Dopamine receptors in the learning, memory and drug reward circuitry.
(2009)
Journal - Seminars in cell & developmental biology (England )
Abstract :
As primary targets of a variety of abused drugs G-protein-coupled dopamine receptors in the brain play an important role in mediating the various drug-induced alterations in neural and psychological processes thought to underlie the transition from voluntary drug use to habitual and progressively compulsive drug-taking. This review considers the functional involvement of the five major dopamine receptor subtypes in drug reinforcement and reward and discusses the development of addiction as a series of learning transitions from initial goal-directed behaviour to pathological stimulus-response habits in which drug-seeking behaviours are automatically elicited and maintained by cues and stimuli associated with drug rewards.
Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry.
(2008)
Journal - Pharmacology, biochemistry, and behavior (United States )
Abstract :
Impulsive acts and decisions are a part of everyday normal behavior. However, in its pathological forms, impulsivity can be a debilitating disorder often associated with a number of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). This article reviews recent progress in our understanding of the neurobiology of impulsivity using examples from recent investigations in experimental animals. Evidence is reviewed from several well-established paradigms with putative utility in assessing distinct forms of impulsive behavior in rodents, including the 5-choice serial reaction time (5CSRT) task and the delay discounting paradigm. We discuss, in particular, recent psychopharmacological and in-vivo neurochemical data in task-performing rats showing functional heterogeneity of the forebrain dopamine (DA), noradrenaline (NA), serotonin (5-HT) and acetylcholine (ACh) systems and identify how these systems normally function to facilitate flexible goal-directed behavior in situations that tax basic attentional functions and inhibitory response control mechanisms. We also discuss future research needs in terms of understanding the functional diversity of different sub-regions of prefrontal cortex (PFC) and how these systems normally interact with the striatum and main nuclei of origin of DA and NA neurons. Finally, we argue in line with others that animal paradigms are unlikely to model all aspects of complex psychiatric conditions such as ADHD but components of such syndromes may be amenable to investigation using sophisticated animal models based on highly-defined psychiatric endophenotypes.
| ISSN : | 0091-3057 |
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| Mesh Heading : | Acetylcholine Animals Attention Deficit Disorder with Hyperactivity Conditioning, Operant Corpus Striatum Dopamine Humans Prefrontal Cortex Reaction Time Serotonin secretion drug therapy etiology metabolism physiology physiology |
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| Mesh Heading Relevant : | Impulsive Behavior physiology physiology |
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Enduring deficits in sustained visual attention during withdrawal of intravenous methylenedioxymethamphetamine self-administration in rats: results from a comparative study with d-amphetamine and methamphetamine.
(2007)
Journal - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (United States )
Abstract :
Although amphetamine-derived stimulants are widely associated with neurotoxicity, it is poorly understood whether extended exposure to such drugs produces lasting effects on neurocognitive function. This study investigates whether chronically self-administered d-amphetamine, methamphetamine (MA), or methylenedioxymethamphetamine (MDMA) leads to residual deficits in a rodent test of sustained visual attention and impulsivity. Rats were trained on a five-choice serial reaction time task and subsequently trained to self-administer d-amphetamine, MA, or MDMA (all 50 microg/infusion), intravenously, for 3 weeks. Effects on performance were evaluated 24 h after drug discontinuation and for several weeks thereafter, including various challenge sessions to increase the attentional demands of the task. The results indicate divergent patterns of self-administration among the three drugs tested with increasing rates of intake evident in rats self-administering amphetamine, but not MA, and widely fluctuating rates in the MDMA group. Withdrawal of MA resulted in severe behavioral disturbances, with significant effects on accuracy, omissions, response latency, and impulsivity that lasted up to 2 weeks in some cases. Amphetamine and MDMA withdrawal were associated with similar, but shorter-lasting effects on performance. However, when challenged with a high event rate session 6 weeks after drug discontinuation, rats previously exposed to MDMA continued to show deficits in the accuracy and speed of responding. These findings show that amphetamine-derived stimulants have both short- and long-term consequences for psychomotor functioning. The demonstration of residual deficits in rats chronically exposed to MDMA raises some concern about the potential harm caused by this drug in human ecstasy users.
| ISSN : | 0893-133X |
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| Mesh Heading : | Amphetamine-Related Disorders Amphetamines Animals Attention Attention Deficit Disorder with Hyperactivity Brain Central Nervous System Stimulants Cognition Disorders Dextroamphetamine Hallucinogens Male Methamphetamine N-Methyl-3,4-methylenedioxyamphetamine Perceptual Disorders Psychomotor Performance Rats Reaction Time Substance Withdrawal Syndrome Time Visual Perception drug effects chemically induced physiopathology physiopathology adverse effects physiopathology adverse effects adverse effects adverse effects chemically induced physiopathology drug effects physiology drug effects drug effects |
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| Mesh Heading Relevant : | physiopathology adverse effects drug effects chemically induced adverse effects physiopathology |
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Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement.
