Sex, but not juvenile stress, affects reversal learning and DRL performance following cocaine administration.

INTRODUCTION: Early adversity, impulsivity and sex all contribute to the risk of developing substance use disorder. Using rats, we examined how juvenile stress interacts with sex and cocaine to affect performance on a serial reversal task and a differential reinforcement of low rates 10 s (DRL10) task. The expression of dopamine-related proteins in several brain areas was also assessed. METHODS: From postnatal days (PND) 25-29, rats were exposed to a variable stress protocol. In adulthood, rats were trained on the reversal task and the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. Next, rats were trained on the DRL10 task and the effects of cocaine on performance were assessed. Finally, brains were extracted, and Western blot analyses conducted. RESULTS: Juvenile stress did not affect behavior. Sex did not affect baseline performance in either task. In the reversal task, cocaine decreased % high probability responses and the number of rewards earned in both sexes. Cocaine had sex-dependent effects on omissions, low probability responses and response latencies. In the DRL10 task, cocaine decreased the peak latency to respond and the number of rewards earned in both sexes. Cocaine had sex-dependent effects on peak rate of responding, response efficiency, burst responses and long responses. Female rats exhibited increased expression of DRD1 receptors in the striatum. DISCUSSION: These data contribute to the growing literature demonstrating sex differences in the behavioral effects of cocaine and suggest that DRD1 receptors could contribute to the observed behavioral sex differences.

Juvenile stress increases cocaine-induced impulsivity in female rats.

In humans, adverse childhood experiences are associated with an increased risk of developing a neuropsychiatric disorder. Changes in social behavior and cognitive function are hallmarks of numerous neuropsychiatric disorders. Here we examined the effects of exposure to variable stress during the juvenile period on social behavior, reward, and cognitive function (as measured in the 5-choice serial reaction time task (5CSRTT)) in rats. From postnatal days (PND) 25-29 male and female rats were exposed to a variable stress protocol. In adulthood, social interactions and sucrose preference were assessed prior to training on the 5CSRTT. Once successfully trained, rats were challenged with different task versions, and then the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. A follow-up experiment examined the ability of the D2 receptor antagonist eticlopride (0.0, 0.025, 0.05 mg/kg, IP) to block the effects of cocaine on 5CSRTT performance in female rats. Male rats exposed to juvenile stress tended to engage in less social behavior and had an increased correct response latency in the 5CSRTT following cocaine administration. Female rats exposed to juvenile stress exhibited a trend towards increased social behavior and demonstrated increased cocaine-induced impulsivity. The increase in impulsivity was not blocked by co-administration of eticlopride. Juvenile stress had minimal effects on adult behavior in male rats, but increased cocaine-induced impulsivity in female rats. Such an effect could contribute to the enhanced escalation of drug-use observed in females that experience juvenile stress. This possibility awaits further testing.

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.

Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABAA agonist, GABAA antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABAA agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABAA receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them.

Decreasing GABA function within the medial prefrontal cortex or basolateral amygdala decreases sociability.

INTRODUCTION: Decreased sociability is a symptom of psychiatric conditions including autism-spectrum disorder and schizophrenia. Both of these conditions are associated with decreases in GABA function, particularly in the medial prefrontal cortex (PFC) and the basolateral amygdala (BLA); structures that are components of the social brain. Here, we determined if decreasing GABA transmission within either the PFC or the BLA decreases social behavior. METHODS: Rats were implanted with cannulae aimed at either the medial PFC or the BLA and then were tested on up to 4 behavioral tests following bilateral infusions of 0.5µl bicuculline methiodide (BMI, a GABAA receptor antagonist) at doses of 0, 25, or 50ng/µl. Rats were tested in the social interaction test, the social preference test, the sucrose preference test and for locomotor activity (BLA infusions only). RESULTS: Intra-BLA or PFC BMI infusions decreased the amount of time and the number of social interactions in the social interaction test. Further, in the social preference test, rats infused with 50ng BMI no longer exhibited a preference to explore a social over a non-social stimulus. The change in sociability was not due to a change in reward processing or locomotor behavior. DISCUSSION: Decreasing GABA transmission in either the medial PFC or BLA decreased sociability. Thus, changes in GABA signaling observed in conditions such as autism or schizophrenia may mediate the social withdrawal characteristic of these conditions. Moreover, they suggest that social withdrawal may be treated by drugs that potentiate GABA transmission.

Effects of chronic inhibition of GABA synthesis on attention and impulse control.

BACKGROUND: Cortical GABA regulates a number of cognitive functions including attention and working memory and is dysregulated in a number of psychiatric conditions. In schizophrenia for example, changes in GABA neurons [reduced expression of glutamic acid decarboxylase (GAD), parvalbumin (PV) and the GABA reuptake transporter (GAT1)] suggest reduced cortical GABA synthesis and release; these changes are hypothesized to cause the cognitive deficits observed in this disorder. The goals of this experiment were to determine whether chronically reducing GAD function within the rat PFC causes attention deficits and alterations in PV and GAT1 expression. METHODS: Male Sprague Dawley rats were trained on the 5-choice serial reaction time task (5CSRTT, a task of attention) until they reached criterion performance and then were implanted with a bilateral cannula aimed at the medial PFC. Cannulae were connected to osmotic minipumps that infused the GAD inhibitor l-allylglycine (LAG, 3.2µg/0.5µl/h) for 13days. Following a 5-day recovery from surgery rats were tested on the standard 5CSRTT for 5 consecutive days and then tested on two modifications of the 5CSRTT. Finally, locomotor activity was assessed and the rats sacrificed. Brains were rapidly extracted and flash frozen and analyzed for the expression of GAD67, PV, GAT1 and the obligatory NMDA receptor subunit NR1. RESULTS: Chronic LAG infusions transiently impaired attention, persistently impaired impulse control and increased locomotor activity. Behavioral changes were associated with an upregulation of GAD67, but no change in PV, GAT1 or NR1 expression. SUMMARY: Chronic inhibition of GABA synthesis within the medial PFC, increased impulsive behavior and locomotion, but did not impair attention; results consistent with previous research following acute inhibition of GABA synthesis. Moreover, our data do not support the hypothesis that decreasing GABA synthesis and release is sufficient to cause changes in other GABA-related proteins.

