Browsing by Subject "Dopamine"
- Results Per Page
- Sort Options
Item Open Access Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging.(Am J Psychiatry, 2002-06) Due, Deborah L; Huettel, Scott A; Hall, Warren G; Rubin, David COBJECTIVE: The authors sought to increase understanding of the brain mechanisms involved in cigarette addiction by identifying neural substrates modulated by visual smoking cues in nicotine-deprived smokers. METHOD: Event-related functional magnetic resonance imaging (fMRI) was used to detect brain activation after exposure to smoking-related images in a group of nicotine-deprived smokers and a nonsmoking comparison group. Subjects viewed a pseudo-random sequence of smoking images, neutral nonsmoking images, and rare targets (photographs of animals). Subjects pressed a button whenever a rare target appeared. RESULTS: In smokers, the fMRI signal was greater after exposure to smoking-related images than after exposure to neutral images in mesolimbic dopamine reward circuits known to be activated by addictive drugs (right posterior amygdala, posterior hippocampus, ventral tegmental area, and medial thalamus) as well as in areas related to visuospatial attention (bilateral prefrontal and parietal cortex and right fusiform gyrus). In nonsmokers, no significant differences in fMRI signal following exposure to smoking-related and neutral images were detected. In most regions studied, both subject groups showed greater activation following presentation of rare target images than after exposure to neutral images. CONCLUSIONS: In nicotine-deprived smokers, both reward and attention circuits were activated by exposure to smoking-related images. Smoking cues are processed like rare targets in that they activate attentional regions. These cues are also processed like addictive drugs in that they activate mesolimbic reward regions.Item Open Access Activity in descending dopaminergic neurons represents but is not required for leg movements in the fruit fly Drosophila.(Physiol Rep, 2015-03) Tschida, Katherine; Bhandawat, VikasModulatory descending neurons (DNs) that link the brain to body motor circuits, including dopaminergic DNs (DA-DNs), are thought to contribute to the flexible control of behavior. Dopamine elicits locomotor-like outputs and influences neuronal excitability in isolated body motor circuits over tens of seconds to minutes, but it remains unknown how and over what time scale DA-DN activity relates to movement in behaving animals. To address this question, we identified DA-DNs in the Drosophila brain and developed an electrophysiological preparation to record and manipulate the activity of these cells during behavior. We find that DA-DN spike rates are rapidly modulated during a subset of leg movements and scale with the total speed of ongoing leg movements, whether occurring spontaneously or in response to stimuli. However, activating DA-DNs does not elicit leg movements in intact flies, nor do acute bidirectional manipulations of DA-DN activity affect the probability or speed of leg movements over a time scale of seconds to minutes. Our findings indicate that in the context of intact descending control, changes in DA-DN activity are not sufficient to influence ongoing leg movements and open the door to studies investigating how these cells interact with other descending and local neuromodulatory inputs to influence body motor output.Item Open Access Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.(Psychopharmacology, 2020-06) Levin, Edward D; Wells, Corinne; Hawkey, Andrew; Holloway, Zade; Blair, Graham; Vierling, Alexander; Ko, Ashley; Pace, Caroline; Modarres, John; McKinney, Anthony; Rezvani, Amir H; Rose, Jed ERationale
A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration.Objectives
The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration.Methods
Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment.Results
Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects.Conclusions
These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.Item Open Access An Actor-Critic Circuit in the Songbird Enables Vocal Learning(2020) Kearney, MatthewThe ability to learn and to modify complex vocal sequences requires extensive practice coupled with performance evaluation through auditory feedback. An efficient solution to the challenge of vocal learning, stemming from reinforcement learning theory, proposes that an “actor” learns correct vocal behavior through the instructive guidance of an auditory “critic.” However, the neural circuit mechanisms supporting performance evaluation and even how “actor” and “critic” circuits are instantiated in biological brains are fundamental mysteries. Here, I use a songbird model to dissociate “actor” and “critic” circuits and uncover biological mechanisms for vocal learning.
First, I employ closed-loop optogenetic methods in singing birds to identify two inputs to midbrain dopamine neurons that operate in an opponent fashion to guide vocal learning. Next, I employ electrophysiological methods to establish a microcircuit architecture underlying this opponent mechanism. Notably, I show that disrupting activity in these midbrain dopamine inputs precisely when auditory feedback is processed impairs learning, showing that they function as “critics.” Conversely, I show that disrupting activity in a downstream premotor region prior to vocal production prevents learning, consistent with an “actor” role. Taken together, these experiments dissociate discrete “actor” and “critic” circuits in the songbird’s brain and elucidate neural circuit and microcircuit mechanisms by which “actors” and “critics” working cooperatively enable vocal learning.