(2007)
Journal - Science (New York, N.Y.) (United States )
Abstract :
Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.
| ISSN : | 1095-9203 |
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| Mesh Heading : | Animals Basal Ganglia Benzamides Cocaine Corpus Striatum Dopamine Dopamine Antagonists Male Nucleus Accumbens Positron-Emission Tomography Pyrrolidines Rats Reaction Time Receptors, Dopamine D2 Receptors, Dopamine D3 Self Administration Synaptic Transmission metabolism radionuclide imaging metabolism metabolism psychology metabolism radionuclide imaging metabolism metabolism pharmacology radionuclide imaging metabolism |
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| Mesh Heading Relevant : | Cocaine-Related Disorders Impulsive Behavior Reinforcement (Psychology) administration & dosage metabolism metabolism metabolism |
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Cognitive sequelae of intravenous amphetamine self-administration in rats: evidence for selective effects on attentional performance.
(2005)
Journal - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (United States )
Abstract :
Characterizing the nature and severity of cognitive deficits associated with chronic stimulant abuse may provide new insights into the neural substrates of drug addiction because such deficits may contribute to the chronic relapsing nature of compulsive drug use. This investigation examines in rats the long-term cognitive consequences of intravenously self-administered amphetamine, specifically on performance of a 5-choice serial reaction time task (5-CSRTT), which assesses visuo-spatial attention and impulsivity. Rats experienced 5 days of intravenous (i.v.) amphetamine self-administration and were then withdrawn for a period of 9 days, during which time testing on the 5-CSRTT took place. This was repeated on five consecutive occasions for a period of 10 weeks. Controls experienced identical training on the 5-CSRTT but during the self-administration sessions received yoked i.v. infusions of normal saline. The results reveal a selective and reproducible pattern of deficits on the 5-CSRTT following repeated withdrawal from amphetamine self-administration, with deleterious effects on the speed and accuracy of responding as well as increased omission errors. Premature (impulsive) responding, perseveration, and food consumption latencies were not significantly affected. Deficits in attentional performance fully recovered 4-5 days after amphetamine cessation and there was no evidence of any long-term disturbances, even when the attentional load was increased. However, following a 2-month abstinence period, abnormalities in the subsequent effects of acute noncontingent amphetamine were found, with increased omissions, slower response times, and reduced impulsivity. Thus, contingent i.v. amphetamine administration has both short- and long-term consequences, which may be relevant to the complex disturbances that accompany drug addiction.
| ISSN : | 0893-133X |
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| Mesh Heading : | Amphetamine Animals Attention Choice Behavior Cognition Injections, Intravenous Male Rats Rats, Inbred Strains Reaction Time Self Administration administration & dosage blood drug effects drug effects |
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| Mesh Heading Relevant : | pharmacology physiology physiology |
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Time-limited modulation of appetitive Pavlovian memory by D1 and NMDA receptors in the nucleus accumbens.
(2005)
Journal - Proceedings of the National Academy of Sciences of the United States of America (United States )
Abstract :
Recent research has implicated the nucleus accumbens (NAc) in consolidating recently acquired goal-directed appetitive memories, including spatial learning and other instrumental processes. However, an important but unresolved issue is whether this forebrain structure also contributes to the consolidation of fundamental forms of appetitive learning acquired by Pavlovian associative processes. In addition, although dopaminergic and glutamatergic influences in the NAc have been implicated in instrumental learning, it is unclear whether similar mechanisms operate during Pavlovian conditioning. To evaluate these issues, the effects of posttraining intra-NAc infusions of D1, D2, and NMDA receptor antagonists, as well as d-amphetamine, were determined on Pavlovian autoshaping in rats, which assesses learning by discriminated approach behavior to a visual conditioned stimulus predictive of food reward. Intracerebral infusions were given either immediately after each conditioning session to disrupt early memory consolidation or after a delay of 24 h. Findings indicate that immediate, but not delayed, infusions of both D1 (SCH 23390) and NMDA (AP-5) receptor antagonists significantly impair learning on this task. By contrast, amphetamine and the D2 receptor antagonist sulpiride were without significant effect. These findings provide the most direct demonstration to date that D1 and NMDA receptors in the NAc contribute to, and are necessary for, the early consolidation of appetitive Pavlovian learning.
| ISSN : | 0027-8424 |
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| Mesh Heading : | Animals Appetite Benzazepines Brain Mapping Conditioning, Classical Dextroamphetamine Habituation, Psychophysiologic Male Memory Nucleus Accumbens Rats Rats, Inbred Strains Receptors, Dopamine D1 Receptors, N-Methyl-D-Aspartate Sulpiride Time Factors pharmacology pharmacology drug effects drug effects drug effects drug effects pharmacology |
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| Mesh Heading Relevant : | physiology physiology physiology physiology physiology physiology |
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Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin.
