Early life adversity potentiates expression of addiction-related traits.

Many individuals sporadically and circumstantially sample addictive drugs, yet few become addicted. The individual vulnerabilities underlying the development of addiction are not well understood. Correlational findings show that early life adversity is associated with a greater propensity to develop drug addiction. However, the mechanisms by which early life adversity increases addiction vulnerability are unknown. Separate lines of research have found that several traits are associated with addiction. Here, we examined the effects of early life adversity on addiction-related traits in adulthood. We weaned male and female Sprague-Dawley rats (postnatal day - PND21) and randomly assigned them to either a non-adversity group (N-ADV) or an adversity group (ADV). ADV rats experienced adversity from PND 21-35, they were: a) singly housed, b) food restricted for 12h/day, c) subjected to forced-swim sessions, and d) restrained and exposed to predator odour (1h). As adults, rats were tested for impulsivity, anxiety-like behaviour, novelty preference, and attribution of incentive salience to a reward cue. ADV rats showed enhanced novelty preference and attributed greater incentive value to a reward cue. Compared to N-ADV rats, a greater proportion of ADV rats expressed multiple addiction risk traits. Furthermore, fewer ADV rats expressed no addiction risk traits. This effect was most evident in female ADV rats.

Functionally Distinct Dopamine Signals in Nucleus Accumbens Core and Shell in the Freely Moving Rat.

Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine. SIGNIFICANCE STATEMENT: Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine.

Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function.

Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not.

Propagation of maternal behavior across generations is associated with changes in non-maternal cognitive and behavioral processes.

Over a number of years we have studied the phenomenology of maternal behavior from endocrine, neural, experiential, and ontogenetic perspectives. Here, we focus on the effects of early life experiences with and without the mother on subsequent maternal and non-maternal behaviors of the offspring. We have used an artificial rearing procedure, which entails removing rat pups from their mother and raising them in isolation, while controlling and manipulating several aspects of their upbringing. As adults, mother-reared (MR) and artificially-reared (AR) rats are assessed on their own maternal behavior, as well several other behaviors. While both AR and MR rats nurse and successfully wean their young, the AR rats spend less time licking, grooming, and crouching over their young. Hence, being raised in social isolation does not seem to affect primary maternal motivational dynamics. Instead, isolation rearing produces alterations in the ongoing execution of the behavior and its effective organization. Here, we present evidence that changes in maternal behavior, as a result of social isolation from mother and siblings, are due to changes in top-down (e.g., sustained attention, flexibility) and bottom-up process (e.g., increased stimulus-driven behavior). These changes are likely due to alterations in brain dopamine systems, which are sensitive to early life manipulations and are modulators of bottom-up and top-down processes. Finally, we draw parallels between the rat and human maternal behavior. This article is part of a Special Issue entitled: In Honor of Jerry Hogan.

Rapid dopamine transmission within the nucleus accumbens: dramatic difference between morphine and oxycodone delivery.

While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psychostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxycodone, in drug-naïve rats using fast-scan cyclic voltammetry and rapid (1 min) microdialysis coupled with high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS). In addition to measuring rapid dopamine transmission, microdialysis HPLC-MS measures changes in GABA, glutamate, monoamines, monoamine metabolites and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug-evoked dopamine transmission differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid-induced neurotransmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior.

Variation in the form of Pavlovian conditioned approach behavior among outbred male Sprague-Dawley rats from different vendors and colonies: sign-tracking vs. goal-tracking.

Even when trained under exactly the same conditions outbred male Sprague-Dawley (SD) rats vary in the form of the Pavlovian conditioned approach response (CR) they acquire. The form of the CR (i.e. sign-tracking vs. goal-tracking) predicts to what degree individuals attribute incentive salience to cues associated with food or drugs. However, we have noticed variation in the incidence of these two phenotypes in rats obtained from different vendors. In this study, we quantified sign- and goal-tracking behavior in a reasonably large sample of SD rats obtained from two vendors (Harlan or Charles River), as well as from individual colonies operated by both vendors. Our sample of rats acquired from Harlan had, on average, more sign-trackers than goal-trackers, and vice versa for our sample of rats acquired from Charles River. Furthermore, there were significant differences among colonies of the same vendor. Although it is impossible to rule out environmental variables, SD rats at different vendors and barriers may have reduced phenotypic heterogeneity as a result of genetic variables, such as random genetic drift or population bottlenecks. Consistent with this hypothesis, we identified marked population structure among colonies from Harlan. Therefore, despite sharing the same name, investigators should be aware that important genetic and phenotypic differences exist among SD rats from different vendors or even from different colonies of the same vendor. If used judiciously this can be an asset to experimental design, but it can also be a pitfall for those unaware of the issue.