Item Open Access Characterizing antipsychotic behavioral and corticostriatal neurophysiological effects to psychotomimetic challenge(2022) Thomas, Gwenaëlle E.Schizophrenia is marked by significant disruptions to dopaminergic signaling across the mesolimbic and mesocortical circuits. Antipsychotic drugs have been largely unsuccessfully treating cognitive symptoms that debilitate the schizophrenia patient population. Dopamine 2 Receptor (D2R)- βeta arrestin 2 (βarr2) biased signaling, independent of the canonical G protein signaling, has emerged as a potential mechanism for antipsychotic drugs to restore dopaminergic signaling and improve treatment resistant cognitive symptoms. In the following experiments, I described gene editing tools to systematically investigate D2R signaling in a region or cell specific manner. Next, I evaluated the behavioral effects of two functionally selective D2-like βarr2 biased ligands against psychotomimetic challenge from phencyclidine or amphetamine. Then I employed chemogenetics to perform synthetic pharmacology experiments e.g. studying the signaling cascade of a drug without using the drug, to discover how D2- R βarr2 signaling produces antipsychotic effects in the prefrontal cortex. Lastly, I characterized the neurophysiological changes induced by phencyclidine and a D2R βarr2 biased ligand within relevant brain regions in the meso -limbic and -cortical circuits. Our results determined antipsychotic like activity is 1) regulated by excitation-inhibitory balance maintained by cortical GABA interneurons 2) dependent on βarr2.
Item Open Access Cognitive Neurostimulation: Learning to Volitionally Invigorate Mesolimbic Reward Network Activation(2015) MacInnes, JeffThe brain’s dopaminergic system is critical to adaptive behaviors, and is centrally implicated in various pathologies. For decades, research has aimed at better characterizing what drives the mesolimbic dopamine system and the resulting influence on brain physiology and behavior in both humans and animals. To date, the dominant modes of research have relied on extrinsic approaches: pharmacological manipulations, direct brain stimulation, or delivering behavioral incentives in laboratory tasks. A critical open question concerns whether individuals can modulate activation within this system volitionally. That is, can individuals use self-generated thoughts and imagery to invigorate this system on their own? This process can be referred to as “cognitive neurostimulation” -- a precise and non-invasive stimulation of neural systems via cognitive and behavioral strategies. And if not, can they be taught to do so? Recent technological advances make it feasible to present human participants with information about ongoing neural activations in a fast and spatially precise manner. Such feedback signals might enable individuals to eventually learn to control neural systems via fine-tuning of behavioral strategies. The studies described herein investigate whether individuals can learn to volitionally invigorate activation within the mesolimbic reward network. We demonstrate that under the right training context, individuals can successfully learn to generate cognitive states that elicit and sustain activation in the ventral tegmental area (VTA), the source of dopamine production within the mesolimbic network. Although participants were explicitly trained to increase VTA activation, multiple mesolimbic regions exhibited increased connectivity during and after training. Together, these findings suggest new frameworks for aligning psychological and biological perspectives, and for understanding and harnessing the power of neuromodulatory systems.
