Jordan Blacktop - Academia.edu (original) (raw)
Papers by Jordan Blacktop
Neuropsychopharmacology
We previously reported that a small, circumscribed region of the lateral hypothalamus, the anteri... more We previously reported that a small, circumscribed region of the lateral hypothalamus, the anterior dorsal region (LHAad), stains heavily for PNNs and dense extracellular matrix (PNNs/ECM) with Wisteria floribunda agglutinin (WFA), and critically contributes to the acquisition of cocaine-induced conditioned place preference and cocaine self-administration. Here we tested the role of LHAad PNNs/ECM in cue-induced reinstatement in cocaine self-administering (SA) rats and identified how it is embedded in the circuitry of motivated behavior and drug reward. Degradation of PNNs/ECM in the LHAad using chondroitinase ABC (Ch-ABC) blocked the expression of cue-induced reinstatement of cocaine-but not sucrose-seeking behavior. We also identified for the first time the phenotype of LHAad PNN/ECM-surrounded neurons. LHAad neurons co-localized mainly with parvalbumin (PV+) and GABA. Predominant co-localization of WFA with VGLUT2 and GABA but not with GAD65/67 or glutamate indicates that the PNN/ECM-rich LHAad is predominantly GABAergic and receives dense glutamatergic input. The LHAad did not express significant amounts of melanin-concentrating hormone (MCH), orexin, or galanin; neuropeptides that regulate both food-induced and cocaine-induced behavior. In addition, retrobead injections demonstrated that the LHAad receives robust prelimbic prefrontal cortex (PFC) input and provides moderate input to the prelimbic PFC and ventral tegmental area (VTA), with no apparent input to the nucleus accumbens. In summary, the dense PNN/ECM zone in the LHAad embedded within the circuitry associated with reward pinpoints a novel region that controls the expression of cocaine-seeking behavior.
The Journal of Neuroscience
The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determi... more The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 ϫ 6 h/d) but not short-access (ShA; 14 ϫ 2 h/d) self-administration showed robust shock-induced cocaine seeking. This was associated with a heightened shock-induced prelimbic cortex Fos response and activation of cholera toxin b retro-labeled VTA neurons that project to the prelimbic cortex. Chemogenetic inhibition of this pathway using a dual virus intersectional hM4Di DREADD (designer receptor exclusively activated by designer drug) based approach prevented shock-induced cocaine seeking. Both shock-induced reinstatement and the prelimbic cortex Fos response were prevented by bilateral intra-VTA injections of the CRF receptor 1 (CRFR1) antagonist, antalarmin. Moreover, pharmacological disconnection of the CRF-regulated dopaminergic projection to the prelimbic cortex by injection of antalarmin into the VTA in one hemisphere and the D1 receptor antagonist, SCH23390, into the prelimbic cortex of the contralateral hemisphere prevented shockinduced cocaine seeking. Finally, LgA, but not ShA, cocaine self-administration resulted in increased VTA CRFR1 mRNA levels as measured using in situ hybridization. Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.
Neurobiology of Stress
Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perh... more Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fosbased approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stressrelated drug use.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Nov 9, 2016
Perineuronal nets (PNNs) are unique extracellular matrix structures that wrap around certain neur... more Perineuronal nets (PNNs) are unique extracellular matrix structures that wrap around certain neurons in the CNS during development and control plasticity in the adult CNS. They appear to contribute to a wide range of diseases/disorders of the brain, are involved in recovery from spinal cord injury, and are altered during aging, learning and memory, and after exposure to drugs of abuse. Here the focus is on how a major component of PNNs, chondroitin sulfate proteoglycans, control plasticity, and on the role of PNNs in memory in normal aging, in a tauopathy model of Alzheimer's disease, and in drug addiction. Also discussed is how altered extracellular matrix/PNN formation during development may produce synaptic pathology associated with schizophrenia, bipolar disorder, major depression, and autism spectrum disorders. Understanding the molecular underpinnings of how PNNs are altered in normal physiology and disease will offer insights into new treatment approaches for these diseases.