Early postnatal experience and DRD2 genotype affect dopamine receptor expression in the rat ventral striatum.

Dopamine systems can be altered by experiences such as early life adversity. The intensity of these effects seems to vary as a function of interactions between genetic and environmental influences. In a series of experiments we have investigated the effects of genetic variants and early life adversity on several biobehavioral outcomes. Here we investigated the presence of single nucleotide polymorphisms (SNPs) in the gene coding for dopamine D2 receptors (DRD2) and the interaction between these variants with early life adversity on the expression of D2 receptors in the striatum. Time-mated pregnant female rats underwent restraint stress (gestational days 10-21) or were left undisturbed. Following parturition rat pups were maternally reared (MR) or artificially reared (AR). Subsequent to adult behavioral testing, rats were genotyped and their brains were processed (autoradiography) for D2 receptor expression. We found three variants in the DRD2 gene and these variants interacted with early adversity to affect D2 receptor expression in the nucleus accumbens. Specifically, artificially reared rats with AG DRD2 variant showed significantly higher D2 expression compared to mother reared rats with the AG DRD2 variant as well as the artificially reared rats with a GG DRD2 variant. These findings show that adult D2 expression is significantly influenced by the interaction of DRD2 SNPs and early developmental factors. These finding may explain why there are significant individual differences in the impact of early life adversity on dopamine-dependent processes and disorder vulnerabilities.

Quantifying individual variation in the propensity to attribute incentive salience to reward cues.

If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have found, however, that there is considerable individual variation in the extent to which animals attribute Pavlovian incentive motivational properties ("incentive salience") to reward cues. The purpose of this paper was to develop criteria for identifying and classifying individuals based on their propensity to attribute incentive salience to reward cues. To do this, we conducted a meta-analysis of a large sample of rats (N = 1,878) subjected to a classic Pavlovian conditioning procedure. We then used the propensity of animals to approach a cue predictive of reward (one index of the extent to which the cue was attributed with incentive salience), to characterize two behavioral phenotypes in this population: animals that approached the cue ("sign-trackers") vs. others that approached the location of reward delivery ("goal-trackers"). This variation in Pavlovian approach behavior predicted other behavioral indices of the propensity to attribute incentive salience to reward cues. Thus, the procedures reported here should be useful for making comparisons across studies and for assessing individual variation in incentive salience attribution in small samples of the population, or even for classifying single animals.

Cocaine must enter the brain to evoke unconditioned dopamine release within the nucleus accumbens shell.

In addition to blocking dopamine (DA) uptake, cocaine also causes an unconditioned increase in DA release. In drug naive rats, this effect is most robust within the nucleus accumbens (NAc) shell. Recent studies have shown that, in rats trained to self-administer cocaine, cocaine may act in the periphery to enhance mesolimbic DA release. Further, these studies have suggested that peripheral cocaine action may also enhance unconditioned DA release. Here, we test if it is necessary for cocaine to enter the brain to evoke unconditioned increases in DA release within the NAc shell. Administration of a cocaine analogue that crosses the blood brain barrier (cocaine HCl) enhances electrically evoked DA release and the number of cocaine-evoked phasic DA release events (i.e., DA transients) within the NAc shell. However, administration of a cocaine analogue that does not cross the blood brain barrier (cocaine MI) does not alter either measure. We therefore conclude that cocaine must act within the central nervous system to evoke unconditioned DA release within the NAc shell.

Early-life maternal separation and social isolation produce an increase in impulsive action but not impulsive choice.

