Browsing by Author "Chambers, R. Andrew"
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Item Adult Hippocampal Neurogenesis in the Pathogenesis of Addiction and Dual Diagnosis Disorders(Elsevier, 2013) Chambers, R. Andrew; Psychiatry, School of MedicineBackground: As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Methods: Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. Results: While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Conclusions: Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders.Item The adverse childhood experiences questionnaire: Two decades of research on childhood trauma as a primary cause of adult mental illness, addiction, and medical diseases(Taylor & Francis, 2019-01-01) Zarse, Emily M.; Neff, Mallory R.; Yoder, Rachel; Hulvershorn, Leslie; Chambers, Joanna E.; Chambers, R. Andrew; Psychiatry, School of MedicineObjective. In 1998, Felitti and colleagues published the first study of the Adverse Childhood Experiences-Questionnaire (ACE-Q), a 10-item scale used to correlate childhood maltreatment and adverse rearing contexts with adult health outcomes. This paper qualitatively reviews nearly two decades of research utilizing the ACE-Q, highlighting its contribution to our understanding of the causal roots of common, interlinked comorbidities of the brain and body.Methods. An OVID/PubMed search was conducted for English language articles published before 2016, containing the phrase “Adverse Childhood Experiences” in which the ACE-Q was utilized. Source review included a manual search of bibliographies, resulting in 134 articles, including 44 based on the original ACE-Q study population.Results. ACE-Q research has demonstrated that exposures to adverse childhood experiences converge dose-dependently to potently increase the risk for a wide array of causally interlinked mental illnesses, addictions, and multi-organ medical diseases. The intergenerational transmission of this disease burden via disrupted parenting and insecure rearing contexts is apparent throughout this literature. However, the ACE-Q does not tease out genetic or fetal drug exposure components of this transmission.Conclusions. Adverse childhood experiences and rearing may generate a public health burden that could rival or exceed all other root causes. Translating this information to health-care reform will require strengthening brain-behavioral health as core public and preventative health-care missions. Greater integration of mental health and addiction services for parents should be accompanied by more research into brain mechanisms impacted by different forms and interactions between adverse childhood experiences.Item Adverse childhood experiences, insecure attachment, and appointment compliance in an outpatient addiction psychiatry treatment population(Wiley, 2025) Chambers, Joanna E.; Perkins, Susan M.; Mosesso, Kelly M.; Ahdoot, Azziza; Arnaudo, Camila L.; Chambers, R. Andrew; Psychiatry, School of MedicineBackground and objectives: Suffering adverse childhood experiences (ACEs) increases the probability of developing adult mental illness, addictions, and insecure attachment. This study determined how ACEs and insecure attachment are associated with each other, and how they may predict treatment engagement in an integrated dual diagnosis treatment clinic. Methods: A sample of n = 264 patients entering a university-affiliated addiction psychiatry clinic underwent diagnostic intakes supplemented by assessments of attachment styles (Anxious/Avoidant, using the 36-item Experiences in Close Relationships-Relationship Structures (ECR-RS) scale) and childhood adversity (10-item Adverse Childhood Experiences Questionnaire (ACE-Q) scale). Compliance with psychotherapy versus medication appointments was tracked for 6 months post intake. Results: ACE-Q scores (median of 4) were significantly associated with higher anxious and avoidant attachment scores and the number of mental health diagnoses. Only one in five patients obtained 75% or higher compliance rates with psychotherapy; two in five achieved 75% or higher compliance with medication appointments. Greater anxious attachment predicted lower show rates for both psychotherapy and medication appointments, whereas greater avoidant attachment predicted lower compliance for psychotherapy only. Discussion and conclusions: This study confirms the linkage of ACEs and insecure attachment patterns in dual-diagnosis patients seeking integrated addiction psychiatry care. Insecure attachment patterns differentially predicted lower appointment compliance, particularly for psychotherapies. Scientific significance: Childhood trauma and associated adult attachment dysfunction warrant further investigation not only as causes and correlates of mental illness and addiction but also for improving treatment engagement, therapeutic attachments, and recovery outcomes.Item Auditory steady state responses in a schizophrenia rat model probed by excitatory/inhibitory receptor manipulation(Elsevier, 2012) Vohs, Jenifer L.; Chambers, R. Andrew; O’Donnell, Brian