Neuropharmacology, May 15, 2017
Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which inc... more Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which includes the medial forebrain bundle and the lateral hypothalamic area. Emerging at the forefront of neuroplasticity regulation are specialized extracellular matrix (ECM) structures that form perineuronal nets (PNNs) around certain neurons, mainly parvalbumin positive (PV(+)), fast-spiking interneurons (FSINs), making them a promising target for the regulation of drug-induced neuroplasticity. Despite the emerging significance of PNNs in drug-induced neuroplasticity and the well-established role of the lateral hypothalamic area (LHA) in reward, reinforcement, and motivation, very little is known about how PNN-expressing neurons control drug-seeking behavior. We found that a discrete region of the anterior dorsal LHA (LHAad) exhibited robust PNN and dense ECM expression. Approximately 87% of parvalbumin positive (PV(+)) neurons co-expressed the PNN marker Wisteria floribunda agglutinin (WFA),...
Journal of Neuroscience, 2015
which appeared on pages 4190-4202 of the March 11, 2015 issue, there were errors in the y-axis sc... more which appeared on pages 4190-4202 of the March 11, 2015 issue, there were errors in the y-axis scales of Figure 7, C and E. The y-axis scale on Figure 7C should be the y-axis scale on Figure 7E, and the y-axis scale on Figure 7E should be the y-axis scale on Figure 7C. This error does not affect any of the conclusions or interpretations in our paper. The correct Figure 7 is shown below.
Neural Plasticity, 2016
Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related me... more Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related memories. These changes in plasticity and persistent drug memories are believed to produce aberrant motivation and reinforcement contributing to addiction. Most studies have explored the effect drugs of abuse have on pre- and postsynaptic cells and astrocytes; however, more recently, attention has shifted to explore the effect these drugs have on the extracellular matrix (ECM). Within the ECM are unique structures arranged in a net-like manner, surrounding a subset of neurons called perineuronal nets (PNNs). This review focuses on drug-induced changes in PNNs, the molecules that regulate PNNs, and the expression of PNNs within brain circuitry mediating motivation, reward, and reinforcement as it pertains to addiction.
No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and... more No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and relapse to cocaine use. Stress is a major factor in causing relapse in cocaine dependent individuals. Cocaine use is positively correlated with stress-induced craving and relapse outcomes. Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide that plays an important role in the stress response and in the reinstatement rodent model of stress-induced relapse. CRF is released during stress in brain regions associated with the effects of drugs of abuse, notably the ventral tegmental area (VTA). This dissertation addresses key unknown mechanisms behind drug-induced neuroplasticity and how that neuroplasticity gates the ability of stress to cause relapse. Chapter two reports that stress and intra-VTA CRF administration produces robust reinstatement in animals allowed extended long-access (LgA) but not short-access (ShA) cocaine selfadministration. Moreover, LgA cocaine use increases susceptibility to stressorinduced relapse in part by augmenting CRF receptor 1 (CRF-R1) dependent regulation of VTA neurocircuitry. Chapter three characterizes VTA dopamine neuron activation under conditions where stress reinstates cocaine seeking. Dopamine neuron activation was significantly increased in ShA but not LgA rats. However, when examined across groups only in rats that display relapse in response to stress is a significant increase in dopamine neuron activation observed. This suggests that stress-induced reinstatement is associated with increased activation of VTA dopamine neurons. Lastly, chapter 4 addresses the necessity of VTA glutamate and GABA receptors in footshock and intra-VTA CRF dependent reinstatement of cocaine seeking. Intra-VTA administration of NMDA, AMPA, and GABAA receptor antagonists fail to block reinstatement. In contrast, GABAB receptor antagonism blocked reinstatement by both footshock and intra-VTA CRF suggesting GABAB activation is necessary for CRF actions in the VTA. The findings from this dissertation provide much needed insight into the neuroadaptations that occur in the VTA to regulate later stressor induced relapse in cocaine addicts. The hope is that these findings will help with the understanding and eventual long-term management of stressor-induced relapse in abstinent cocaine addicts. TABLE OF CONTENTS ACKNOWLEDGEMENTS……………………………………………… i LIST OF TABLES……………………………………………………….. ix LIST OF FIGURES……………………………………………………… x CHAPTER 1 BACKGROUND AND SIGNIFICANCE……………………………......
