Schizophrenia- Like Attentional Deficits Following Blockade Of Prefrontal Cortex Gaba(a) Receptors

Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in gamma-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 (2011) 36, 1703-1713; doi:10.1038/npp.2011.51; published online 13 April 201

Cue-induced conditioned activity does not incubate but is mediated by the basolateral amygdala

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 (BLA), 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 GABAA 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 a fundamental difference in the manner by which contingent and non-contingent presentations of drug-associated cues influence behavior

Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: Reversal by D1 receptor antagonist administration

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 of the medial PFC 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 (0.03 mg/kg), but not haloperidol (0.015–0.03 mg/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

Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats

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

Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention behavior in rats

Background: 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. Methods: 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. Results: 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. Conclusions: 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

Basic Atomic Physics

Contains reports on four research projects.Joint Services Electronics Program Contract DAAL03-92-C-0001National Science Foundation Grant PHY 89-19381U.S. Navy - Office of Naval Research Grant N00014-90-J-1322National Science Foundation Grant PHY 89-21769U.S. Army - Office of Scientific Research Contract DAAL03-89-K-0082U.S. Navy - Office of Naval Research Grant N00014-89-J-1207U.S. Navy - Office of Naval Research Grant N00014-90-J-164

Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task

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

The 5-choice serial reaction time task: a task of attention and impulse control for rodents

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

Effects of antipsychotic drugs on MK-801-induced attentional deficits in rats

Background: Attentional 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. Methods: Acute 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. Results: Acute 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. Discussion: Acute 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

Contribution of GABAA receptor subunits to attention and social behavior

Introduction: GABA dysfunction is associated with a number of psychiatric conditions including schizophrenia, autism and depression. Blocking cortical GABAA receptors in rodents causes behavioral deficits, including impaired attention and sociability, that are consistent with the symptoms of these conditions. The subunit composition of GABAA receptors is diverse and can affect receptor function. The current experiment examined the role of GABAA receptors containing different α-subunits in social behavior and attention. Methods: Male Sprague-Dawley rats were administered FG7142 (0.0–5.0 mg/kg; a non-selective GABAA receptor inverse agonist), L-655,708 (0–1.0 mg/kg; a low efficacy inverse agonist at α5-containing GABAA receptors), MRK-016 (0.0–2.0 mg/kg; a high efficacy inverse agonist at α5-containing GABAA receptors), or L-838,417 (0.0–3.0 mg/kg; an antagonist at α1-containing receptors and a partial agonist at α2, α3, α5-containing GABAA receptors) and either tested on the social interaction and social preference tests or the 5-choice serial reaction time task. Results: FG7142 decreased social interactions and impaired attention. MRK-016 impaired attention but did not affect social behavior. Neither L-655,708 nor L-838,417 significantly affected either social behavior or attention. Discussion: Systemic reduction in GABAA receptor signaling decreased sociability and attention, a result consistent with past research demonstrating cortical GABAA receptor blockade impairs social behavior and attention. Overall, the effects of the receptor subtype selective ligands were minimal; α5-containing GABAA receptors may contribute to the attentional deficit but do not contribute to the decrease in sociability. Further research is needed to determine the GABAA receptor subunits that contribute to social behavior and attention