Tracie A Paine

Oberlin College, Oberlin, OH, United States

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Publications (11)48.83 Total impact

  • Samuel K Asinof, Tracie A Paine
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    ABSTRACT: This protocol describes the 5-choice serial reaction time task, which is an operant based task used to study attention and impulse control in rodents. Test day challenges, modifications to the standard task, can be used to systematically tax the neural systems controlling either attention or impulse control. Importantly, these challenges have consistent effects on behavior across laboratories in intact animals and can reveal either enhancements or deficits in cognitive function that are not apparent when rats are only tested on the standard task. The variety of behavioral measures that are collected can be used to determine if other factors (i.e., sedation, motivation deficits, locomotor impairments) are contributing to changes in performance. The versatility of the 5CSRTT is further enhanced because it is amenable to combination with pharmacological, molecular, and genetic techniques.
    Journal of visualized experiments : JoVE. 01/2014;
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    ABSTRACT: Decision-making is a complex cognitive process that is impaired in a number of psychiatric disorders. In the laboratory, decision-making is frequently assessed using "gambling" tasks that are designed to simulate real-life decisions in terms of uncertainty, reward and punishment. Here, we investigate whether lesions of the medial prefrontal cortex (PFC) cause impairments in decision-making using a rodent gambling task (rGT). In this task, rats have to decide between 1 of 4 possible options: 2 options are considered "advantageous" and lead to greater net rewards (food pellets) than the other 2 "disadvantageous" options. Once rats attained stable levels of performance on the rGT they underwent sham or excitoxic lesions and were allowed to recover for 1 week. Following recovery, rats were retrained for 5 days and then the effects of a dopamine D1-like receptor antagonist (SCH23390) or a D2-like receptor antagonist (haloperidol) on performance were assessed. Lesioned rats exhibited impaired decision-making: they made fewer advantageous choices and chose the most optimal choice less frequently than did sham-operated rats. Administration of SCH23390 (0.03mg/kg), but not haloperidol (0.015-0.03mg/kg) attenuated the lesion-induced decision-making deficit. These results indicate that the medial PFC is important for decision-making and that excessive signaling at D1 receptors may contribute to decision-making impairments.
    Behavioural brain research 01/2013; · 3.22 Impact Factor
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    ABSTRACT: Re-exposure to drug-associated cues causes significant drug craving in recovering addicts, which may precipitate relapse. In animal models of craving, drug-seeking responses for contingent delivery of drug-associated cues sensitizes or "incubates" across drug withdrawal. To date there is limited evidence supporting an incubation effect for behaviors mediated by non-contingent presentation of drug-associated cues. Here we used a model of cue-induced conditioned activity to determine if the conditioned locomotor response to a non-contingent presentation of a drug-associated cue sensitizes across drug withdrawal. In addition, because cue-induced drug-seeking responses are mediated by the rostral basolateral amygdala (rBLA), we investigated whether this structure is critical for the expression of cue-induced conditioned activity. A conditioned association between cocaine (15 mg/kg) and a compound discrete cue (flashing bicycle light + a metronome) was established over 12 conditioning sessions in male Sprague-Dawley rats. In experiment 1, cue-induced conditioned activity was assessed on 3 occasions: 3, 14 and 28 days following the final drug-cue conditioning session. Cocaine-conditioned rats demonstrated reliable cue-induced conditioned activity across all 3 test sessions, however there was no evidence of an incubation effect. To determine whether repeated testing prevented the observation of an incubation effect, rats in experiment 2 were tested either 3-days or 28-days following conditioning; again no incubation effect was observed. In experiment 3, either saline or the GABA(A) receptor agonist muscimol was infused prior to testing. Intra-BLA infusions of muscimol prevented the expression of cue-induced conditioned activity. These data support the role of the rBLA in mediating conditioned responses to drug-associated cues. The failure to observe an incubation effect for cue-induced conditioned activity may point to fundamental difference in the manner by which contingent and non-contingent presentations of drug-associated cues influence behavior.
    Pharmacology Biochemistry and Behavior 01/2013; · 2.82 Impact Factor
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  • Samuel K Asinof, Tracie A Paine