Neuropharmacology, Jan 17, 2015
Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) act... more Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 x 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 sec; range 10-70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 11, 2015
Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking... more Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking behavior in humans and rodents. Activity of these neurons is significantly modulated by GABAergic, parvalbumin-containing, fast-spiking interneurons, the majority of which are enveloped by specialized structures of extracellular matrix called perineuronal nets (PNNs), which are integral to the maintenance of many types of plasticity. Using a conditioned place preference (CPP) procedure, we found that removal of PNNs primarily from the prelimbic region of the mPFC of adult, male, Sprague Dawley rats impaired the acquisition and reconsolidation of a cocaine-induced CPP memory. This impairment was accompanied by a decrease in the number of c-Fos-positive cells surrounded by PNNs. Following removal of PNNs, the frequency of inhibitory currents in mPFC pyramidal neurons was decreased; but following cocaine-induced CPP, both frequency and amplitude of inhibitory currents were decreased. Our f...
Stress, 2014
Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobi... more Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobiological processes through which stress contributes to drug use is a critical goal for addiction researchers and will likely be important for the development of effective medications aimed at relapse prevention. In this paper, we review work from our laboratory and others focused on determining the neurobiological mechanisms that underlie and contribute to stress-induced relapse of cocaine use with an emphasis on the actions of corticotropin-releasing factor in the ventral tegmental area (VTA) and a key pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine and beta adrenergic receptors. Additionally, we discuss work suggesting that the influence of stress in cocaine addiction changes and intensifies with repeated cocaine use in an intake-dependent manner and examine the potential role of glucocorticoid hormones in the underlying drug-induced neuroadaptations. It is our hope that research in this area will inform clinical practice and medication development aimed at minimizing the contribution of stress to the addiction cycle, thereby improving treatment outcomes and reducing the societal costs of addiction.
Neuropharmacology, 2014
The ability of stressful life events to trigger drug use is particularly problematic for the mana... more The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress-induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake-dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a "stage setter" for drug use-increasing sensitivity to cocaine and drug-associated cues-under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven.
Journal of Neuroscience, 2011
Neuropsychopharmacology
We previously reported that a small, circumscribed region of the lateral hypothalamus, the anteri... more We previously reported that a small, circumscribed region of the lateral hypothalamus, the anterior dorsal region (LHAad), stains heavily for PNNs and dense extracellular matrix (PNNs/ECM) with Wisteria floribunda agglutinin (WFA), and critically contributes to the acquisition of cocaine-induced conditioned place preference and cocaine self-administration. Here we tested the role of LHAad PNNs/ECM in cue-induced reinstatement in cocaine self-administering (SA) rats and identified how it is embedded in the circuitry of motivated behavior and drug reward. Degradation of PNNs/ECM in the LHAad using chondroitinase ABC (Ch-ABC) blocked the expression of cue-induced reinstatement of cocaine-but not sucrose-seeking behavior. We also identified for the first time the phenotype of LHAad PNN/ECM-surrounded neurons. LHAad neurons co-localized mainly with parvalbumin (PV+) and GABA. Predominant co-localization of WFA with VGLUT2 and GABA but not with GAD65/67 or glutamate indicates that the PNN/ECM-rich LHAad is predominantly GABAergic and receives dense glutamatergic input. The LHAad did not express significant amounts of melanin-concentrating hormone (MCH), orexin, or galanin; neuropeptides that regulate both food-induced and cocaine-induced behavior. In addition, retrobead injections demonstrated that the LHAad receives robust prelimbic prefrontal cortex (PFC) input and provides moderate input to the prelimbic PFC and ventral tegmental area (VTA), with no apparent input to the nucleus accumbens. In summary, the dense PNN/ECM zone in the LHAad embedded within the circuitry associated with reward pinpoints a novel region that controls the expression of cocaine-seeking behavior.