Early life environment, events, and context, such as mother-offspring relationship, can have profound effects on future behavior and physiology. We investigated the effects of long-term maternal and social separation, through artificial rearing, on adult impulsivity. Rats were maternally reared (MR) or artificially reared (AR) and half of the AR rats were provided with replacement somatosensory stimulation intended to simulate maternal licking. There are at least 2 forms of impulsivity and we compared rats on 1 test of impulsive action (differential reinforcement of low rates of responding-DRL-20s) and 2 tests of impulsive choice (delay discounting and fixed consecutive number schedule-FCN). We found that AR rats are more action impulsive; however, this effect can be reduced by maternal licking-like stimulation. In contrast, AR rats did not display an increase in impulsive choice. Overall, these experiments show that early life maternal and social separation have different effects on the 2 forms of impulsivity.

Rats prone to attribute incentive salience to reward cues are also prone to impulsive action.

Animals vary considerably in the degree to which they attribute incentive salience to cues predictive of reward. When a discrete cue (conditional stimulus) is repeatedly paired with delivery of a food reward (unconditional stimulus) only some rats ("sign-trackers"; STs) come to find the cue itself an attractive and desirable incentive stimulus. For other rats ("goal-trackers"; GTs) the cue is an effective conditional stimulus - it evokes a conditional response - but it is less attractive and less desirable. Given that STs have particular difficulty resisting reward cues, and are thought to have poor inhibitory control over their behavior, we hypothesized that they may also be more impulsive. There are, however, multiple forms of impulsivity; therefore, we compared STs and GTs on two tests of so-called impulsive action - a 2-choice serial reaction time task and a differential reinforcement of low rates of responding task, and one test of impulsive choice - a delay discounting choice procedure. We found that relative to GTs, STs were more impulsive on the two tests of impulsive action, but not on the test of impulsive choice. We speculate that when these two traits combine, that is, when an individual is not only prone to attribute incentive salience to reward cues but also prone to impulsive action, they may be especially susceptible to impulse control disorders, including addiction.

Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats.

Despite its importance for development, relatively little is known about how allelic variation interacts with both pre- and postnatal stress. We examined the interaction between serotonin transporter (5-HTT) genotype, prenatal and postnatal stress on glucocorticoid receptor (GR) mRNA expression, corticosteroid stress responses, and behavior in adult male rats. Prenatal stress involved a daily restraint of pregnant dams from gestational Day 10-21. Postnatal stress involved raising pups after parturition either by their mothers (MR) or in the artificial rearing (AR) paradigm, with or without additional "licking-like" stroking stimulation. 5-HTT genotype, hippocampal GR mRNA level, corticosteroid stress response, and behaviors including startle response, prepulse inhibition (PPI), and locomotor activity were measured in adult male rat offspring. We found significant genotype by prenatal stress interactions for hippocampal GR mRNA levels and for the corticosterone stress responses in adulthood. In contrast, behavioral endpoints tended to be more clearly affected by an interaction between genotype and postnatal environment. These findings suggest that allelic variation in the 5-HTT gene interacts with the prenatal environment to affect the hypothalamic-pituitary-adrenal (HPA) axis physiology and the postnatal environment to affect behavior. These results are the first to indicate a role for genetic variation in the 5-HTT gene in physiology and behavior in the rat.

Inadequate early social experience increases the incentive salience of reward-related cues in adulthood.

The mechanisms by which childhood abuse and/or neglect become risk factors for the development of drug addiction, problem gambling, and other disorders of behavioral inhibition are unknown. The loss of behavioral inhibition is often triggered by reward-related cues that acquire incentive salience. This study examined whether inadequate early-life social experience in rats affects the incentive salience of reward-related cues. Rats were deprived of early-life social experience with the mother and litter through artificial-rearing (AR). A group of AR rats (AR+STM) received additional tactile stimulation that mimicked maternal licking, a critical component of rat maternal care. Control rats were maternally reared (MR). The incentive salience attributed to a food cue was measured in adult rats using a conditioned approach task, where a conditional stimulus (CS; lever) was paired with food delivery, and in a conditional reinforcement task. The dependent measures were approach towards the CS (sign-tracking) versus approach towards the place of food delivery (goal-tracking) and instrumental responding for the CS. AR rats made significantly more sign-tracking responses than MR rats. AR rats also made more instrumental responses when reinforced with the CS. AR+STM rats' responses were intermediate to MR and AR rats. Thus, inadequate early-life social experience enhanced the incentive salience of a reward-related cue in adulthood. Replacement of maternal licking partially reversed this effect. These results highlight a potential link between early-life social adversity and susceptibility to disorders of behavioral inhibition.