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    ABSTRACT: Attention deficits are a core cognitive symptom of schizophrenia; the neuropathology underlying these deficits is not known. Attention is regulated, at least in part, by the prefrontal cortex (PFC), a brain area in which pathology of γ-aminobutyric acid (GABA) neurons has been consistently observed in post-mortem analysis of the brains of people with schizophrenia. Specifically, expression of the 67-kD isoform of the GABA synthesis enzyme glutamic acid decarboxylase (GAD67) is reduced in parvalbumin-containing fast-spiking GABA interneurons. Thus it is hypothesized that reduced cortical GABA synthesis and release may contribute to the attention deficits in schizophrenia. Here the effect of reducing cortical GABA synthesis with l-allylglycine (LAG) on attention was tested using three different versions of the 5-choice serial reaction time task (5CSRTT). Because 5CSRTT performance can be affected by locomotor activity, we also measured this behavior in an open field. Finally, the expression of Fos protein was used as an indirect measure of reduced GABA synthesis. Intra-cortical LAG (10 μg/0.5 μl/side) infusions increased Fos expression and resulted in hyperactivity in the open field. Intra-cortical LAG infusions did not affect attention in any version of the 5CSRTT. These results suggest that a general decrease in GABA synthesis is not sufficient to cause attention deficits. It remains to be tested whether a selective decrease in GABA synthesis in parvalbumin-containing GABA neurons could cause attention deficits. Decreased cortical GABA synthesis did increase locomotor activity; this may reflect the positive symptoms of schizophrenia.
    Neuropharmacology 09/2012; 65C:39-47. · 4.11 Impact Factor
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    ABSTRACT: Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in γ-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA(A) receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA(A) receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased Fos immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased Fos immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2011; 36(8):1703-13. · 8.68 Impact Factor
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    ABSTRACT: Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance. We examined the effects of two drugs that cause disruptions in perception and cognition in humans-the kappa-opioid receptor (KOR) agonist salvinorin A (salvA; 0.125-4.0 mg/kg) and the non-competitive NMDA receptor antagonist ketamine (0.63-20 mg/kg)-on behavior in rats using the 5-choice serial reaction time task (5CSRTT), a food-motivated test that quantifies attention. We also compared the binding profiles of salvA and ketamine at KORs and NMDA receptors. SalvA and ketamine produced the same pattern of disruptive effects in the 5CSRTT, characterized by increases in signs often associated with reduced motivation (omission errors) and deficits in processing (elevated latencies to respond correctly). Sessions in which rats were fed before testing suggest that reduced motivation produces a subtly different pattern of behavior. Pretreatment with the KOR antagonist JDTic (10 mg/kg) blocked all salvA effects and some ketamine effects. Binding and function studies revealed that ketamine is a full agonist at KORs, although not as potent or selective as salvA. SalvA and ketamine have previously under-appreciated similarities in their behavioral effects and pharmacological profiles. By implication, KORs might be involved in some of the cognitive abnormalities observed in psychiatric disorders such as schizophrenia.
    Psychopharmacology 04/2010; 210(2):263-74. · 4.06 Impact Factor
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    ABSTRACT: Previous work demonstrates that microinjections of dopamine D1 receptor agonists and antagonists directly into the medial prefrontal cortex (mPFC) of rats can affect attention in the 5-choice serial reaction time task (5CSRTT), a rodent test analogous to the continuous performance task used to study attention in humans. These studies were designed to determine if intra-mPFC modulation of cAMP-dependent protein kinase (PKA), an intracellular target of D1 receptor stimulation, also affects attention. We examined the effects of localized microinfusions of the cAMP analog Sp-cAMPS (to activate PKA) or Rp-cAMPS (to inhibit PKA) in the 5CSRTT. In parallel, we examined the effects of these manipulations on activity levels in an open field, as well as on motivation and the capacity to make complex operant responses using the intracranial self-stimulation (ICSS) test. Inhibition of PKA reduced accuracy in the 5CSRTT and caused substantial increases in locomotor activity without affecting motivation or the capacity to emit operant responses at high rates. Stimulation of PKA also affected some measures of performance in the 5CSRTT, but this effect was associated with reduced capacity to respond at high rates. Viral vector-mediated disruption of cAMP response element-binding protein (CREB), a transcription factor directly activated by PKA, also reduced accuracy in the 5CSRTT, raising the possibility that acute inhibition of PKA and sustained inhibition of CREB affect attention through common mechanisms. These studies indicate that PKA inhibition within the mPFC of rats produces inattention and hyperactivity, and thus might be useful in modeling human attention disorders.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2009; 34(9):2143-55. · 8.68 Impact Factor