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.

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 (15mg/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 28days 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 3days or 28days 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.

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.

Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors.

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.

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

Effects of antipsychotic drugs on MK-801-induced attentional and motivational 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.

Attention deficits and hyperactivity following inhibition of cAMP-dependent protein kinase within the medial prefrontal cortex of rats.

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.

N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid receptor agonist with oral efficacy.

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.

Sensitivity of the five-choice serial reaction time task to the effects of various psychotropic drugs in Sprague-Dawley rats.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Alcohol-induced impulsivity in rats: an effect of cue salience?

RATIONALE: There is a common assumption that alcohol produces impulsive behaviors, thereby increasing the preference for immediate over delayed rewards. An alternative explanation, provided by alcohol myopia theory, is that alcohol alters attentional processes such that intoxicated individuals respond exclusively to the most salient cues in their environment. OBJECTIVES: We tested these two hypotheses in rats using standard (impulsivity) and modified (cue salience) versions of the delayed reinforcement task. METHODS: In the impulsivity paradigm, rats were trained to choose between a small immediate reward (2 sucrose pellets) and a large delayed reward (12 sucrose pellets after 10 s) in a T-maze. In the cue salience paradigm, a light in one arm predicted either the small or the large reward, but the arm paired with the light varied across trials. In separate experiments, we examined how changes in delay to the large reward, alcohol administration, or alcohol combined with either a serotonin agonist [para-chloroamphetamine (pCA) at doses of 0.1, 0.4, 0.7, and 1.0 mg/kg, s.c.)] or a dopamine antagonist [cis-(Z)-flupenthixol dihydrochloride (alpha-flupenthixol) at doses of 0.0125, 0.025, 0.05, and 0.1 mg/kg, i.p.] affected performance in each task. RESULTS: Increasing the delay to the large reward increased impulsivity in both paradigms, but it had no effect on responding to a salient cue. Alcohol (0.6, 0.9, 1.2, and 1.8 g/kg, i.p.) increased the choice of the immediate reward and increased the choice of the lit arm, regardless of whether it signaled the small or the large reward. pCA selectively reduced alcohol-induced impulsivity, whereas alpha-flupenthixol selectively reduced responding to a salient cue. CONCLUSIONS: Rats, like humans, are influenced by cue salience when intoxicated. Although this alcohol myopia effect could explain alcohol-induced impulsivity, the two processes are probably distinct because they are mediated by dissociable pharmacological mechanisms.

Cocaine disrupts both behavioural inhibition and conditional discrimination in rats.

RATIONALE: Stimulant addicts exhibit increased behavioural disinhibition under the influence of the drug. In laboratory animals, however, the effects of amphetamine on behavioural disinhibition are equivocal, and the effects of cocaine have not been investigated. OBJECTIVES: The current set of experiments was designed to test the effects of cocaine on behavioural disinhibition and to assess whether the possible impairments are due to deficits in conditional discrimination or attention. METHODS: Separate groups of rats were trained to respond in an asymmetrically reinforced Go/No-go task, a Conditional discrimination task or a Vigilance task. Upon reaching criterion performance, animals were treated with cocaine (0-20 mg/kg) immediately prior to testing. RESULTS: Cocaine (15 mg/kg) increased No-go interval responses, indicating an increase in behavioural disinhibition. Conditional discrimination was also impaired by cocaine (15 and 20 mg/kg); animals made more incorrect trials per completed trial. Cocaine-treated animals also made more premature responses in this task, indicating increased behavioural disinhibition independent of a conditional discrimination deficit. Finally, cocaine (0-20 mg/kg) had no effect on vigilance. CONCLUSIONS: Administration of moderate to high doses of cocaine increases behavioural disinhibition, and this increase may be independent of an impairment in conditional discrimination.

Effects of chronic cocaine on impulsivity: relation to cortical serotonin mechanisms.

Drug addiction can be considered an impulse control disorder in that addicts exhibit increased impulsivity on both behavioural and self-report measures. We investigated whether chronic cocaine affects delay of gratification and/or behavioural disinhibition in rats using the delayed reinforcement and Go/No-go paradigms. Animals were treated with saline or cocaine (15 mg/kg) three times per day for 14 days; all behavioural tests occurred prior to daily injections. To assess the effectiveness of the cocaine treatment, sucrose intake, behavioural sensitization and serotonin (5-HT)-dependent (dorsal raphe-stimulated) cortical activation were also measured. Chronic cocaine caused a transient (days 7-8) increase in impulsivity in the delayed reinforcement paradigm, but did not influence behaviour in the Go/No-go paradigm. As expected, chronic cocaine increased behavioural sensitization scores, although it did not affect sucrose consumption. Although, cocaine treatment did not affect dorsal raphe-stimulated electrocorticographic activation, the serotonergic receptor antagonist methiothepin (0.1 mg/kg) was more effective in blocking cortical activation in cocaine- than in saline-treated animals. The electrocorticographic changes may be the result of a pre-synaptic 5-HT deficit and the compensatory supersensitivity of post-synaptic 5-HT receptors. Given the differential time courses of the behavioural and electrocorticographic data, however, this change probably does not mediate the effects of chronic cocaine in the delayed reinforcement paradigm.