Item Open Access Cooperativity between the Phosphorylation of Thr(95) and Ser(77) of NHERF-1 in the Hormonal Regulation of Renal Phosphate Transport(JOURNAL OF THE ROYAL SOCIETY INTERFACE, 2013-01-06) Weinman, Edward J; Steplock, Deborah; Zhang, Yinghua; Biswas, Rajatsubhra; Bloch, Robert J; Shenolikar, ShirishThe phosphorylation of the sodium-hydrogen exchanger regulatory factor-1 (NHERF-1) plays a key role in the regulation of renal phosphate transport by parathyroid hormone (PTH) and dopamine. Ser(77) in the first PDZ domain of NHERF-1 is a downstream target of both hormones. The current experiments explore the role of Thr(95), another phosphate acceptor site in the PDZ I domain, on hormone-mediated regulation of phosphate transport in the proximal tubule of the kidney. The substitution of alanine for threonine at position 95 (T95A) significantly decreased the rate and extent of in vitro phosphorylation of Ser(77) by PKC. In NHERF-1-null proximal tubule cells, neither PTH nor dopamine inhibited sodium-dependent phosphate transport. Infection of the cells with adenovirus expressing full-length WT GFP-NHERF-1 increased basal phosphate transport and restored the inhibitory effect of both PTH and dopamine. Infection with full-length NHERF-1 containing a T95A mutation, however, increased basal phosphate transport but not the responsiveness to either hormone. As determined by surface plasmon resonance, the substitution of serine for aspartic acid (S77D) in the PDZ I domain decreased the binding affinity to the sodium-dependent phosphate transporter 2a (Npt2a) as compared with WT PDZ I, but a T95D mutation had no effect on binding. Finally, cellular studies indicated that both PTH and dopamine treatment increased the phosphorylation of Thr(95). These studies indicate a remarkable cooperativity between the phosphorylation of Thr(95) and Ser(77) of NHERF-1 in the hormonal regulation of renal phosphate transport. The phosphorylation of Thr(95) facilitates the phosphorylation of Ser(77). This, in turn, results in the dissociation of NHERF-1 from Npt2a and a decrease in phosphate transport in renal proximal tubule cells.Item Open Access Developmental exposure to the flame retardant, triphenyl phosphate, causes long-lasting neurobehavioral and neurochemical dysfunction.(Birth defects research, 2023-02) Hawkey, Andrew B; Evans, Janequia; Holloway, Zade R; Pippen, Erica; Jarrett, Olivia; Kenou, Bruny; Slotkin, Theodore A; Seidler, Frederic J; Levin, Edward DBackground
Human exposures to organophosphate flame retardants result from their use as additives in numerous consumer products. These agents are replacements for brominated flame retardants but have not yet faced similar scrutiny for developmental neurotoxicity. We examined a representative organophosphate flame retardant, triphenyl phosphate (TPP) and its potential effects on behavioral development and dopaminergic function.Methods
Female Sprague-Dawley rats were given low doses of TPP (16 or 32 mg kg-1 day-1 ) via subcutaneous osmotic minipumps, begun preconception and continued into the early postnatal period. Offspring were administered a battery of behavioral tests from adolescence into adulthood, and littermates were used to evaluate dopaminergic synaptic function.Results
Offspring with TPP exposures showed increased latency to begin eating in the novelty-suppressed feeding test, impaired object recognition memory, impaired choice accuracy in the visual signal detection test, and sex-selective effects on locomotor activity in adolescence (males) but not adulthood. Male, but not female, offspring showed marked increases in dopamine utilization in the striatum, evidenced by an increase in the ratio of the primary dopamine metabolite (3,4-dihydroxyphenylacetic acid) relative to dopamine levels.Conclusions
These results indicate that TPP has adverse effects that are similar in some respects to those of organophosphate pesticides, which were restricted because of their developmental neurotoxicity.Item Open Access Dopamine regulation of human speech and bird song: a critical review.(Brain Lang, 2012-09) Simonyan, Kristina; Horwitz, Barry; Jarvis, Erich DTo understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and song production. In this review, we bring together the two fields of investigations of dopamine action on voice control in humans and songbirds, who share similar behavioral and neural mechanisms for speech and song production. While human studies investigating the role of dopamine in speech control are limited to reports in neurological patients, research on dopaminergic modulation of bird song control has recently expanded our views on how this system might be organized. We discuss the parallels between bird song and human speech from the perspective of dopaminergic control as well as outline important differences between these species.Item Open Access Dopamine, Drugs, and Estradiol: The Roles of ERα and ERβ in the Mesencephalic Dopamine System and Dopamine-Mediated Behaviors of Mice(2012) Van Swearingen, Amanda Elyse DaySex differences in drug addiction are mediated in part by effects of the ovarian hormone estradiol (E2) within the ascending dopamine (DA) system from the midbrain to the striatum. Estradiol enhances the effects of psychostimulants, but the exact underlying mechanisms are unknown. Mice could serve as an ideal genetically-tractable model for mechanistic studies into sex and hormone effects within the DA system but have been under-utilized. This study sought to: 1) characterize psychostimulant-induced behavior in mice as an indirect but quantifiable measure of DA neurotransmission, and 2) elucidate the mechanism underlying E2's enhancement of psychostimulant effects in females using surgical, pharmacological, and genetic manipulations. The spontaneous behavior of mice during habituation to a novel environment and after the psychostimulants d-amphetamine (AMPH; 1, 2.5, and/or 5 mg/kg) and cocaine (COC; 5, 15, and/or 30 mg/kg) were assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Behaviors were assessed in the following groups of mice: intact males and females; ovariectomized mice replaced with either E2 for 2 days or 30 minutes or with estrogen receptor-selective agonists; and female mice lacking either ERα (αERKO) or ERβ (βERKO) versus wildtype (WT) littermates. Brain psychostimulant concentrations and tissue content of DA and its metabolites were determined at the time of maximum behavioral stimulation. Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Intact female mice exhibited more patterned locomotion and a shift towards higher behavior scores after psychostimulants despite having lower AMPH and equivalent COC brain levels as males. Actively ovariectomized mice exhibited fewer ambulations and lower behavior scores during habituation and after psychostimulants than Sham females. Two days but not 30 minutes of E2 replacement restored COC-induced behavioral responses to Sham levels. ERα-selective PPT replacement in ovariectomized mice and genetic ablation of ERα in αERKO mice altered COC-stimulated behavior. Immunohistochemistry revealed that midbrain DA neurons in mice express ERβ but not ERα, and that non-DA cells in the midbrain and the striatum express ERα. These results indicate that E2 enhances COC-stimulated locomotion in mice through an indirect effect of ERα. ERα may alter behavior through presynaptic effects on DA neuron activity and/or through postsynaptic effects on transcription and signal transduction pathways within striatal neurons.
Item Open Access Dopaminergic mechanisms of individual differences in the discounting and subjective value of rewards(2022) Castrellon, JaimeEveryday, animals make decisions that require balancing tradeoffs like time delays, uncertainty, and physical effort demands with the prospect of rewards like food or money. The tendency to devalue rewards according to these tradeoffs is also known as discounting and depends on how much subjective value an animal places on a reward. These discounting decisions are supported by different neural systems. The influence of dopamine signaling is well-characterized as a modulator of motivation and decision making. However, the role of dopamine as a marker of interindividual differences of reward sensitivity and valuation is less clearly understood. Using a combination of neuroimaging techniques (functional magnetic resonance imaging and positron emission tomography), behavioral experiments, and meta-analyses, this dissertation identifies how trait-like variation in dopamine function explains the way people differ in their preferences and neural computations of value. Overall, the findings indicate that while dopamine may exert acute influence over reward discounting behavior, these associations may not extend to trait-like differences. Specifically, individual differences in dopamine receptor availability are related to discounting behavior in clinical populations but not healthy adults. Nevertheless, individual differences in dopamine are related to functional brain activation associated with the subjective valuation of rewards—the input to choice behavior. These results highlight that interindividual variation in dopamine is more directly linked to neural computations than observed behaviors and that dopamine-mediated psychopathology does not precisely map on to acute pharmacodynamics.
Item Open Access Dopaminergic modulation of retinal processing from starlight to sunlight.(Journal of pharmacological sciences, 2019-05-04) Roy, Suva; Field, Greg DNeuromodulators such as dopamine, enable context-dependent plasticity of neural circuit function throughout the central nervous system. For example, in the retina, dopamine tunes visual processing for daylight and nightlight conditions. Specifically, high levels of dopamine release in the retina tune vision for daylight (photopic) conditions, while low levels tune it for nightlight (scotopic) conditions. This review covers the cellular and circuit-level mechanisms within the retina that are altered by dopamine. These mechanisms include changes in gap junction coupling and ionic conductances, both of which are altered by the activation of diverse types of dopamine receptors across diverse types of retinal neurons. We contextualize the modulatory actions of dopamine in terms of alterations and optimizations to visual processing under photopic and scotopic conditions, with particular attention to how they differentially impact distinct cell types. Finally, we discuss how transgenic mice and disease models have shaped our understanding of dopaminergic signaling and its role in visual processing. Cumulatively, this review illustrates some of the diverse and potent mechanisms through which neuromodulation can shape brain function.Item Open Access Emotional Modulation of Time Perception(2014) Lake, JessicaOur perception of time is not veridical but rather is consistently modulating by changing dynamics in our environment. Anecdotal experiences suggest that emotions can be powerful modulators of time perception; nevertheless, the mechanisms underlying emotion-induced temporal distortions remain unclear. Widely accepted pacemaker-accumulator models of time perception suggest that changes in arousal and attention have unique influences on temporal judgments and contribute to emotional distortions of time perception. However, such models conflict with current views of arousal and attention and their interaction from the perspective of affective and cognitive science. The aim of this dissertation was to more clearly examine the role of arousal and attention in driving emotion-induced temporal distortions by explicitly manipulating and measuring these constructs using well-established timing procedures within the context of affective manipulations induced via classical conditioning and drug administration. Measures of physiological arousal and subjective measures of top-down attention to emotional stimuli were assessed both within and across subjects. The findings reported here suggest that current models of time perception do not adequately explain the variability in emotion-induced temporal distortions. Instead these findings provide support for a new theoretical model of emotion-induced temporal distortions proposed in the current manuscript that emphasizes both the unique and interactive influences of arousal and attention on time perception, dependent on temporal dynamics, event relationships, and individual differences. Collectively, these findings may point to plausible neurobiological mechanisms of emotion-induced temporal distortions and have important implications for our understanding of how emotions may modulate our perceptual experiences in service of adaptively responding to biologically relevant stimuli.