The Journal of Neuroscience
The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determi... more The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 ϫ 6 h/d) but not short-access (ShA; 14 ϫ 2 h/d) self-administration showed robust shock-induced cocaine seeking. This was associated with a heightened shock-induced prelimbic cortex Fos response and activation of cholera toxin b retro-labeled VTA neurons that project to the prelimbic cortex. Chemogenetic inhibition of this pathway using a dual virus intersectional hM4Di DREADD (designer receptor exclusively activated by designer drug) based approach prevented shock-induced cocaine seeking. Both shock-induced reinstatement and the prelimbic cortex Fos response were prevented by bilateral intra-VTA injections of the CRF receptor 1 (CRFR1) antagonist, antalarmin. Moreover, pharmacological disconnection of the CRF-regulated dopaminergic projection to the prelimbic cortex by injection of antalarmin into the VTA in one hemisphere and the D1 receptor antagonist, SCH23390, into the prelimbic cortex of the contralateral hemisphere prevented shockinduced cocaine seeking. Finally, LgA, but not ShA, cocaine self-administration resulted in increased VTA CRFR1 mRNA levels as measured using in situ hybridization. Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.
Neurobiology of Stress
Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perh... more Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fosbased approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stressrelated drug use.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Nov 9, 2016
Perineuronal nets (PNNs) are unique extracellular matrix structures that wrap around certain neur... more Perineuronal nets (PNNs) are unique extracellular matrix structures that wrap around certain neurons in the CNS during development and control plasticity in the adult CNS. They appear to contribute to a wide range of diseases/disorders of the brain, are involved in recovery from spinal cord injury, and are altered during aging, learning and memory, and after exposure to drugs of abuse. Here the focus is on how a major component of PNNs, chondroitin sulfate proteoglycans, control plasticity, and on the role of PNNs in memory in normal aging, in a tauopathy model of Alzheimer's disease, and in drug addiction. Also discussed is how altered extracellular matrix/PNN formation during development may produce synaptic pathology associated with schizophrenia, bipolar disorder, major depression, and autism spectrum disorders. Understanding the molecular underpinnings of how PNNs are altered in normal physiology and disease will offer insights into new treatment approaches for these diseases.
Neuropharmacology, May 15, 2017
Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which inc... more Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which includes the medial forebrain bundle and the lateral hypothalamic area. Emerging at the forefront of neuroplasticity regulation are specialized extracellular matrix (ECM) structures that form perineuronal nets (PNNs) around certain neurons, mainly parvalbumin positive (PV(+)), fast-spiking interneurons (FSINs), making them a promising target for the regulation of drug-induced neuroplasticity. Despite the emerging significance of PNNs in drug-induced neuroplasticity and the well-established role of the lateral hypothalamic area (LHA) in reward, reinforcement, and motivation, very little is known about how PNN-expressing neurons control drug-seeking behavior. We found that a discrete region of the anterior dorsal LHA (LHAad) exhibited robust PNN and dense ECM expression. Approximately 87% of parvalbumin positive (PV(+)) neurons co-expressed the PNN marker Wisteria floribunda agglutinin (WFA),...
Journal of Neuroscience, 2015
which appeared on pages 4190-4202 of the March 11, 2015 issue, there were errors in the y-axis sc... more which appeared on pages 4190-4202 of the March 11, 2015 issue, there were errors in the y-axis scales of Figure 7, C and E. The y-axis scale on Figure 7C should be the y-axis scale on Figure 7E, and the y-axis scale on Figure 7E should be the y-axis scale on Figure 7C. This error does not affect any of the conclusions or interpretations in our paper. The correct Figure 7 is shown below.
Neural Plasticity, 2016
Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related me... more Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related memories. These changes in plasticity and persistent drug memories are believed to produce aberrant motivation and reinforcement contributing to addiction. Most studies have explored the effect drugs of abuse have on pre- and postsynaptic cells and astrocytes; however, more recently, attention has shifted to explore the effect these drugs have on the extracellular matrix (ECM). Within the ECM are unique structures arranged in a net-like manner, surrounding a subset of neurons called perineuronal nets (PNNs). This review focuses on drug-induced changes in PNNs, the molecules that regulate PNNs, and the expression of PNNs within brain circuitry mediating motivation, reward, and reinforcement as it pertains to addiction.
