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Susan L Andersen

Publications and source records attributed to Susan L Andersen.

18 recordsLinked to original sources

Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable?

Recent studies have reported an association between exposure to childhood abuse or neglect and alterations in brain structure or function. One limitation of these studies is that they are correlational and do not provide evidence of a cause-effect relationship. Preclinical studies on the effects of exposure to early life stress can demonstrate causality, and can enrich our understanding of the clinical research if we hypothesize that the consequences of early abuse are predominantly mediated through the induction of stress responses. Exposure to early abuse and early stress has each been associated with the emergence of epileptiform electroencephalogram (EEG) abnormalities, alterations in corpus callosum area, and reduced volume or synaptic density of the hippocampus. Further, there is evidence that different brain regions have unique periods when they are maximally sensitive to the effects of early stress. To date, preclinical studies have guided clinical investigations and will continue to provide important insight into studies on molecular mechanisms and gene-environment interactions.

Animals↗

Mapping dopamine D2/D3 receptor function using pharmacological magnetic resonance imaging.

RATIONALE: Regulation of dopamine release and synthesis occurs via pre-synaptic dopamine (DA) D2/D3 autoreceptors (DARs). Mapping of DAR function in vivo is difficult and is usually best assessed using invasive measures of DA release, such as microdialysis at discrete sites. We wished to show that pharmacological magnetic resonance imaging (phMRI) may prove useful for this purpose. OBJECTIVE: To demonstrate that the relative cerebral blood volume (rCBV) changes induced by amphetamine can be modulated by DA D2 receptor antagonists and agonists in a manner consistent with modulation of DAR function and to compare these effects with microdialysis. METHODS: We used phMRI with iron oxide contrast agents to map changes in rCBV in response to an amphetamine challenge, pre-treatment and post-treatment with varying doses of the D2 antagonist eticlopride and the D2 agonist quinpirole. We also compared the effects of D2 antagonism using microdialysis measurements of DA release. RESULTS: Antagonism of D2 receptors with eticlopride potentiated rCBV changes induced by amphetamine in the nucleus accumbens and caudate putamen in a dose-dependent manner. The amphetamine-induced increase in rCBV in the accumbens in animals pre-treated with eticlopride was paralleled by a similar percentage increase in DA release measured by means of microdialysis. Conversely, agonism of D2 receptors using quinpirole reduced amphetamine-induced rCBV changes in the caudate putamen and nucleus accumbens. The effects of both quinpirole and eticlopride on amphetamine-induced rCBV changes were largest in the nucleus accumbens. CONCLUSIONS: These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.

Amphetamine↗

Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats.

BACKGROUND: Methylphenidate (MPH) is prescribed for the treatment of attention and hyperactivity disorders. We showed previously that early developmental exposure to MPH in rats causes behavioral alterations during adulthood, including reduced cocaine reward in place conditioning studies. Here we examined if early MPH exposure alters the ability of cocaine to potentiate the rewarding effects of electrical stimulation of the medial forebrain bundle (MFB) using intracranial self-stimulation (ICSS). METHODS: Rats received MPH or saline during pre-adolescence (P20-35) and were implanted with MFB stimulating electrodes at adulthood (P60). Rats then were tested with cocaine in the ICSS paradigm. RESULTS: Cocaine dose-dependently decreased ICSS thresholds in all rats, but the threshold-lowering effects of cocaine were smaller in rats exposed to MPH during pre-adolescence. There were no differences between groups in sensitivity to the rewarding effects of MFB stimulation itself. CONCLUSIONS: Early developmental exposure to MPH reduces the reward-related effects of cocaine in the ICSS paradigm. These results are consistent with previous studies in which early exposure to MPH reduced the ability of cocaine to establish conditioned place preferences, as well as the rewarding effects of sucrose and sexual behavior. Reduced sensitivity to these various types of reward may reflect general dysfunctions of brain reward systems.

Age Factors↗

Stimulants and the developing brain.

For almost 70 years, children have received stimulants for the treatment of attention deficit hyperactivity disorder [ADHD (initially called hyperkinetic syndrome)], with little understanding of the long-term effects of these drugs on brain development. The maturation and refinement of the brain during childhood and adolescence, including the overproduction and selective elimination of synapses, is based on genetic programming and experience. The effects of stimulant drugs during different stages of this process have unique short-term, acute effects that also influence their long-term effects. Chronic, pre-pubertal exposure alters the expected developmental trajectory of brain structure and function and results in a different topography in adulthood. The timing of exposure (childhood versus adolescence), the age of examination after drug exposure (immediately or delayed into adulthood) and sex influence the observable effects. Preclinical studies of the effects of stimulant exposure provide increased understanding about the impact of stimulant drugs on brain development and provide insight into new treatment options for ADHD and other disorders of childhood.