Item Open Access Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice.(J Neurosci, 2003-11-12) Bohn, Laura M; Gainetdinov, Raul R; Sotnikova, Tatyana D; Medvedev, Ivan O; Lefkowitz, Robert J; Dykstra, Linda A; Caron, Marc GThe reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of mu-opioid receptors (muOR). Both mu-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of proteins. GPCRs are known to undergo desensitization involving phosphorylation of the receptor and the subsequent binding of beta(arrestins), which prevents further receptor-G-protein coupling. Mice lacking beta(arrestin)-2 (beta(arr2)) display enhanced sensitivity to morphine in tests of pain perception attributable to impaired desensitization of muOR. However, whether abrogating muOR desensitization affects the reinforcing and psychomotor properties of morphine has remained unexplored. In the present study, we examined this question by assessing the effects of morphine and cocaine on locomotor activity, behavioral sensitization, conditioned place preference, and striatal dopamine release in beta(arr2) knock-out (beta(arr2)-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the beta(arr2)-KO mice, morphine induced more pronounced increases in striatal extracellular dopamine than in WT mice. Moreover, the rewarding properties of morphine in the conditioned place preference test were greater in the beta(arr2)-KO mice when compared with the WT mice. Thus, beta(arr2) appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.Item Open Access Expectation Modulates Episodic Memory Formation via Dopaminergic Circuitry(2016) Stanek, Jessica KateEpisodic memory formation is shaped by expectation. Events that generate expectations have the capacity to influence memory. Additionally, whether subsequent events meet or violate expectations has consequences for memory. However, clarification is still required to illuminate the circumstances and direction of memory modulation. In the brain, the mechanisms by which expectation modulates memory formation also require consideration. The dopamine system has been implicated in signaling events associated with different states of expectancy; it has also been shown to modulate episodic memory formation in the hippocampus. Thus, the studies included in this dissertation utilized both functional magnetic resonance imaging (fMRI) and behavioral testing to examine when and how the dopaminergic system supports the modulation of memory by expectation. The work aimed to characterize the activation of dopaminergic circuitry in response to cues that generate expectancy, during periods of anticipation, and in response to outcomes that resolve expectancy. The studies also examined how each of these event types influenced episodic memory formation. The present findings demonstrated that novelty and expectancy violation both drive dopaminergic circuitry capable of contributing to memory formation. Consistent with elevated dopaminergic midbrain and hippocampus activation for each, expected versus expectancy violating novelty did not differentially affect memory success. We also showed that high curiosity expectancy states drive memory formation. This was supported by activation in dopaminergic circuitry that was greater for subsequently remembered information only in the high curiosity state. Finally, we showed that cues that generate high expected reward value versus high reward uncertainty differentially modulate memory formation during reward anticipation. This behavioral result was consistent with distinct temporal profiles of dopaminergic action having differential downstream effects on episodic memory formation. Integrating the present studies with previous research suggests that dopaminergic circuitry signals events that are unpredicted, whether cuing or resolving expectations. It also suggests that contextual differences change the contribution of the dopaminergic system during anticipation, depending on the nature of the expectation. And finally, this work is consistent with a model in which dopamine elevation in response to expectancy events positively modulates episodic memory formation.
