background and rationale-Epidemiological evidence suggests that people who begin experimenting wi... more Background and rationale-Epidemiological evidence suggests that people who begin experimenting with drugs of abuse during early adolescence are more likely to develop substance use disorders (SUDs), but this correlation does not guarantee causation. Animal models, in which age of onset can be tightly controlled, offer a platform for testing causality. Many animal models address drug effects that might promote or discourage drug intake and drug-induced neuroplasticity. Methods-We have reviewed the preclinical literature to investigate whether adolescent rodents are differentially sensitive to rewarding, reinforcing, aversive, locomotor, and withdrawal-induced effects of drugs of abuse. Results and conclusions-The rodent model literature consistently suggests that the balance of rewarding and aversive effects of drugs of abuse is tipped toward reward in adolescence. However, increased reward does not consistently lead to increased voluntary intake: age effects on voluntary intake are drug and method specific. On the other hand, adolescents are consistently less sensitive to withdrawal effects, which could protect against compulsive drug seeking. Studies examining neuronal function have revealed several age-related effects but have yet to link these effects to vulnerability to SUDs. Taken together, the findings suggest factors which may promote recreational drug use in adolescents, but evidence relating to pathological drug-seeking behavior is lacking. A call is made for future studies to address this gap using behavioral models of pathological drug seeking and for neurobiologic studies to more directly link age effects to SUD vulnerability.

Alcoholism: Clinical and Experimental Research, Sep 22, 2010

Background-Many people experiment with alcohol and other drugs of abuse during their teenage year... more Background-Many people experiment with alcohol and other drugs of abuse during their teenage years. Epidemiological evidence suggests that younger initiates into drug taking are more likely to develop problematic drug seeking behavior, including binge and other high-intake behaviors. The level of drug intake for any individual depends on the balance of rewarding and aversive effects of the drug in that individual. Multiple rodent studies have demonstrated that aversive effects of drugs of abuse are reduced in adolescent compared to adult animals. In the present study we addressed two key questions: First, do reduced aversive effects of ethanol in younger rats correlate with increased ethanol consumption? Second, are the reduced aversive effects in adolescents attributable to reduced sensitivity to ethanol's physiological effects? Methods-Adolescent and adult rats were tested for ethanol conditioned taste aversion followed by a voluntary drinking period, including post-deprivation consumption. Multivariate regression was used to assess correlations. In separate experiments, adolescent and adult rats were tested for their sensitivity to the hypothermic and sedative effects of ethanol, and for blood ethanol concentrations (BECs). Results-We observed that in adolescent rats but not adults, taste aversion was inversely correlated with post-deprivation consumption. Adolescents also exhibited a greater increase in consumption after deprivation than adults. Furthermore, the age difference in ethanol conditioned taste aversion was not attributable to differences in hypothermia, sedation, or BECs. Conclusions-These results suggest that during adolescence, individuals that are insensitive to aversive effects are most likely to develop problem drinking behaviors. These results underscore the importance of the interaction between developmental stage and individual variation in sensitivity to alcohol.

Developmental Cognitive Neuroscience, Oct 1, 2011

Drugs of abuse induce complex motivational states in their users which have been shown to vary de... more Drugs of abuse induce complex motivational states in their users which have been shown to vary developmentally. In addition to developmental variation, interindividual variation in the rewarding and aversive effects of drugs of abuse is an important consideration. A rat model was used to assess whether the conditioned rewarding/aversive effects of cocaine were maintained as individuals matured from adolescence into adulthood. We tested rats in the cocaine conditioned taste aversion task as adolescents and again in adulthood. We observed a wide range of approach/avoidance behaviors in this task, and also observed that the relative interindividual differences in approach/avoidance are remarkably stable across the two developmental stages. Furthermore, we observed that these interindividual differences are not attributable to individual differences in cocaine-induced locomotor effects or individual differences in blood or brain cocaine levels. Taken together, these findings indicate that sensitivity to cocaine's motivational effects is stable across development and part of a unique neurological process.

Pharmacology, Biochemistry and Behavior, Apr 1, 2012

Delay discounting is a key component of many psychiatric disorders, including drug addiction, com... more Delay discounting is a key component of many psychiatric disorders, including drug addiction, compulsive gambling, ADHD, and obesity. However, its underlying mechanisms are not yet fully characterized. One impediment to full characterization of such mechanisms is the fact that rodent models of the task are often complicated and involve extended training of subjects, often requiring more than a month before a stable baseline is obtained. We have therefore characterized a version of the rodent delay discounting task which generates data more quickly than most other published versions. In this version of the task, learning of the operant response is established prior to introduction of the delay component, and delay is tested across subsequent daily sessions with a single delay length per day. We demonstrate here that this version generates a delay discounting curve similar to many published tasks, and is sensitive to changes in reward magnitude and to chronic treatment with cocaine. Furthermore, we present a detailed description of the withinsession patterns of behavior in the task, which provides evidence of within-session learning and establishment of stable response patterns. This faster version of the delay discounting task will facilitate future studies involving pharmacological, electrophysiological, and other mechanistic studies of the underlying basis of this important disease process.