No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and... more No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and relapse to cocaine use. Stress is a major factor in causing relapse in cocaine dependent individuals. Cocaine use is positively correlated with stress-induced craving and relapse outcomes. Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide that plays an important role in the stress response and in the reinstatement rodent model of stress-induced relapse. CRF is released during stress in brain regions associated with the effects of drugs of abuse, notably the ventral tegmental area (VTA). This dissertation addresses key unknown mechanisms behind drug-induced neuroplasticity and how that neuroplasticity gates the ability of stress to cause relapse. Chapter two reports that stress and intra-VTA CRF administration produces robust reinstatement in animals allowed extended long-access (LgA) but not short-access (ShA) cocaine selfadministration. Moreover, LgA cocaine use increases susceptibility to stressorinduced relapse in part by augmenting CRF receptor 1 (CRF-R1) dependent regulation of VTA neurocircuitry. Chapter three characterizes VTA dopamine neuron activation under conditions where stress reinstates cocaine seeking. Dopamine neuron activation was significantly increased in ShA but not LgA rats. However, when examined across groups only in rats that display relapse in response to stress is a significant increase in dopamine neuron activation observed. This suggests that stress-induced reinstatement is associated with increased activation of VTA dopamine neurons. Lastly, chapter 4 addresses the necessity of VTA glutamate and GABA receptors in footshock and intra-VTA CRF dependent reinstatement of cocaine seeking. Intra-VTA administration of NMDA, AMPA, and GABAA receptor antagonists fail to block reinstatement. In contrast, GABAB receptor antagonism blocked reinstatement by both footshock and intra-VTA CRF suggesting GABAB activation is necessary for CRF actions in the VTA. The findings from this dissertation provide much needed insight into the neuroadaptations that occur in the VTA to regulate later stressor induced relapse in cocaine addicts. The hope is that these findings will help with the understanding and eventual long-term management of stressor-induced relapse in abstinent cocaine addicts. TABLE OF CONTENTS ACKNOWLEDGEMENTS……………………………………………… i LIST OF TABLES……………………………………………………….. ix LIST OF FIGURES……………………………………………………… x CHAPTER 1 BACKGROUND AND SIGNIFICANCE……………………………......
Neuropharmacology, Jan 17, 2015
Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) act... more Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 x 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 sec; range 10-70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 11, 2015
Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking... more Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking behavior in humans and rodents. Activity of these neurons is significantly modulated by GABAergic, parvalbumin-containing, fast-spiking interneurons, the majority of which are enveloped by specialized structures of extracellular matrix called perineuronal nets (PNNs), which are integral to the maintenance of many types of plasticity. Using a conditioned place preference (CPP) procedure, we found that removal of PNNs primarily from the prelimbic region of the mPFC of adult, male, Sprague Dawley rats impaired the acquisition and reconsolidation of a cocaine-induced CPP memory. This impairment was accompanied by a decrease in the number of c-Fos-positive cells surrounded by PNNs. Following removal of PNNs, the frequency of inhibitory currents in mPFC pyramidal neurons was decreased; but following cocaine-induced CPP, both frequency and amplitude of inhibitory currents were decreased. Our f...
Stress, 2014
Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobi... more Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobiological processes through which stress contributes to drug use is a critical goal for addiction researchers and will likely be important for the development of effective medications aimed at relapse prevention. In this paper, we review work from our laboratory and others focused on determining the neurobiological mechanisms that underlie and contribute to stress-induced relapse of cocaine use with an emphasis on the actions of corticotropin-releasing factor in the ventral tegmental area (VTA) and a key pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine and beta adrenergic receptors. Additionally, we discuss work suggesting that the influence of stress in cocaine addiction changes and intensifies with repeated cocaine use in an intake-dependent manner and examine the potential role of glucocorticoid hormones in the underlying drug-induced neuroadaptations. It is our hope that research in this area will inform clinical practice and medication development aimed at minimizing the contribution of stress to the addiction cycle, thereby improving treatment outcomes and reducing the societal costs of addiction.
Neuropharmacology, 2014
The ability of stressful life events to trigger drug use is particularly problematic for the mana... more The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress-induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake-dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a "stage setter" for drug use-increasing sensitivity to cocaine and drug-associated cues-under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven.
Journal of Neuroscience, 2011