F.; Krishnan, Giri P.; Morzorati, Sandra L.; Psychiatry, School of MedicineAlterations in neural synchrony and oscillations may contribute to the pathophysiology of schizophrenia and reflect aberrations in cortical glutamatergic and GABAergic neurotransmission. We tested the effects of a GABA agonist and a NMDA antagonist on auditory steady state responses (ASSRs) in awake rats with neonatal ventral hippocampal lesions (NVHLs) as a neurodevelopmental model of schizophrenia. NVHL vs. SHAM lesioned rats were injected with saline then either ketamine (NMDA antagonist) or muscimol (GABAA agonist). Time-frequency analyses examined alterations in phase locking (consistency) across trials and changes in total power (magnitude). ASSRs were compared at 5 stimulation frequencies (10, 20, 30, 40, and 50 Hz). In SHAM rats, phase locking and power generally increased with stimulation frequency. Both ketamine and muscimol also increased phase locking and power in SHAM rats, but mostly in the 20 to 40 Hz range. NVHL and ketamine altered the frequency dependence of phase locking, while only ketamine changed power frequency dependence. Muscimol affected power, but not phase locking, in the NVHL rats. NVHL and ketamine models of schizophrenia produce similar independent effects on ASSR, potentially representing similar forms of cortical network/glutamatergic dysfunction, albeit the effects of ketamine were more robust. Muscimol produced NVHL-dependent reductions in ASSR measures, suggesting that cortical networks in this model are intolerant to post-synaptic GABAergic stimulation. These findings suggest the utility of combining lesion, pharmacological, and ASSR approaches in understanding neural mechanisms underlying disturbed synchrony in schizophrenia.Item Chemotherapy, estrogen, and cognition : neuroimaging and genetic variation(2014-02-25) Conroy, Susan Kim; McDonald, Brenna C.; Saykin, Andrew J.; Chambers, R. Andrew; Miller, Kathy (Kathy D.); Yoder, Karmen K.The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.Item Deep Network Pharmacology: Targeting Glutamate Systems as Integrative Treatments for Jump-Starting Neural Networks and Recovery Trajectories(Hapres, 2021) Chambers, R. Andrew; Toombs, Christopher; Psychiatry, School of MedicineSignificant advances in pharmacological treatments for mental illness and addiction will require abandoning old monoaminergic theories of psychiatric disorders and traditionally narrow approaches to how we conduct treatment research. Reframing our efforts with a view on integrative treatments that target core neural network function and plasticity may provide new approaches for lifting patients out of chronic psychiatric symptom sets and addiction. For example, we discuss new treatments that target brain glutamate systems at key transition points within longitudinal courses of care that integrate several treatment modalities. A reconsideration of what our novel and already available medications are intended to achieve and how and when we deliver them for patients with complex illness trajectories could be the key to unlocking new advances in general and addiction psychiatry.Item Effects of Nicotine Exposure in Adolescent Rats on Acquisition of Alcohol Drinking and Response to Nicotine in Adulthood(2009-09-30T19:25:40Z) Bracken, Amy L.; McBride, William J.; Chambers, R. Andrew; Murphy, James M.; Rodd, Zachary A.Nicotine is one of the most widely abused drugs in the world, and most smokers begin smoking during their adolescent years. Adolescence is a unique developmental period during which vulnerability to the effects of drug exposure is especially high. This dissertation uses rodent models to investigate the persistent effects of adolescent nicotine exposure on both neurobiological and behavioral measures of drug sensitivity in adulthood. The aims of this dissertation were to 1) determine whether nicotine would be self-administered into the posterior ventral tegmental area (pVTA), a neuroanatomical component of the mesolimbic dopamine (DA) system, which is known to be involved in reward and reinforcement; 2) investigate whether adolescent nicotine exposure would alter the sensitivity of the mesolimbic DA system as measured by DA release in the nucleus accumbens (NAc) in response to nicotine microinjections into the pVTA; 3) examine the effects of adolescent nicotine exposure on behavioral sensitization to nicotine in adulthood; and 4) investigate whether adulthood alcohol drinking behavior, in both Wistar and alcohol-preferring (P) rats, would be augmented by nicotine exposure during adolescence. Results of this dissertation demonstrated that 1) the pVTA is a neuroanatomical site that supports nicotine self-administration; and that adolescent nicotine exposure results in 2) increased nicotine-stimulated DA release in the NAc during adulthood; 3) augmented behavioral sensitization to nicotine in adult animals; and 4) enhanced acquisition of alcohol drinking behavior in adult Wistar and P rats. Overall, this dissertation provides insight into the diverse and persistent