Impulsive rats are less maternal.

Early life environment and maternal care can have long-lasting effects on behavior and physiology. Previously, we found that compared to mother-reared (MR) female rats, rats reared without mothers, siblings, and nest, through artificially rearing (AR), show reduced levels of maternal behavior when they grow up. These effects can be reversed if AR pups are provided with extra "licking-like" tactile stimulation during the preweaning period [Gonzalez et al. [2001] Developmental Psychobiology, 38(1), 11-42]. We also found that AR rats are more action impulsive and have reduced attentional capacities in comparison to their MR siblings [Lovic, Fletcher, & Fleming, in preparation; Lovic & Fleming [2004] Behavioural Brain Research 148: 209-219]. However, it is unknown whether increased impulsivity contributes to reduced levels of maternal behaviors. The purpose of this study was to assess the relationship between impulsivity and maternal behavior in AR and MR rats. Female rats were reared with (MR) or without mothers (AR) and half of the AR rats received additional stroking stimulation. As adults, AR and MR rats were mated and maternal behavior towards their own pups was assessed. In addition, rats were assessed on impulsive action (differential reinforcement of low-rate schedule; DRL-20s). Consistent with previous findings, AR rats were both less maternal and more action impulsive than MR rats. Partial correlations revealed that impulsivity was inversely related to pup licking-impulsive rats were less maternal.

Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stress-induced corticosterone release in adult female Sprague-Dawley rats.

This study investigated the effects of prenatal stress and complete maternal deprivation, using the artificial rearing (AR) paradigm, on the expression of neural plasticity markers and hypothalamic-pituitary-adrenal (HPA) axis responsivity to stress. Rats were exposed to stress during gestation (day 10-21) and postnatally were either artificially reared (AR) or mother reared (MR). AR involves complete separation of the pup from both the dam and the litter throughout the pre-weaning period. In adulthood, we measured levels of corticosterone (CORT) in response to restraint stress. Also, we examined the expression of synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (MPFC) and the nucleus accumbens (Nacc), areas of the brain that mediate behavioral activation and attention, among other behaviors. Earlier work on the same rats indicated that these behavioral endpoints, such as locomotor activity and sensorimotor gating, are affected by our prenatal and postnatal manipulations. Prenatal stress decreased CORT at 20 and 90 min post-stressor in MR, but not in AR, animals. Also, in comparison to MR groups, AR decreased SYN and BDNF expression in the MPFC and Nacc. Additional somatosensory 'licking-like' stroking stimulation partially reversed the effects of AR. Prenatal stress did not have a robust main effect but affected the impact of the postnatal rearing condition on SYN expression and stress-induced CORT. These results suggest that both prenatal and postnatal adversities have an influence on HPA axis responsivity and alter the expression of plasticity related neuronal proteins.

Medial prefrontal cortex lesions in the female rat affect sexual and maternal behavior and their sequential organization.

Temporal sequences of sexual and maternal behaviors in female rats and their correlation with each other and with performance on a sensory-motor gating response inhibition task assessed by prepulse inhibition (PPI) were investigated following medial prefrontal cortex (mPFC) lesions. Following excitotoxic mPFC (n = 10) or sham (n = 9) lesions, sexual behaviors across the ovarian cycle were scored. After mating and parturition, maternal interactions were scored until pups reached postnatal Day 10. After resumption of the ovarian cycle, the female rats were tested for PPI. Compared with sham lesions, mPFC lesions impaired proceptive behaviors and some maternal behaviors (e.g., pup retrieval, pup licking) but did not affect others (e.g., nest building, pup mouthing). Lesions disrupted temporal sequences of solicitations (number of male orientations followed, within 4 s, by a level change) and pup retrievals (number of pup retrievals followed, within 5 s, by another retrieval). These sequential behavior patterns were significantly correlated with each other and with PPI. However, when PPI effects were partialled out, group differences were less strong, but persisted. This study demonstrated that mPFC manipulations affect actions rich in sequential structure in response to biologically relevant stimuli.

