Craig W Berridge
University Of Wisconsin Madison
Project start date: 2009-05-02
Project end date: 2014-02-28
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Craig W Berridge
AMPHETAMINE-LIKE STIMULANTS: NOREPINEPHRINE & BEHAVIOR
Craig W Berridge, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R01DA010681-09 from National Institute On Drug Abuse IRG: ZRG1
Abstract: Stimulant drug abuse is highly prevalent, constituting a major public health concern. To gain better insight into mechanisms contributing to stimulant drug abuse, the neurochemical mechanisms subserving the behavioral effects of these drugs have been intensively examined. Neurochemically, these drugs increase synaptic concentrations of dopamine (DA) and norepinephrine (NE). Evidence indicates that actions of DA within the striatum and nucleus accumbens are critical components of the rewarding and locomotor activating effects of stimulants. It is generally believed that NE serves a minimal contributory role in these behavioral actions of stimulants. However, recent observations by the PI indicate that previous studies may not have adequately addressed this issue. The rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). The ability of stimulants to maintain waking and enhance alertness has long been exploited and is a contributing factor to the widespread use of these drugs. However, the degree to which NE or DA participates in the "arousal"-enhancing actions of stimulants and which anatomical site(s) subserve such actions remains enigmatic. A variety of observations suggest that noradrenergic systems participates in the modulation of behavioral state. Previous studies by the PI demonstrated potent actions of the locus coeruleus (LC) on EEG and behavioral indices of waking via actions of beta-receptors located within structures located within the medial basal forebrain. Additional studies demonstrated potent arousal-enhancing effects of amphetamine when infused into these regions. These observations suggest that at least some of the arousal-enhancing actions of stimulants may be due to enhanced release of NE within the basal forebrain. Utilizing a combination of behavioral, pharmacological, and anatomical methods, the proposed studies will provide novel information concerning the degree to which NE participates in the behavioral effects of stimulants and the receptor mechanisms and circuitry involved in these actions. Information obtained in these studies may provide insight into mechanisms subserving, and treatment of, stimulant drug abuse.
Keywords: amphetamine, dopamine, neuroanatomy, neuropharmacology, norepinephrine, prosencephalon, psychopharmacology, substance abuse related behavior, arousal, attention, drug interaction, frontal lobe /cortex, innervation, neurotransmitter receptor, preoptic area, wakefulness, behavioral /social science research tag, electroencephalography, electromyography, histology, immunocytochemistry, laboratory rat, mature animal
Project start date: 1997-02-10
Project end date: 2006-11-30
5R01DA010681-09 (2005): $252000
5R01DA010681-08 (2004): $252000
2R01DA010681-05 (2001): $242980
NEUROCHEMISTRY OF AMPHETAMINE INDUCED AROUSAL
Craig W Berridge, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5K02DA000389-05 from National Institute On Drug Abuse IRG: ZDA1
Abstract: Stimulant drug abuse is a highly prevalent problem that constitutes a major public health concern. To gain better insight into mechanisms contributing to stimulant drug abuse, the neurochemical mechanisms subserving the behavioral effects of these drugs have been intensively examined. Neurochemically, these drugs increase synaptic concentrations of dopamine (DA) and norepinephrine (NE). Evidence indicates that actions of DA within the striatum and nucleus accumbens are critical components of the rewarding and locomotor activating effects of stimulants. In contrast, NE appears to serve a minimal contributory role in these behavioral actions of stimulants. The potent rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). The ability of stimulants to maintain waking and enhance alertness has long been exploited and is a contributing factor to the widespread use/abuse of these drugs. However, the degree to which NE or DA participates in the "arousal"-enhancing actions of stimulants and which anatomical site(s) subserve which actions remains enigmatic. A variety of observations suggests that the locus-coeruleus (LC)-noradrenergic system participates in the modulation of behavioral state. Previous studies by the PI demonstrated potent actions of LC on EEG and behavioral indices of waking via actions on beta- receptors located within a region of the basal forebrain encompassing the medial septum and the posterior shell of the nucleus accumbens (MS). Preliminary studies indicate that potent arousal-enhancing effects are observed following amphetamine infusions into this region (e.g. induction and maintenance of waking). These observations suggest that, at least some of, the arousal-enhancing actions of stimulants may be due to enhanced release of NE within MS. The propose multi-disciplinary studies assess the degree to which amphetamine acts within this region of the basal forebrain to enhance EEG, EMG, and behavioral indices of arousal and to assess the degree to which NE participates in these actions. As such, these studies will provide novel information concerning the degree to which NE participates in the behavioral effects of stimulants.