  • Tracie A. Paine, William A. Carlezon
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    ABSTRACT: BackgroundAttentional deficits that accompany schizophrenia are not effectively treated by available antipsychotic medications. Disruption of NMDA receptor function is often used to model aspects of this disorder in rodents. We used the 5-choice serial reaction time task (5CSRTT) to characterize attentional deficits caused by acute administration or withdrawal from chronic administration of the NMDA receptor antagonist MK-801, and determine if they are ameliorated by haloperidol or clozapine.MethodsAcute studies involved tests in the presence of MK-801: rats were administered haloperidol (0.008–0.125 mg/kg, SC) or clozapine (0.16–2.5 mg/kg, SC) in combination with MK-801 (0.25 mg/kg, IP) prior to daily test sessions. Chronic studies involved tests in the absence of MK-801: following daily tests, rats were administered MK-801 (0.5 mg/kg, IP) and tested 24 h later in the absence or presence of haloperidol or clozapine.ResultsAcute MK-801 disrupted performance: it decreased accuracy while increasing omissions, premature responses, and magazine entries. Haloperidol reduced disruptive effects associated with increased activation, whereas it exacerbated other deficits. Clozapine dose-dependently attenuated several of the MK-801-induced performance deficits. Withdrawal from chronic MK-801 progressively increased omissions and response latencies and decreased premature responding, suggesting an amotivational state. Neither haloperidol nor clozapine ameliorated these performance deficits.DiscussionAcute administration and withdrawal from chronic MK-801 administration produced distinct behavioral profiles in the 5CSRTT. Acute MK-801 impaired attention and impulse control whereas chronic MK-801 withdrawal caused signs consistent with amotivation. Haloperidol and clozapine were more effective at attenuating deficits caused by acute MK-801 administration.
    Neuropharmacology 01/2009; · 4.11 Impact Factor
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    ABSTRACT: Several preclinical studies indicate that selective kappa-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (K(i) = 0.11-6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.
    Journal of Pharmacology and Experimental Therapeutics 02/2008; 324(1):188-95. · 3.89 Impact Factor
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    ABSTRACT: Attentional deficits accompany many psychiatric disorders, underscoring the need for rodent models of attention to screen novel therapeutic agents and characterize the biological basis of attention. The five-choice serial reaction time task (5CSRTT) is one such model. Here, we characterized the effects of four standard psychotropic agents on performance in the 5CSRTT. Male Sprague-Dawley rats were trained in the 5CSRTT (5-sec inter-trial interval and .5-sec stimulus duration) until they reliably performed at > 60% accuracy and < 20% omissions. They were then treated systemically with the stimulant methylphenidate (MPH) (.063-2.0 mg/kg), the N-methyl-D-aspartate antagonist dizocilpine (MK-801) (.008-.25 mg/kg), the norepinephrine reuptake inhibitor desipramine (DMI) (.63-10 mg/kg), or the kappa-receptor agonist U69,593 (.25-2.0 mg/kg) 30 min before testing. Methylphenidate (.5 mg/kg) increased accuracy. Dizocilpine impaired accuracy (.25 mg/kg), increased premature responses (.063-.25 mg/kg), and increased omissions (.25 mg/kg). Desipramine decreased premature responses (5.0 mg/kg) but increased omissions (10 mg/kg), correct response latencies (5.0-10.0 mg/kg), and reward latencies (5.0-10.0 mg/kg). The kappa-opioid agonist U69,593 (1.0-2.0 mg/kg) increased omissions and correct response latencies. In Sprague-Dawley rats, psychotropic drugs with distinct pharmacological profiles produced distinguishable effects in the 5CSRTT. The effects of these classes of drugs under our testing conditions are qualitatively similar to their effects in humans.
    Biological Psychiatry 09/2007; 62(6):687-93. · 9.25 Impact Factor

Publication Stats

146 Citations
48.83 Total Impact Points


  • 2012–2013
    • Oberlin College
      • Department of Neuroscience
      Oberlin, OH, United States
  • 2007–2011
    • Harvard Medical School
      • Department of Psychiatry
      Boston, MA, United States
  • 2009
    • McLean Hospital
      • Behavioral Genetics Laboratory
      Cambridge, Massachusetts, United States