Pharmacology, Biochemistry and Behavior, Jun 1, 2006

In humans, most drug use is initiated during adolescence and adolescent users are more likely to ... more In humans, most drug use is initiated during adolescence and adolescent users are more likely to become drug-dependent than adult users. Repeated, high levels of use are required for the transition from use to addiction. Individual levels of drug use are thought to result from a balance between the pleasant or rewarding and the unpleasant or aversive properties of the drug. Repeated high levels of drug use are required for the transition from drug use to dependence. We hypothesized that diminished aversive effects of drugs of abuse during adolescence might be one reason for higher rates of use and addiction during this phase. We therefore tested adolescent and adult CD rats in single-dose cocaine conditioned taste aversion (CTA) at a range of doses (10-40 mg/kg), and examined whether various behavioral markers of addiction vulnerability were correlated to outcome in cocaine CTA. We found that adolescents are indeed less susceptible to cocaine CTA. In fact, age was the predominant predictor of CTA outcome, predominating over measures of novelty-seeking, anxiety, and stress hormone levels, which are all known to be related to drug intake in other models. Furthermore, we found that adolescent rats are also less susceptible to conditioned taste aversion to a low dose of a non-addictive substance, lithium chloride. These results suggest that one explanation for elevated drug use and addiction among adolescents is reduced aversive or use-limiting effects of the drugs. This contributes to our understanding of why adolescence is a particularly vulnerable period for development of drug abuse.

Psychopharmacology, Oct 26, 2013

Rationale-Vulnerability to alcoholism is determined by many factors, including the balance of ple... more Rationale-Vulnerability to alcoholism is determined by many factors, including the balance of pleasurable vs. aversive alcohol-induced sensations: pleasurable sensations increase drinking, aversive sensations reduce it. Both female sex and adolescent age are associated with fewer uselimiting effects of ethanol and more rapid development of alcohol abuse. Objectives-This study assessed voluntary drinking and the aversive effects of alcohol in adolescent and adult male and female rats, to determine whether these measures are inversely related across the sexes and development. Methods-Voluntary drinking of 20% ethanol in an every-other-day (EOD) availability pattern and the full dose-response relationship of ethanol CTA were assessed in male and female adolescent and adult rats. Results-CTA was sex-specific in adult but not adolescent rats, with adult females exhibiting less aversion. Voluntary ethanol consumption varied according to age and interindividual differences in consumption patterns but was not sex-specific. Adolescents initially drank more than adults, exhibited greater day-today variation in consumption, were more susceptible to the alcohol deprivation effect, and took longer to establish individual differences in consumption patterns. Conclusions-These results show that the evolution of drinking patterns differs in adolescents and adults. While a small cohort of adults establish high consumption patterns quickly, most adolescents drink at high levels initially and show marked deprivation-induced increases, but a significant percentage reduce intake as they become adult. High drinking adolescents do not ramp up like adults, but maintain adolescent drinking patterns into adulthood. Sex differences were not observed in EOD drinking during either adolescence or adulthood.

Neuropsychopharmacology, Oct 5, 2005

Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous rese... more Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.

Neuropsychopharmacology, Oct 5, 2005

Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous rese... more Drugs of abuse affect behavior by altering neuronal communication within the brain. Previous research examining the effects of intraperitoneally administered cocaine has revealed that cocaine alters excitatory glutamatergic signaling, both directly through regulation of synaptic function, and indirectly through regulation of cellular excitability in areas of the drug reward circuitry such as the nucleus accumbens (NAcc) and ventral tegmental area. We have now extended these findings by testing the hypothesis that self-administration of cocaine might elicit similar alterations in excitatory signaling in the NAcc shell. We observed that cocaine self-administration reduces synaptically evoked excitatory responses recorded extracellularly in the NAcc shell compared to saline self-administration. This alteration was not accompanied by alterations in paired pulse ratio of synaptically evoked responses or in potentiation of these responses by application of the adenylyl cyclase activator forskolin. This reduction in glutamatergic signaling may be one mechanism by which cocaine exerts its long-term behavioral effects.

Criminal Behaviour and Mental Health, Jan 30, 2023

Psychopharmacology, 2011

Rationale-Early-onset drug taking is associated with increased likelihood of addiction, but it is... more Rationale-Early-onset drug taking is associated with increased likelihood of addiction, but it is unclear whether early onset is causal in development of addiction. Many other factors are associated with increased risk of addiction and also promote early intake. Here, a rodent model is used to explore the causality of early onset in development of self-administration and addictionlike behavior and to examine factors that promote self-administration. Methods-We used cocaine self-administration to examine drug taking and addiction-like behavior in adolescent and adult rats a priori characterized for their locomotor responses to novelty and cocaine and behavior in the light-dark task. Results-Adolescent animals initially sought more cocaine than adults. However, as the adolescents matured, their intake fell and they did not differ from adults in terms of unreinforced lever-pressing, extinction or reinstatement behavior. For both age groups, self-administration was positively correlated with the locomotor response to novelty, the locomotor response to cocaine, and with time in light in the light-dark task. The rats that were insensitive to cocaine's locomotor effects and that spent the least time in light in the light-dark task sought the least cocaine, appearing to be "protected" from the reinforcing effects of cocaine. There was no difference between the two age groups in appearance of this "protected" phenotype.