Keywords: amphetamine, arousal, dopamine, neuroanatomy, neurochemistry, norepinephrine, adrenergic receptor, central nervous system stimulant, dopamine receptor, dosage, drug abuse, hypothalamus, locus coeruleus, neocortex, neurotransmitter antagonist, nucleus accumbens, preoptic area, prosencephalon, psychopharmacology, electroencephalography, electromyography, halothane, injection /infusion, laboratory rat
Project start date: 1999-05-10
Project end date: 2004-03-31
5K02DA000389-05 (2003): $130248
5K02DA000389-04 (2002): $103314
5K02DA000389-03 (2001): $80024
5K02DA000389-02 (2000): $75929
1K02DA000389-01A1 (1999): $72042
Neurobiology Of Orexin/Hypocretin-Induced Arousal
Craig W Berridge, Professor
Psychologyuniversity Of Wisconsin Madison
21 N. Park Street, Suite 6401
madison, Wi 537151218
Grant 1R01MH062359-01A1 from National Institute Of Mental Health IRG: ZRG1
Abstract: Orexins are a newly identified peptide family comprised of two peptides, orexin-A and orexin-B, which are synthesized by a limited population of neurons located within the lateral and dorsal hypothalamus. Initially, these peptides were demonstrated to stimulate feeding, when administered in relatively high doses. However, orexin neurons project widely throughout the brain and spinal cord, including to regions associated with the regulation of behavioral state. Consistent with these observations, substantial evidence suggests dysregulation of orexin neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Further, recent evidence suggests that these peptides exert an activating influence on forebrain and behavioral state. In preliminary studies, the PI has observed potent arousal-enhancing actions of orexin when administered into sleeping/resting animals, at doses substantially below those that elicit feeding. The neural mechanisms that underlie these arousal-enhancing actions remain unknown. Work by the PI demonstrates that the locus coeruleus (LC)-noradrenergic system exerts a potent activational influence on forebrain neuronal and behavioral activity states. These actions derive, in part, from actions of norepinephrine within a subset of basal forebrain structures. Given this, it is of interest that orexin-containing fibers innervate LC, these same basal forebrain structures, as well as other regions implicated in the regulation of behavioral state. The proposed studies will complete preliminary studies that characterize the dose-dependent effects of orexin-A and -B on behavioral state. Additionally, these studies will characterize the anatomical organization of the orexin efferent projection system. Finally, these studies will provide initial assessment of a number of potential neural mechanisms underlying orexin-enhanced arousal. Specifically, the extent to which orexins alter behavioral state via actions within certain basal forebrain and brainstem structures will be examined. These studies will provide a better understanding of the neurobiology of orexin, the neurobiology of sleep and waking, and the potential role of orexin in narcolepsy and other disorders of arousal
Keywords: arousal, neurobiology, neurotransmitter, wakefulness brain stem, locus coeruleus, neural transmission, prosencephalon laboratory rat
Project start date: 2001-09-04
Project end date: 2005-06-30
1R01MH062359-01A1 (2001): $241567
5R01MH062359-04 (2004): $218250
Sponsored Links Excellgen http://Excellgen.com
LOW-DOSE METHYLPHENIDATE AND THE PREFRONTAL CORTEX
Craig W Berridge
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 1R01MH081843-01A2 from National Institute Of Mental Health
Abstract: Low doses of psychostimulants, including methylphenidate (MPH/Ritalin), are widely used clinically due to their behavioral-calming and cognition-enhancing actions. Less well-recognized is the fact that these drugs exert similar actions in both normal human and animal subjects. Of particular relevance to the proposed studies are the well-documented facilitatory actions of low- doses of MPH and other psychostimulants on prefrontal cortex (PFC)-dependent cognition (i.e. working memory and sustained attention). Despite these cognition-enhancing actions, these drugs possess certain risks, including toxicity and abuse/addiction. For this reason, there is much concern about the widespread use of these drugs, particularly in children. Moreover, these risks preclude use of these drugs in other disorders/conditions associated with relatively modest impairment in PFC- dependent cognition (i.e. normal aging, sleep deprivation). To better develop non-stimulant drugs for the treatment of ADHD and other disorders and conditions associated with impaired PFC- dependent cognition, it is important to understand the neural mechanisms responsible for the cognition-enhancing actions of low-dose psychostimulants. Surprisingly, little is known about the neural substrates underlying the behavioral/cognitive actions of low-dose stimulants. We recently demonstrated that at low doses that improve both working memory and sustained attention in rats, PFC catecholamine efflux displays a greater sensitivity than catecholamine efflux in a number of cortical and subcortical regions outside the PFC. Additional studies indicate that cognition-enhancing doses of MPH increase PFC neuronal responsivity, an effect not observed in the somatosensory cortex. Combined, these observations suggest a prominent role of the PFC in the cognition-enhancing actions of low-dose MPH. The proposed studies are designed to further test this hypothesis and to provide insight into the neural mechanisms that underlie these actions. These studies will use a combination of microdialysis measures of catecholamine release, electrophysiological measurement of PFC neuronal activity, pharmacological manipulations and tests PFC-dependent cognition. These studies will provide novel insight into the neurobiological mechanisms through which low-dose psychostimulants improve cognitive function. Additionally, these studies will provide important information for the development of new pharmacological treatments for ADHD and other disorders/conditions associated with PFC dysfunction. These studies will provide novel insight into the neural mechanisms that underlie the cognition- enhancing actions of low-dose psychostimulants as well as the neurobiology of higher cognitive function. Importantly, these studies will provide information necessary for the development of new pharmacological treatments lacking the potential adverse actions of psychostimulants for a variety of cognitive/behavioral disorders associated with prefrontal cortical dysfunction
