Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats.

Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B-) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus-reward contingencies were changed (A- vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.

Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence.

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.

Dissociable effects of lesions to orbitofrontal cortex subregions on impulsive choice in the rat.

The orbitofrontal cortex (OFC) is implicated in a variety of adaptive decision-making processes. Human studies suggest that there is a functional dissociation between medial and lateral OFC (mOFC and lOFC, respectively) subregions when performing certain choice procedures. However, little work has examined the functional consequences of manipulations of OFC subregions on decision making in rodents. In the present experiments, impulsive choice was assessed by evaluating intolerance to delayed, but economically optimal, reward options using a delay-discounting paradigm. Following initial delay-discounting training, rats received bilateral neurotoxic or sham lesions targeting whole OFC (wOFC) or restricted to either mOFC or lOFC subregions. A transient flattening of delay-discounting curves was observed in wOFC-lesioned animals relative to shams--differences that disappeared with further training. Stable, dissociable effects were found when lesions were restricted to OFC subregions; mOFC-lesioned rats showed increased, whereas lOFC-lesioned rats showed decreased, preference for the larger-delayed reward relative to sham-controls--a pattern that remained significant during retraining after all delays were removed. When locations of levers leading to small-immediate versus large-delayed rewards were reversed, wOFC- and lOFC-lesioned rats showed retarded, whereas mOFC-lesioned rats showed accelerated, trajectories for reversal of lever preference. These results provide the first direct evidence for dissociable functional roles of the mOFC and lOFC for impulsive choice in rodents. The findings are consistent with recent human functional imaging studies and suggest that functions of mOFC and lOFC subregions may be evolutionarily conserved and contribute differentially to decision-making processes.

Prefrontal and monoaminergic contributions to stop-signal task performance in rats.

Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the α2-adrenergic agonist guanfacine and the D(1)/D(2) antagonist α-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by α-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.

Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats.

Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to attention deficit/hyperactivity disorder (ADHD), schizophrenia, obsessive-compulsive disorder, and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition [stop-signal reaction time (SSRT)], psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear. This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions of the dopamine D1 receptor (DRD1) antagonist SCH 23390 or dopamine D2 receptor (DRD2) antagonist sulpiride into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC). DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation.

An intra-cerebral drug delivery system for freely moving animals.

Microinfusions of drugs directly into the central nervous system of awake animals represent a widely used means of unravelling brain functions related to behaviour. However, current approaches generally use tethered liquid infusion systems and a syringe pump to deliver drugs into the brain, which often interfere with behaviour. We address this shortfall with a miniaturised electronically-controlled drug delivery system (20 × 17.5 × 5 mm³) designed to be skull-mounted in rats. The device features a micropump connected to two 8-mm-long silicon microprobes with a cross section of 250 × 250 µm² and integrated fluid microchannels. Using an external electronic control unit, the device allows infusion of 16 metered doses (0.25 µL each, 8 per silicon shaft). Each dosage requires 3.375 Ws of electrical power making the device additionally compatible with state-of-the-art wireless headstages. A dosage precision of 0.25 ± 0.01 µL was determined in vitro before in vivo tests were carried out in awake rats. No passive leakage from the loaded devices into the brain could be detected using methylene blue dye. Finally, the device was used to investigate the effects of the NMDA-receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid, (R)-CPP, administered directly into the prefrontal cortex of rats during performance on a task to assess visual attention and impulsivity. In agreement with previous findings using conventional tethered infusion systems, acute (R)-CPP administration produced a marked increase in impulsivity.

Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour.

The Prader-Willi syndrome (PWS) genetic interval contains several brain-expressed small nucleolar (sno)RNA species that are subject to genomic imprinting. In vitro studies have shown that one of these snoRNA molecules, h/mbii-52, negatively regulates editing and alternative splicing of the serotonin 2C receptor (5htr2c) pre-RNA. However, the functional consequences of loss of h/mbii-52 and subsequent increased post-transcriptional modification of 5htr2c are unknown. 5HT2CRs are important in controlling aspects of cognition and the cessation of feeding, and disruption of their function may underlie some of the psychiatric and feeding abnormalities seen in PWS. In a mouse model for PWS lacking expression of mbii-52 (PWS-IC+/-), we show an increase in editing, but not alternative splicing, of the 5htr2c pre-RNA. This change in post-transcriptional modification is associated with alterations in a number of 5HT2CR-related behaviours, including impulsive responding, locomotor activity and reactivity to palatable foodstuffs. In a non-5HT2CR-related behaviour, marble burying, loss of mbii-52 was without effect. The specificity of the behavioural effects to changes in 5HT2CR function was further confirmed using drug challenges. These data illustrate, for the first time, the physiological consequences of altered RNA editing of 5htr2c linked to mbii-52 loss that may underlie specific aspects of the complex PWS phenotype and point to an important functional role for this imprinted snoRNA.

IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.

Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.

Increased impulsivity during withdrawal from cocaine self-administration: role for DeltaFosB in the orbitofrontal cortex.

Increased impulsivity caused by addictive drugs is believed to contribute to the maintenance of addiction and has been linked to hypofunction within the orbitofrontal cortex (OFC). Recent data indicate that cocaine "self-administration" induces the transcription factor DeltaFosB in the OFC that alters the effects of investigator-administered cocaine on impulsivity. Here, using viral-mediated gene transfer, the effects of overexpressing DeltaFosB within the OFC were assessed on the cognitive sequelae of chronic cocaine self-administration as measured by the 5-choice serial reaction time task (5CSRT). Cognitive testing occurred in the mornings, and self-administration sessions in the evenings, to enable the progressive assessment of repeated volitional drug intake on performance. Animals self-administering cocaine initially made more omissions and premature or impulsive responses on the 5CSRT but quickly developed tolerance to these disruptive effects. However, withdrawal from cocaine dramatically increased premature responding. When access to cocaine was increased, animals overexpressing DeltaFosB failed to regulate their intake as effectively and were more impulsive during withdrawal. In summary, rats develop tolerance to the cognitive disruption caused by cocaine self-administration and show a deficit in impulse control that is unmasked during withdrawal. Our findings suggest that induction of DeltaFosB within the OFC is one mediator of these effects and, thereby, increases vulnerability to addiction.

Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum.

Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.

DeltaFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction.

Current cocaine users show little evidence of cognitive impairment and may perform better when using cocaine, yet withdrawal from prolonged cocaine use unmasks dramatic cognitive deficits. It has been suggested that such impairments arise in part through drug-induced dysfunction within the orbitofrontal cortex (OFC), yet the neurobiological mechanisms remain unknown. We observed that chronic cocaine self-administration increased expression of the transcription factor deltaFosB within both medial and orbitofrontal regions of the rat prefrontal cortex. However, the increase in OFC deltaFosB levels was more pronounced after self-administered rather than experimenter-administered cocaine, a pattern that was not observed in other regions. We then used rodent tests of attention and decision making to determine whether deltaFosB within the OFC contributes to drug-induced alterations in cognition. Chronic cocaine treatment produced tolerance to the cognitive impairments caused by acute cocaine. Overexpression of a dominant-negative antagonist of deltaFosB, deltaJunD, in the OFC prevented this behavioral adaptation, whereas locally overexpressing deltaFosB mimicked the effects of chronic cocaine. Gene microarray analyses identified potential molecular mechanisms underlying this behavioral change, including an increase in transcription of metabotropic glutamate receptor subunit 5 and GABA(A) receptors as well as substance P. Identification of deltaFosB in the OFC as a mediator of tolerance to the effects of cocaine on cognition provides fundamentally new insight into the transcriptional modifications associated with addiction.

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

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.

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.

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of guanfacine in the rat.

RATIONALE: Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DbetaH)-saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT. OBJECTIVES: The aim of this work is to examine (1) the effect of cortical noradrenaline depletion on sustained attentional performance in the 5CSRT under a variety of test conditions and (2) the effects of guanfacine, a selective alpha-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats. MATERIALS AND METHODS: Animals received either intramedial prefrontal anti-DbetaH-saporin or vehicle and were tested on the baseline task with a variety of additional manipulations including (1) decreasing target duration, (2) increasing rate and (3) temporal unpredictability of target presentation and (4) systemic guanfacine. RESULTS: Anti-DbetaH-saporin infused into the PFC produced a substantial loss of DbetaH-positive fibers in that region and in other adjacent cortical areas. There was no significant depletion of DA or 5-HT. NA-depleted animals were not impaired on the baseline task, but were slower to respond correctly under high event rate conditions, and their discriminative accuracy was reduced when stimulus predictability decreased. Guanfacine significantly reduced discriminative accuracy in NA-depleted animals only. CONCLUSION: Selective cortical NA depletion produced deficits on the 5CSRT test of sustained attention, especially when the attentional load was increased and in response to systemic guanfacine. These results are consistent with a role of coeruleo-cortical NA in the regulation of effortful attentional processes.

Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice.

The orbitofrontal cortex (OFC) and basolateral nucleus of the amygdala (BLA) share many reciprocal connections, and a functional interaction between these regions is important in controlling goal-directed behavior. However, their relative roles have proved hard to dissociate. Although injury to these brain regions can cause similar effects, it has been suggested that the resulting impairments arise through damage to different, yet converging, cognitive processes. Patients with OFC or amygdala lesions exhibit maladaptive decision making and aberrant social behavior often described as impulsive. Impulsive choice may be measured in both humans and rodents by evaluating intolerance to delay of reinforcement. Rats with excitotoxic lesions of the BLA and OFC were tested on such a delay-discounting procedure. Although lesions of the BLA increased choice of the small immediate reward, indicating greater impulsivity, OFC lesions had the opposite effect, increasing preference for the larger but delayed reward. The fact that the delay did not devalue the large reward to such an extent in OFC-lesioned animals supports the suggestion that the OFC is involved in updating the incentive value of outcomes in response to devaluation. In contrast, the BLA-lesioned animals markedly decreased their preference for the large reward when it was delayed, potentially because of an inability to maintain a representation of the reward in its absence. This is the first time that lesions to these two structures have produced opposite behavioral effects, indicating their distinct contributions to cognition.

Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.

Cognitive sequelae of intravenous amphetamine self-administration in rats: evidence for selective effects on attentional performance.

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.

Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin.

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.

Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex.

Converging lines of evidence suggest that dysfunction of brain serotonergic systems may underlie impulsive behavior. However, the nature of this deficit remains poorly understood because indirect indices of serotonin (5-HT) function are often used in clinical and experimental studies. In this investigation we measured 5-HT release directly in the prefrontal cortex of rats using in vivo microdialysis during performance of a visual attentional task. A number of performance measures were taken, including the number of premature responses made during the inter-trial interval before the onset of the visual discriminanda. This form of behavioral disinhibition was defined as impulsive, after. Lengthening the inter-trial interval increased the sensitivity of the task for detecting impulsive tendencies. Cortical levels of 5-HT and its metabolite 5-HIAA remained at pre-task levels over 1 h of task performance. By contrast, levels of dopamine (DA) and its metabolite DOPAC increased during this period. Regression analysis established a positive relationship between premature (impulsive) responses and 5-HT efflux, both under basal (r = 0.49) and task-related (r = 0.42) conditions (n = 31). No such relationship was found for prefrontal levels of DA. However, post-mortem analysis revealed that animals that were more impulsive had a higher turnover of DA in anterior cingulate, prelimbic and infralimbic cortices but no detectable abnormalities in 5-HT function. These data indicate that elevated 5-HT release in the prefrontal cortex may underlie deficits in impulse control on this task. Additionally, DA dysfunction in this region may be another, possibly independent, trait marker of impulsivity.

Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior.

Reducing levels of 5-HT in the central nervous system has been associated with increases in impulsive behavior. However, the impulsivity construct describes a wide range of behaviors, including the inability to withhold a response, intolerance to delay of reward and perseveration of a nonrewarded response. Although these behaviors are generally studied using instrumental paradigms, impulsivity may also be reflected in simple Pavlovian tasks such as autoshaping and conditioned activity. This experiment aimed to characterize further the effects of central 5-HT depletion and to investigate whether different behavioral measures of impulsivity are inter-related, thus validating the construct. Rats received intracerebroventricular (ICV) infusions of vehicle (n=10) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (n=12) which depleted forebrain 5-HT levels by about 90%. Lesioned animals showed significant increases in the speed and number of responses made in autoshaping, increased premature responding on a simple visual attentional task, enhanced expression of locomotor activity conditioned to food presentation, yet no change in impulsive choice was observed, as measured by a delay-discounting paradigm. Significant positive correlations were found between responses made in autoshaping and the level of conditioned activity, indicating a possible common basis for these behaviors, yet no correlations were found between other behavioral measures. These data strengthen and extend the hypothesis that 5-HT depletion increases certain types of impulsive responding. However, not all measures of impulsivity appear to be uniformly affected by 5-HT depletion, or correlate with each other, supporting the suggestion that impulsivity is not a unitary construct.