changes, in both neurobiology and behavior, caused by exposure to nicotine during the critical developmental period of adolescence.Item Nicotine effects in adolescence and adulthood on cognition and α₄β₂-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia(Springer, 2015-05) Berg, Sarah A.; Sentir, Alena M.; Bell, Richard L.; Engleman, Eric A.; Chambers, R. Andrew; Department of Psychiatry, IU School of MedicineRational Nicotine use in schizophrenia has traditionally been explained as ‘self-medication’ of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. Objectives We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Methods Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. Results NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food–reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p<0.05) but not ventral striatum (<5% changes, p>.40), whereas nicotine history elevated nAChRs across both regions (>30%, p<0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Conclusions Although replicating nicotine-induced up-regulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.Item Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions(Wiley Blackwell (Blackwell Publishing), 2014-11) Berg, Sarah A.; Sentir, Alena M.; Cooley, Benjamin S.; Engleman, Eric A.; Chambers, R. Andrew; Department of Psychiatry, IU School of MedicineNicotine dependence is the leading cause of death in the United States. However, research on high rates of nicotine use in mental illness has primarily explained this co-morbidity as reflecting nicotine's therapeutic benefits, especially for cognitive symptoms, equating smoking with 'self-medication'. We used a leading neurodevelopmental model of mental illness in rats to prospectively test the alternative possibility that nicotine dependence pervades mental illness because nicotine is simply more addictive in mentally ill brains that involve developmental hippocampal dysfunction. Neonatal ventral hippocampal lesions (NVHL) have previously been demonstrated to produce post-adolescent-onset, pharmacological, neurobiological and cognitive-deficit features of schizophrenia. Here, we show that NVHLs increase adult nicotine self-administration, potentiating acquisition-intake, total nicotine consumed and drug seeking. Behavioral sensitization to nicotine in adolescence prior to self-administration is not accentuated by NVHLs in contrast to increased nicotine self-administration and behavioral sensitization documented in adult NVHL rats, suggesting periadolescent neurodevelopmental onset of nicotine addiction vulnerability in the NVHL model. Delivering a nicotine regimen approximating the exposure used in the sensitization and self-administration experiments (i.e. as a treatment) to adult rats did not specifically reverse NVHL-induced cortical-hippocampal-dependent cognitive deficits and actually worsened cognitive efficiency after nicotine treatment stopped, generating deficits that resemble those due to NVHLs. These findings represent the first prospective evidence demonstrating a causal link between disease processes in schizophrenia and nicotine addiction. Developmental cortical-temporal limbic dysfunction in mental illness may thus amplify nicotine's reinforcing effects and addiction risk and severity, even while producing cognitive deficits that are not specifically or substantially reversible with nicotine.Item Nicotine Use in Schizophrenia: a part of the cure or the disease?(2012-03-16) Berg, Sarah A.; Chambers, R. Andrew; Czachowski, Cristine L.; Grahame, Nicholas J.; Breier, Alan, 1953-Nicotine use among individuals with schizophrenia occurs at extremely high rates. The prevailing theory is that individuals with schizophrenia smoke as a form of self-medication to ameliorate sensory and cognitive deficits. However, these individuals also have enhanced rates of addiction to several drugs of abuse and may therefore smoke as a result of enhanced addiction liability. The experiments described herein explored these two hypotheses by assessing the effect that nicotine has on working memory, addiction vulnerability (locomotor sensitization and self-administration), and nicotinic acetylcholine receptor (nAChR) expression as well as the developmental expression of these characteristics in the neonatal ventral hippocampal (NVHL) neurodevelopmental animal model of schizophrenia. The results from these studies indicate that NVHLs had working memory impairments in both adolescence and adulthood, with nicotine having a negligible effect. Additionally, NVHLs displayed enhanced locomotor sensitization to nicotine which emerged in adulthood as well as an enhanced acquisition of nicotine self-administration, administering more nicotine overall. These behavioral differences cannot be attributed to nAChR expression as nicotine upregulated nAChR to a similar extent between NVHL and SHAM control animals. These data indicate that the enhanced rates of nicotine use among individuals with schizophrenia may occur as a result of an enhanced vulnerability to nicotine addiction.