Animals↗

Childhood neglect is associated with reduced corpus callosum area.

BACKGROUND: Childhood abuse has been associated with abnormalities in brain development, particularly corpus callosum (CC) morphology. The impact of neglect has not been assessed, though it is the most prevalent form of childhood maltreatment. METHODS: Regional CC area was measured from magnetic resonance imaging scans in 26 boys and 25 girls admitted for psychiatric evaluation (28 with abuse or neglect) and compared with CC area in 115 healthy control subjects. Data were analyzed by multivariate analysis of covariance, with age and midsagittal area as covariates. RESULTS: Total CC area of the abused/neglected patients was 17% smaller than in control subjects (p =.0001) and 11% smaller than in psychiatric patients who had not been abused or neglected (contrast group; p =.01). Control subjects and the contrast group did not differ in total CC area. Neglect was the strongest experiential factor and was associated with a 15%-18% reduction in CC regions 3, 4, 5, and 7 (all p <.02). In contrast, sexual abuse seemed to be the strongest factor associated with reduced CC size in girls. CONCLUSIONS: These data are consistent with animal research that demonstrated reduced CC size in nursery-reared compared with semi-naturally reared primates. Early experience might also affect the development of the human CC.

Adolescent↗

Transient dopamine synthesis modulation in prefrontal cortex: in vitro studies.

The present study provides further evidence for transient D1 autoreceptor-like synthesis modulation in prefrontal cortex, but not striatum, of developing rats. DOPA accumulation was attenuated in a concentration-dependent manner in slices from the prefrontal cortex and striatum at 15 days of age by the partial D1 agonist SKF 38393 (0.01-10 microM) and the full D1 agonist SKF-81297 (0.01-10 microM) following NSD-1015; the response was no longer apparent by 40 days. Both agonists had greater potency in prefrontal cortex than striatum, and SKF-81297 exerted greater maximal inhibitory effects than SKF-38393. The inhibitory effects of both agonists were antagonized by pre-incubation with the D1 antagonist SCH-23390 in cortex, but not in striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Regulation of working memory by dopamine D4 receptor in rats.

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D1 and D2 receptors, with most evidence suggesting a dominant role for the D1 receptor. Since the dopamine D4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D4 receptor in working memory, and suggest innovative, D4-based, treatment of cognitive deficits associated with neuropsychiatric disorders.

Animals↗

Delayed effects of early stress on hippocampal development.

Early maternal separation has been shown in animal models to produce enduring morphological changes in the hippocampus and other brain structures, which may not become evident until adulthood. Postnatally, the trajectory of overproduction and pruning of axons, dendrites, synapses and receptors shapes the brain between puberty and adulthood. The objective of the study was to ascertain whether this normal trajectory was affected by repeated maternal separation. Rat pups were separated from their mother for 4 h a day between postnatal days 2 and 20 (ISO group), and compared to rat pups that remained with their mother in the animal facilities (AFR group) and were exposed to minimal handling. Immunoreactivity to synaptophysin was quantified in the hippocampus CA1 and CA3, amygdala, and prefrontal cortex using optical densitometry (OD) at 25, 40, 60, 80, and 100 days in male and female rats. Synaptophysin OD increased dramatically in CA1 and CA3 between 25 and 60 days in the AFR group and fell by the same degree between 60 and 100 days, showing the expected sequence of overproduction and pruning. No difference between groups in synaptophysin OD was observed at 25 and 40 days. However, at day 60 synaptophysin was 34-36% lower in CA1 and CA3 of the ISO group, and remained 24-26% lower at 100 days. Early isolation produced no enduring reduction in synaptophysin OD in the amygdala or prefrontal cortex. Overall, these results suggest that early maternal separation produced a regionally specific delayed effect on the structure of the hippocampus by attenuating rates of synaptic development.

Animals↗

Enduring behavioral effects of early exposure to methylphenidate in rats.

BACKGROUND: Methylphenidate (MPH) is a stimulant prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulant drugs can cause enduring behavioral adaptations, including altered drug sensitivity, in laboratory animals. We examined how early developmental exposure to stimulants affects behavior in several rodent models. METHODS: Rats received MPH or cocaine during preadolescence (P20-35). Behavioral studies began during adulthood (P60). We compared how early exposure to MPH and cocaine affects sensitivity to the rewarding and aversive properties of cocaine using place conditioning. We also examined the effects of early exposure to MPH on depressive-like signs using the forced swim test, and habituation of spontaneous locomotion, within activity chambers. RESULTS: In place-conditioning tests, early exposure to MPH or cocaine each made moderate doses of cocaine aversive and high doses less rewarding. Early MPH exposure also caused depressive-like effects in the forced swim test, and it attenuated habituation to the activity chambers. CONCLUSIONS: Early exposure to MPH causes behavioral changes in rats that endure into adulthood. Some changes (reduced sensitivity to cocaine reward) may be beneficial, whereas others (increases in depressive-like signs, reduced habituation) may be detrimental. The effects of MPH on cocaine-related behaviors may be a general consequence of early stimulant exposure.