Item Open Access Functional Selectivity at the Dopamine D2 Receptor(2015) Peterson, Sean MichaelThe neuromodulator dopamine signals through the dopamine D2 receptor (D2R) to modulate central nervous system functions through diverse signal transduction pathways. D2R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D2R signals through distinct G protein and β-arrestin pathways and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D2R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D2R mutants with strongly biased interactions for either G protein or β-arrestin. Additionally, various permutations of these mutants were used to identify critical determinants of D2R functional selectivity. D2R interactions with the two major downstream signal transducers were effectively dissociated and G protein signaling accounts for D2R canonical MAP kinase signaling cascade activation. Nevertheless, when expressed in mice, the β-arrestin biased D2R caused a significant potentiation of amphetamine-induced locomotion, while the G protein biased D2R had minimal effects. The mutant receptors generated here provide a new molecular tool set that enable a better definition of the individual roles of G protein and β-arrestin signaling in D2R pharmacology, neurobiology and associated pathologies.
Item Open Access Impact of acute nicotine exposure on monoaminergic systems in adolescent and adult male and female rats.(Neurotoxicology and teratology, 2022-09) Eddins, Donnie; Petro, Ann; Levin, Edward DAdolescence is a period of risk for beginning tobacco addiction. Differential neural response to nicotine in adolescents vs. adults may help explain the increased vulnerability to nicotine self-administration seen with adolescent onset. We indexed the effects of acute nicotine ditartrate (0.4 mg/kg, salt weight) administration on dopamine (DA) and serotonin (5HT) as well as the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in several brain regions (nucleus accumbens, striatum and frontal cortex) of 6-week old (adolescent) and 10-week old (young adult) Sprague-Dawley rats. When nicotine was administered DA concentrations in the accumbens were significantly higher in adults than in adolescents, whereas there was no age-related difference without nicotine. However neither age group showed a significant effect of nicotine vs. age-matched controls. DA turnover in the accumbens was significantly greater in adolescent females in response to nicotine, but adult females did not show this effect and neither did males of either age group. DA turnover in the striatum was significantly higher in adolescents than adults regardless of nicotine administration. In the frontal cortex, there was a more complex effect. Without nicotine, adult male rats had higher DA concentrations than adolescent males, whereas female rats did not differ from adolescent to adult ages. When given nicotine, the age effect was no longer seen in males. However, there was not a significant effect of nicotine vs. age-matched controls in either age group. No age or nicotine effects were seen in females. 5HT in the accumbens was significantly increased by nicotine administration in adults but not in adolescents. Altered neural responsivity of adolescents to nicotine-induced neural effects particularly in accumbens DA and 5HT may be related to the increased nicotine dose concentrations they self-administer.Item Open Access Increased renal dopamine and acute renal adaptation to a high-phosphate diet.(American journal of physiology. Renal physiology, 2011-05) Weinman, Edward J; Biswas, Rajatsubhra; Steplock, Deborah; Wang, Peili; Lau, Yuen-Sum; Desir, Gary V; Shenolikar, ShirishThe current experiments explore the role of dopamine in facilitating the acute increase in renal phosphate excretion in response to a high-phosphate diet. Compared with a low-phosphate (0.1%) diet for 24 h, mice fed a high-phosphate (1.2%) diet had significantly higher rates of phosphate excretion in the urine associated with a two- to threefold increase in the dopamine content of the kidney and in the urinary excretion of dopamine. Animals fed a high-phosphate diet had a significant increase in the abundance and activity of renal DOPA (l-dihydroxyphenylalanine) decarboxylase and significant reductions in renalase, monoamine oxidase A, and monoamine oxidase B. The activity of protein kinase A and protein kinase C, markers of activation of renal dopamine receptors, were significantly higher in animals fed a high-phosphate vs. a low-phosphate diet. Treatment of rats with carbidopa, an inhibitor of DOPA decarboxylase, impaired adaptation to a high-phosphate diet. These experiments indicate that the rapid adaptation to a high-phosphate diet involves alterations in key enzymes involved in dopamine synthesis and degradation, resulting in increased renal dopamine content and activation of the signaling cascade used by dopamine to inhibit the renal tubular reabsorption of phosphate.Item Open Access Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease(2011) Hutchinson, Ashley NicoleActivation of monoaminergic receptors is essential to the mechanism by which psychostimulants and antidepressants induce changes in behavior. Although these drugs rapidly increase monoaminergic transmission, they need to be administered for several weeks or months in order to produce long-lasting alterations in behavior. This observation suggests that it is likely that molecular mechanisms downstream of receptor activation contribute to the effects of psychostimulants and antidepressants on behavior.