Keywords: 0-11 years old; 1, 2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 2-Piperidineacetic acid, alpha-phenyl-, methyl ester; 3, 4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1, 2-benzenediol; AD/HD; ADHD; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Animals; Attention; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Behavior; Behavior Disorders; Behavioral; Catecholamines; Child; Child Youth; Children (0-21); Cognition; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Common Rat Strains; Corpus Striatum; Corpus striatum structure; D1 receptor; Development; Disease; Disorder; Disturbance in cognition; Dopamine; Dopamine D1 Receptor; Dose; Drug effect disorder; Drug usage; Drugs; Dysfunction; Functional disorder; Human; Human, Child; Human, General; Hydroxytyramine; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Impaired cognition; Impairment; Infusion; Infusion procedures; Laboratories; Levarterenol; Levonorepinephrine; Mammals, Rats; Man (Taxonomy); Man, Modern; Measurement; Measures; Medication; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Methylphenidate; Microdialysis; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurobiology; Neurochemistry; Neurocyte; Neurons; Noradrenaline; Norepinephrine; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacological Treatment; Physiopathology; Prefrontal Cortex; Rat; Rattus; Receptor Protein; Relative; Relative (related person); Research Design; Risk; Ritalin; Role; Science of neurochemistry; Series; Short-Term Memory; Sleep Deprivation; Somatosensory Cortex; Striate Body; Striatum; Structure; Study Type; Sympathins; Testing; Therapeutic Effect; Toxic effect; Toxicities; addiction; amygdaloid nuclear complex; attention deficit hyperactive disorder; base; behavioral disorder; children; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; disease/disorder; drug action; drug use; drug/agent; improved; insight; neural; neural mechanism; neurobiological; neurobiological mechanism; neurochemistry; neuromechanism; neuronal; normal aging; novel; pathophysiology; psychostimulant; receptor; relating to nervous system; response; social role; somatosensory; somesthetic sensory cortex; striatal; study design; working memory; youngster
Relevance: These studies will provide novel insight into the neural mechanisms that underlie the cognition- enhancing actions of low-dose psychostimulants as well as the neurobiology of higher cognitive function. Importantly, these studies will provide information necessary for the development of new pharmacological treatments lacking the potential adverse actions of psychostimulants for a variety of cognitive/behavioral disorders associated with prefrontal cortical dysfunction
Project start date: 2009-05-02
Project end date: 2014-04-30
Budget start date: 2-MAY-2009
Budget end date: 30-APR-2010
PFA/PA: PA-07-121
1R01MH081843-01A2 (2009): $461942
Neurochemistry Of Amphetamine Induced Arousal
Craig W Berridge, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5K02DA000389-09 from National Institute On Drug Abuse IRG: NIDA
Abstract: Low doses of amphetamine-like stimulants exert arousal- and attention-enhancing actions. The ability of stimulants to enhance alert waking has long-been exploited and is a contributing factor to the widespread illicit use of these drugs. Additionally, these drugs are used widely in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The neurochemical mechanisms subserving the behavioral effects of moderate-to-high doses of these drugs have been examined intensively. Neurochemically, these drugs increase synaptic concentrations of dopamine (DA) and norepinephrine (NE). Evidence indicates that actions of DA within the striatum and nucleus accumbens are critical components of the rewarding and locomotor activating effects of stimulants. The rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). Previous studies by the PI demonstrate potent actions of the locus coeruleus-noradrenergic system on EEG and behavioral indices of waking via actions of beta-and alpha1 -receptors located within the medial basal forebrain. Additionally, the PI has demonstrated that amphetamine acts within the same basal forebrain regions to exert arousal-enhancing (wake-promoting) actions. Recent studies also suggest arousal-enhancing actions of DA. The PI has initiated a research program that assesses the contribution of NE and DA to the arousal-enhancing actions of stimulants and identifies the neurocircuitry underlying these actions. Recent studies demonstrate potent arousal-enhancing actions of the peptides, hypocretins. Dysregulation of hypocretin neurotransmission appears to be an etiological factor in the arousal disorder, narcolepsy. Stimulants elicit an activation of hypocretin neurons, suggesting the participation of hypocretins in at least a subset of the behavioral actions of these drugs, including their therapeutic action in the treatment of narcolepsy. Utilizing a combination of behavioral, pharmacological, and anatomical methods, the proposed studies will provide novel information concerning the degree to which NE, DA and hypocretins participate in the behavioral effects of. Information obtained in these studies may provide insight into mechanisms underlying, and future treatment of, stimulant drug abuse, ADHD and narcolepsy.