Aging↗

Rate dependency revisited: understanding the effects of methylphenidate in children with attention deficit hyperactivity disorder.

Although stimulants are widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), their calming effects are not easily understood. One hypothesis derived from preclinical studies is that stimulants exert "rate-dependent" effects that are inversely related in magnitude and direction to the baseline rate of activity or distraction. Previously, compelling support for this hypothesis has been lacking. We provide preliminary evidence that methylphenidate exerts rate-dependent behavioral effects in children with ADHD. Activity and attention were quantified in children with ADHD tested on placebo and different doses of methylphenidate using objective measures. Higher doses altered activity and attentiveness in a rate-dependent manner after correction for regression-to-the-mean artifacts. These findings illustrate a clear inverse association between symptom severity and degree of therapeutic response that is crucial for our understanding of stimulant effects and effective clinical treatment of ADHD.

Attention↗

Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD).

The transitions that occur in the ascending dopamine systems between childhood and adulthood parallel the emergence, course, and severity of attention-deficit hyperactivity disorder (ADHD) symptoms. Behaviorally, rats are more active in open field during periadolescence, and activity levels decline by 50% in males by adulthood. This peak in behavior parallels a transient overproduction in D1 and D2 dopamine receptors that occurs at puberty in rat striatum (STR) and prefrontal cortex (PFC), followed by a decline in receptor density into adulthood. While tempting to speculate that receptor density plays a role in the waning of ADHD symptoms, receptor overproduction does not occur in the nucleus accumbens (NA), which demonstrates only a modest rise in receptor density (10-20%). Given the importance of the accumbens in locomotor activity, an alternative explanation for increased activity was sought. The second messenger system cyclic adenosine monophosphate (cAMP) has classically been associated with dopamine receptors. The results of these studies demonstrate that cAMP accumulation in the accumbens and the STR parallel the observed rise and fall in activity levels in rats. At puberty, basal cAMP levels are 35% higher relative to adulthood in male accumbens, while a modest 7% change was observed in STR. Forskolin-stimulated cAMP was 240-300% higher in STR and accumbens at puberty before declining with maturation. These findings suggest that, the adolescent dopamine system has a much higher 'tone' relative to adults. However, pharmacological responsiveness of cAMP to D1 or D2 stimulation demonstrates an overall blunted response during puberty relative to adulthood. This finding is consistent with a hyposensitivity to stress and pharmacological agents at puberty in animals that are in a hyperdopaminergic state. These findings of combined elevated cAMP accumulation and reduced cAMP sensitivity during adolescence have clinical implications for hypothesized mechanism and course of ADHD and its treatment. The maturational decline in cAMP activity may explain why this disorder recedes, while, simultaneously cAMP becomes more responsive to D1 and D2 receptor stimulation in adulthood.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Differences in behavior and monoamine laterality following neonatal clomipramine treatment.

Postnatal treatment between 8 to 21 days of age with clomipramine (15 mg/kg, twice daily) produces an animal model that has many of the behavioral hallmarks of depression. In this study, we investigated the enduring behavioral and neurochemical effects of this early treatment in adult animals. Locomotor activity was increased in clomipramine-treated males, but not females, relative to vehicle-treated subjects. Increases in anxiety-like behavior in the elevated plus maze also were observed in clomipramine-exposed adults, but no sex differences were detected. Clomipramine-treated animals had shifts in the laterality of monoamines in limbic regions with lower serotonin levels on the right side while vehicle-treated animals had lower serotonin on the left side. The lateralization of dopamine content demonstrated the same pattern. This decline in monoaminergic content is consistent with clinical studies demonstrating decrements in serotonin as well as alterations in the lateralization of function in individuals with major depressive order.

Analysis of Variance↗

Developmental neurobiology of childhood stress and trauma.

Severe early stress and maltreatment produces a cascade of events that have the potential to alter brain development. The first stage of the cascade involves the stress-induced programming of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems to augment stress responses. These neurohumors then produce effects on neurogenesis, synaptic overproduction and pruning, and myelination during specific sensitive periods. Major consequences include reduced size of the mid-portions of the corpus callosum; attenuated development of the left neocortex, hippocampus, and amygdala along with abnormal frontotemporal electrical activity; and reduced functional activity of the cerebellar vermis. These alterations, in turn, provide the neurobiological framework through which early abuse increases the risk of developing post-traumatic stress disorder (PTSD), depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder, and substance abuse.