Recently, we and others have demonstrated that the methyl-CpG-binding protein 2 (MeCP2) contributes to both neural and behavioral adaptations induced by repeated psychostimulant exposure (Deng et al, 2010, Im et al, 2010). Psychostimulants induce rapid and robust phosphorylation of MeCP2 at Ser421 (pMeCP2), a site that is thought to modulate MeCP2-dependent chromatin regulation (Cohen et al, 2011), and this phosphorylation event is selectively induced in the GABAergic interneurons of the nucleus accumbens (NAc). In order to understand the signaling pathways that contribute to the pattern of pMeCP2 we observe, I characterized the monoaminergic signaling pathways that regulate pMeCP2. I found that activation of dopamine (DA) and serotonin (5-HT) transmission is sufficient to induce pMeCP2. The novel finding that drugs that activate serotonergic signaling induce pMeCP2 suggests that pMeCP2 may be involved in serotonergic mediated behaviors.
To determine the requirement of pMeCP2 in serotonergic mediated behaviors, I utilized mice that bear a knockin (KI) mutation that converts serine to alanine at 421 (S421A) (Cohen et al, 2011). After characterizing the behavioral phenotype of these mice, I conducted tests to assess anxiety- and depression-like behavior. I found that the KI mice do not display heightened anxiety in several assays. However, the KI mice exhibit depression-like behavior in the forced swim and tail suspension but show no differences compared to wild-type (WT) littermates in the sucrose preference test, suggesting that pMeCP2 may be implicated in the behavioral response to stressful stimuli.
Because we are interested in examining the role of pMeCP2 in the behavioral adaptations to chronic monoaminergic signaling, I then put the KI mice and their WT littermates through chronic social defeat stress, a behavioral paradigm in which repeated exposure to aggressive mice causes social avoidance that is reversed by chronic but not acute antidepressant treatment. Although the WT mice show an increase in social interaction following chronic imipramine treatment, the KI mice fail to show a behavioral response to chronic treatment. These data suggest that pMeCP2 may be implicated in the antidepressant action of chronic imipramine. Finally, investigation of the brain regions in which pMeCP2 may be contributing to the behavioral response to chronic imipramine treatment revealed that chronic but not acute imipramine treatment induces pMeCP2 in the lateral habenula (LHb), a brain region involved in the behavioral response to stress and reward. Together, these data implicate a novel role for pMeCP2 in depression-like behavior and the behavioral response to chronic antidepressant treatment.
Item Open Access Neurofunctional Characterization of the At-Risk Mental State for Psychosis(2014) Sumner, Elizabeth JohnsonSchizophrenia is a complex and debilitating psychiatric illness characterized by positive symptoms like hallucinations and delusions and negative symptoms like blunting of affect, avolition, and poverty of thought. This constellation of symptoms is hypothesized to result from dopaminergic dysfunction, glutamatergic dysfunction, and dysfunctional stress-reactivity. Prior to the onset of schizophrenia there is a prodromal period when individuals begin to experience sub-clinical symptoms and decreased functioning. This period is important to study not only to help elucidate biologic mechanisms of the illness but also to potentially alter the course of the illness through early treatment. The difficulty of studying this period lies in its recognizing it prospectively. To address this researchers have begun to study the at-risk mental state, a state that is associated with a high but not inevitable risk of conversion to psychosis. The studies described in this dissertation are aimed at a neurofunctional characterization of the at-risk mental state in three primary domains: reward-anticipation, hippocampus-dependent learning, and stress-reactivity. Individuals at-risk for psychosis and age-matched healthy volunteers underwent functional magnetic resonance imaging while performing tasks targeting these domains. In the reward-anticipation task, at-risk individuals showed decreased ventral tegmental area (VTA) and dorsolateral prefrontal cortex (DLPFC) responses to reward anticipation. In the hippocampus-dependent learning task, at-risk individuals showed deficits in hippocampus-dependent memory, decreased VTA engagement, and increased DLPFC activation during learning of associations between items. In the stress-reactivity task, at-risk individuals showed increased activation in the bed nucleus of the stria terminalis/basal forebrain (BNST), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in response to neutral faces. Collectively, these experiments show that neurofunctional deficits in reward-anticipation, hippocampus-dependent learning, and stress-reactivity are present in the putative prodrome, prior to the onset of psychosis. Regions implicated are those that would be expected based on current models of schizophrenia and neurofunctional studies in those with frank psychosis.