Early life tactile stimulation changes adult rat responsiveness to amphetamine.

Previously, we have found that total maternal deprivation of rat pups, achieved through artificial rearing, leads to a number of behavioral and neurophysiological changes, suggesting a change in the dopamine system. The purpose of this study was to further investigate possible changes in the functioning of dopamine systems, associated with artificial rearing, by examining the locomotor stimulant effects of the dopamine releaser amphetamine and the dopamine reuptake inhibitor methylphenidate. Rats were mother-reared or artificially reared. Some of those artificially reared rats were provided with either a maximum level (artificially reared maximal stimulation) or a minimal level of maternal licking-like tactile stimulation (artificially reared minimal stimulation). In adulthood, rats' locomotion was measured after an injection of d-amphetamine (0, 0.25, 0.5 and 1.0 mg/kg) or methylphenidate (0, 2, 5 and 10 mg/kg). Locomotor activity in response to a novel environment was enhanced in artificially reared rats, although this effect habituated over three daily 1-h sessions. Both amphetamine and methylphenidate dose dependently increased locomotor activity. The effect of amphetamine, but not methylphenidate was greatly enhanced in artificially reared minimally stimulated rats. The enhancement of the effect of amphetamine by artificial rearing was not apparent in artificially reared maximal stimulation rats.

Early adversity alters attention and locomotion in adult Sprague-Dawley rats.

This study investigated the effects of prenatal stress and its interaction with artificial rearing (AR) on adult rat behavior. Pregnant dams underwent restraint stress from Gestational Day 10 to 21. After parturition, pups were raised by their mothers or in the AR paradigm, with or without stroking stimulation. In adulthood, rats were tested on prepulse inhibition (PPI), locomotor activity, elevated plus-maze, and spatial working memory. There were main effects and interactions of both prenatal stress and AR on activity. Additional stimulation reduced activity in nonstressed AR rats but increased activity in prenatally stressed AR rats. AR altered PPI and plus-maze behavior whereas additional stimulation partially reversed these effects. This study demonstrates that prenatal experiences can modulate the effects of postnatal treatments.

Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: tactile stimulation, nest odor, and social rearing prevent these effects.

Maternal and littermate (social) separation, through artificial rearing (AR), disrupts the development of subsequent maternal behavior and social learning in rats. The addition of maternal-licking-like stimulation during AR, partially reverses some of these effects. However, little is know about the role of social stimuli from littermates and nest odors during the preweaning period, in the development of the adult maternal behavior and social learning. The purpose of this study was to examine the effects of peer- and peer-and-odor rearing on the development of maternal behavior and social learning in rats. Female pups were reared with mothers (mother reared-MR) or without mothers (AR) from postnatal day (PND) 3. AR rats received three different treatments: (1) AR-CONTROL group received minimal tactile stimulation, (2) AR-ODOR females received exposure to maternal nest material inside the AR-isolation-cup environment, (3) AR-SOCIAL group was reared in the cup with maternal nest material and a conspecific of the same-age and same-sex and received additional tactile stimulation. MR females were reared by their mothers in the nest and with conspecifics. In adulthood, rats were tested for maternal behavior towards their own pups and in a social learning task. Results confirm our previous report that AR impairs performance of maternal behavior and the development of a social food preference. Furthermore, social cues from a littermate, in combination with tactile stimulation and the nest odor, reversed the negative effects of complete isolation (AR-CONTROL) on some of the above behaviors. Exposure to the odor alone also had effects on some of these olfactory-mediated behaviors. These studies indicate that social stimulation from littermates during the preweaning period, in combination with odor from the nest and tactile stimulation, contributes to the development of affiliative behaviors.

Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.

RATIONALE: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function. OBJECTIVE: The present experiments were conducted to investigate the effects of sensitizing regimens of amphetamine and phencyclidine (PCP) on attentional set shifting. METHODS: Rats received injections of amphetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli. RESULTS: Rats sensitized to amphetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In amphetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D(1) receptor agonist SKF38393 into the medial prefrontal cortex (mPFC). CONCLUSIONS: Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.