Brain↗

Pubertal changes in gonadal hormones do not underlie adolescent dopamine receptor overproduction.

Males, but not females, overproduce dopamine receptors in the striatum of rats across the periadolescent period followed by their elimination during young adulthood. In order to investigate the role that gonadal hormones play in this pubertal process, rats were castrated or ovariectomized at postnatal day (P) 28 when estrogen and testosterone levels are beginning to surge. Dopamine D1 and D2 striatal receptor density was then determined with autoradiography at P40 (adolescence) and P80 (young adulthood) to determine if either testosterone stimulates the overproduction of receptors in males or if estrogen inhibits this process in females. Neither castration nor ovariectomy altered dopamine receptor density, although enhanced testosterone levels increased D1 receptor binding 4.2% and 19.5% in males and females, respectively. The results of this study suggest that the endogenous rise in gonadal steroid hormones during puberty is not responsible for the overproduction of receptors in males or the lack of overproduction in females.

Aging↗

Altered responsiveness to cocaine in rats exposed to methylphenidate during development.

Evidence in laboratory animals indicates that exposure to stimulants produces sensitization to their rewarding effects, a process that in humans would be expected to increase the risk of substance abuse. However, therapeutic administration of stimulants such as methylphenidate (MPH) in children with attention deficit hyperactivity disorder reportedly reduces the risk of substance abuse. Here we show in rats that exposure to MPH during pre-adolescence causes behavioral and neurobiological adaptations that endure into adulthood, and that are consistent with increased sensitivity to the aversive effects of cocaine.

Adaptation, Physiological↗

Altering the course of neurodevelopment: a framework for understanding the enduring effects of psychotropic drugs.

Childhood is a time filled with wondrous changes, as brain plasticity permits experiences to shape the immature brain to meet the demands of the environment. Change occurs at various levels--from neuroanatomy, including within a given region and its connectivity to other regions, to the function of neurotransmitter systems and their reactivity to pharmacological agents in the short- and long-term. The nature and degree to which drug exposure influences the final adult topography is influenced greatly by the maturational phase of these critical factors. Moreover, evidence is slowly emerging that suggests that the long-term effects of drug exposure are delayed and expressed once the vulnerable system reaches maturation (i.e., typically during adulthood). This phenomenon is known as neuronal imprinting and occurs when the effects of drug exposure outlast the drug itself. Thus, understanding the persistent effects critically depends on the window of observation. Embracing this concept should influence how we conduct preclinical assessments of developmental drug exposure, and ultimately how we conduct clinical assessments of drug efficacy, effectiveness, and safety for the treatment of childhood psychiatric disorders. In this article, we present a model to provide a heuristic framework for making predictions about imprinted effects of childhood drug exposure. We then review epidemiological data on attention deficit hyperactivity disorder (ADHD) and childhood depression, prescription practices, and what is known regarding the long-term consequences of drug exposure in these populations. We conclude with a discussion of the current status of preclinical studies on juvenile stimulant exposure.

Adaptation, Physiological↗

Trajectories of brain development: point of vulnerability or window of opportunity?

Brain development is a remarkable process. Progenitor cells are born, differentiate, and migrate to their final locations. Axons and dendrites branch and form important synaptic connections that set the stage for encoding information potentially for the rest of life. In the mammalian brain, synapses and receptors within most regions are overproduced and eliminated by as much as 50% during two phases of life: immediately before birth and during the transitions from childhood, adolescence, to adulthood. This process results in different critical and sensitive periods of brain development. Since Hebb (1949) first postulated that the strengthening of synaptic elements occurs through functional validation, researchers have applied this approach to understanding the sculpting of the immature brain. In this manner, the brain becomes wired to match the needs of the environment. Extensions of this hypothesis posit that exposure to both positive and negative elements before adolescence can imprint on the final adult topography in a manner that differs from exposure to the same elements after adolescence. This review endeavors to provide an overview of key components of mammalian brain development while simultaneously providing a framework for how perturbations during these changes uniquely impinge on the final outcome.

Age Factors↗

The neurobiological consequences of early stress and childhood maltreatment.

Early severe stress and maltreatment produces a cascade of neurobiological events that have the potential to cause enduring changes in brain development. These changes occur on multiple levels, from neurohumoral (especially the hypothalamic-pituitary-adrenal [HPA] axis) to structural and functional. The major structural consequences of early stress include reduced size of the mid-portions of the corpus callosum and attenuated development of the left neocortex, hippocampus, and amygdala. Major functional consequences include increased electrical irritability in limbic structures and reduced functional activity of the cerebellar vermis. There are also gender differences in vulnerability and functional consequences. The neurobiological sequelae of early stress and maltreatment may play a significant role in the emergence of psychiatric disorders during development.

Adolescent↗