Keywords: amphetamine, arousal, neurochemistry, neuropharmacology, brain electrical activity, dopamine, neural information processing, neurotransmitter receptor, norepinephrine, orexin, laboratory rat
Project start date: 1999-05-10
Project end date: 2009-03-31
5K02DA000389-09 (2007): $133650
5K02DA000389-08 (2006): $132678
5K02DA000389-07 (2005): $131706
2K02DA000389-06 (2004): $130734
AMPHETAMINE LIKE STIMULANTS--NOREPINEPHRINE AND BEHAVIOR
Craig W Berridge, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 1R01DA010681-01 from National Institute On Drug Abuse IRG: NIDA
Abstract: Applicant s ) Stimulant drug abuse is a highly prevalent problem that constitutes a major public health concern. To gain better insight into mechanisms contributing to stimulant drug abuse, the neurochemical mechanisms subserving the behavioral effects of these drugs have been intensively examined. Neurochemically, these drugs increase synaptic concentrations of dopamine (DA) and norepinephrine (NE). Evidence indicates that actions of DA within the striatum and nucleus accumbens are critical components of the rewarding and locomotor activating effects of stimulants. In contrast, NE appears to serve a minimal contributory role in these behavioral actions of stimulants. The potent rewarding effects of these drugs are superimposed upon an alert behavioral state (e.g. prolonged periods of waking/enhanced alertness). The ability of stimulants to maintain waking and enhance alertness has long been exploited and is a contributing factor to the widespread use/abuse of these drugs. However, the degree to which NE or DA participates in the "arousal"-enhancing actions of stimulants and which anatomical site(s) subserve such actions remains enigmatic. A variety of observations suggest that the locus-coeruleus (LC)-noradrenergic system participates in the modulation of behavioral state. Previous studies by the PI demonstrated potent actions of LC on EEG and behavioral indices of waking via actions of beta-receptors located within a region of the basal forebrain encompassing the medial septum and the posterior shell of the nucleus accumbens (MS). Preliminary studies indicate that potent arousal-enhancing effects are observed following amphetamine infusions into this region (e.g. induction and maintenance of waking). These observations suggest that, at least some of, the arousal-enhancing actions of stimulants may be due to enhanced release of NE within MS. The proposed studies assess the degree to which amphetamine acts within this region of the basal forebrain to enhance EEG, EMG, and behavioral indices of arousal and to assess the degree to which NE participates in these actions. Utilizing a combination of anesthetized and unanesthetized preparations, local infusions, in vivo microdialysis to assess NE release, and EEG, EMG, and behavioral measures, these studies will provide novel information concerning the degree to which NE participates in the behavioral effects of stimulants. Information obtained in these studies may provide insight into mechanisms subserving, and treatment of, stimulant drug abuse.
Keywords: amphetamine, neuropharmacology, norepinephrine, prosencephalon, psychopharmacology, frontal lobe /cortex, neocortex, neurotransmitter receptor, nucleus accumbens, electroencephalography, electromyography, laboratory rat
Project start date: 1997-02-10
Project end date: 2000-11-30
1R01DA010681-01 (1997): $133175
5R01DA010681-04 (2000): $143829
5R01DA010681-03 (1999): $130836