(2005)
Journal - Psychopharmacology (Germany )
Abstract :
RATIONALE: Identifying the long-term neurocognitive sequelae of drug addiction may have important implications for understanding the compulsive, chronically relapsing nature of this brain disorder. OBJECTIVES: Our aim was to investigate the consequences of chronic intravenous self-administration of cocaine or heroin on visual attentional processes in rats. METHODS: Adult male rats were pretrained on a five-choice serial reaction time task (5-CSRTT) of sustained visual attention and impulsivity and later trained to self-administer cocaine or heroin intravenously during multiple 'long-access' self-administration cycles. Control rats had identical training and surgical experience, but received passive infusions of saline during self-administration sessions. Executive cognitive processes of selection and inhibitory response control were evaluated 24 h after drug discontinuation and for a further 6 days prior to the next cycle of self-administration. RESULTS: Findings indicate similar behavioural disturbances on the five-choice task in cocaine- and heroin-withdrawn rats with significantly impaired attentional accuracy, increased omissions and slower latencies to respond correctly during the early, but not late, withdrawal period. The self-administration of either drug was not associated with significant alterations in impulsive actions, and there was no evidence of persistent alterations in visual attentional performance. However, unlike rats self-administering cocaine, the motivation to collect food reward on the 5-CSRTT was significantly reduced in heroin-withdrawn animals for a period of at least 6 weeks. CONCLUSIONS: These data, together with recent findings of attentional dysfunction during the withdrawal of intravenous self-administration of amphetamine, suggest that generically different drugs of abuse produce similar disturbances in visual attentional performance during the early withdrawal period.
| ISSN : | 0033-3158 |
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| Mesh Heading : | Analgesics Analysis of Variance Animals Attention Deficit Disorder with Hyperactivity Behavior, Animal Choice Behavior Cocaine Conditioning, Operant Drug Administration Routes Extinction, Psychological Heroin Male Rats Reaction Time Reinforcement (Psychology) Self Administration Substance-Related Disorders Time Factors administration & dosage drug effects drug effects administration & dosage drug effects drug effects administration & dosage drug effects psychology |
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| Mesh Heading Relevant : | Motivation adverse effects etiology adverse effects adverse effects complications |
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Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates.
(2004)
Journal - Neuroscience and biobehavioral reviews (United States )
Abstract :
The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated 'supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.
| ISSN : | 0149-7634 |
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| Mesh Heading : | Acetylcholine Animals Brain Chemistry Cognition Decision Making Memory, Short-Term Motor Activity Norepinephrine Prefrontal Cortex Problem Solving Reaction Time metabolism physiology physiology physiology metabolism anatomy & histology |
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| Mesh Heading Relevant : | physiology physiology physiology physiology |
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Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour
(2009)
Journal - Human Molecular Genetics
Abstract :
The Prader–Willi syndrome (PWS) genetic interval containsseveral brain-expressed small nucleolar (sno)RNA species thatare subject to genomic imprinting. In vitro studies have shownthat one of these snoRNA molecules, h/mbii-52, negatively regulatesediting and alternative splicing of the serotonin 2C receptor(5htr2c) pre-RNA. However, the functional consequences of lossof h/mbii-52 and subsequent increased post-transcriptional modificationof 5htr2c are unknown. 5HT2CRs are important in controllingaspects of cognition and the cessation of feeding, and disruptionof their function may underlie some of the psychiatric and feedingabnormalities seen in PWS. In a mouse model for PWS lackingexpression of mbii-52 (PWS-IC+/–), we show an increasein editing, but not alternative splicing, of the 5htr2c pre-RNA.This change in post-transcriptional modification is associatedwith alterations in a number of 5HT2CR-related behaviours, includingimpulsive responding, locomotor activity and reactivity to palatablefoodstuffs. In a non-5HT2CR-related behaviour, marble burying,loss of mbii-52 was without effect. The specificity of the behaviouraleffects to changes in 5HT2CR function was further confirmedusing drug challenges. These data illustrate, for the firsttime, the physiological consequences of altered RNA editingof 5htr2c linked to mbii-52 loss that may underlie specificaspects of the complex PWS phenotype and point to an importantfunctional role for this imprinted snoRNA.