Neural systems involved in delay and risk assessment in the rat

This thesis investigated the contribution of the nucleus accumbens core (AcbC) and the hippocampus (H) to choice and learning involving reinforcement that was delayed or unlikely. Animals must frequently act to influence the world even when the reinforcing outcomes of their actions are delayed. Learning with action–outcome delays is a complex problem, and little is known of the neural mechanisms that bridge such delays. Impulsive choice, one aspect of impulsivity, is characterized by an abnormally high preference for small, immediate rewards over larger delayed rewards, and is a feature of attention-deficit/hyperactivity disorder (ADHD), addiction, mania, and certain personality disorders. Furthermore, when animals choose between alternative courses of action, seeking to maximize the benefit obtained, they must also evaluate the likelihood of the available outcomes. Little is known of the neural basis of this process, or what might predispose individuals to be overly conservative or to take risks excessively (avoiding or preferring uncertainty, respectively), but risk taking is another aspect of the personality trait of impulsivity and is a feature of a number of psychiatric disorders, including pathological gambling and some personality disorders. The AcbC, part of the ventral striatum, is required for normal preference for a large, delayed reward over a small, immediate reward (self-controlled choice) in rats, but the reason for this is unclear. Chapter 3 investigated the role of the AcbC in learning a free-operant instrumental response using delayed reinforcement, performance of a previously learned response for delayed reinforcement, and assessment of the relative magnitudes of two different rewards. Groups of rats with excitotoxic or sham lesions of the AcbC acquired an instrumental response with different delays (0, 10, or 20 s) between the lever-press response and reinforcer delivery. A second (inactive) lever was also present, but responding on it was never reinforced. The delays retarded learning in normal rats. AcbC lesions did not hinder learning in the absence of delays, but AcbC-lesioned rats were impaired in learning when there was a delay, relative to sham-operated controls. Rats were subsequently trained to discriminate reinforcers of different magnitudes. AcbC-lesioned rats were more sensitive to differences in reinforcer magnitude than sham-operated controls, suggesting that the deficit in self-controlled choice previously observed in such rats was a consequence of reduced preference for delayed rewards relative to immediate rewards, not of reduced preference for large rewards relative to small rewards. AcbC lesions also impaired the performance of a previously learned instrumental response in a delay-dependent fashion. These results demonstrate that the AcbC contributes to instrumental learning and performance by bridging delays between subjects’ actions and the ensuing outcomes that reinforce behaviour. When outcomes are delayed, they may be attributed to the action that caused them, or mistakenly attributed to other stimuli, such as the environmental context. Consequently, animals that are poor at forming context–outcome associations might learn action–outcome associations better with delayed reinforcement than normal animals. The hippocampus contributes to the representation of environmental context, being required for aspects of contextual conditioning. It was therefore hypothesized that animals with H lesions would be better than normal animals at learning to act on the basis of delayed reinforcement. Chapter 4 tested the ability of H-lesioned rats to learn a free-operant instrumental response using delayed reinforcement, and their ability to exhibit self-controlled choice. Rats with sham or excitotoxic H lesions acquired an instrumental response with different delays (0, 10, or 20 s) between the response and reinforcer delivery. H-lesioned rats responded slightly less than sham-operated controls in the absence of delays, but they became better at learning (relative to shams) as the delays increased; delays impaired learning less in H-lesioned rats than in shams. In contrast, lesioned rats exhibited impulsive choice, preferring an immediate, small reward to a delayed, larger reward, even though they preferred the large reward when it was not delayed. These results support the view that the H hinders action–outcome learning with delayed outcomes, perhaps because it promotes the formation of context–outcome associations instead. However, although lesioned rats were better at learning with delayed reinforcement, they were worse at choosing it, suggesting that self-controlled choice and learning with delayed reinforcement tax different psychological processes. Chapter 5 examined the effects of excitotoxic lesions of the AcbC on probabilistic choice in rats. Rats chose between a single food pellet delivered with certainty (probability p = 1) and four food pellets delivered with varying degrees of uncertainty (p = 1, 0.5, 0.25, 0.125, and 0.0625) in a discrete-trial task, with the large-reinforcer probability decreasing or increasing across the session. Subjects were trained on this task and then received excitotoxic or sham lesions of the AcbC before being retested. After a transient period during which AcbC-lesioned rats exhibited relative indifference between the two alternatives compared to controls, AcbC-lesioned rats came to exhibit risk-averse choice, choosing the large reinforcer less often than controls when it was uncertain, to the extent that they obtained less food as a result. Rats behaved as if indifferent between a single certain pellet and four pellets at p = 0.32 (sham-operated) or at p = 0.70 (AcbC-lesioned) by the end of testing. When the probabilities did not vary across the session, AcbC-lesioned rats and controls strongly preferred the large reinforcer when it was certain, and strongly preferred the small reinforcer when the large reinforcer was very unlikely (p = 0.0625), with no differences between AcbC-lesioned and sham-operated groups. These results suggest that the AcbC contributes to action selection by promoting the choice of uncertain, as well as delayed, reward

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

The Functional Neurocircuitry of Sign-tracking Behavior

Cues that are paired with unconditioned, rewarding stimuli can acquire rewarding properties themselves through a process known as the attribution of incentive salience. When previously neutral cues are imbued with incentive salience, they become attractive, “wanted” stimuli capable of motivating behavior. Pavlovian conditioned approach procedures are commonly used to investigate the attribution of incentive salience in rodents. During Pavlovian conditioned approach training, two conditioned responses develop: sign-tracking (behavior directed towards a reward-related cue) and goal-tracking (behavior directed towards the site of reward delivery). Goal-trackers and sign-trackers both use the reward-related cue as a predictor of reward delivery; however, only sign-trackers attribute it with incentive salience and are more vulnerable to addiction-like behaviors, such as cue-induced reinstatement of drug-seeking. Currently, it is known that sign-tracking behavior is dependent on dopamine in the nucleus accumbens, a central hub in the ‘motive circuit,’ an array of mesocorticolimbic brain regions that process incentive stimuli. However, the role of other signaling pathways and the contribution of afferent brain regions within the motive circuit to sign-tracking behavior is poorly understood. In this dissertation, I demonstrate that the ventral hippocampus is a part of the motive circuit, regulating sign-tracking behavior and dopamine signaling in the nucleus accumbens. In addition, I show that the motive circuit can be manipulated environmentally and pharmacologically using prolonged stress and subanesthetic ketamine, respectively, to decrease sign-tracking behavior. Taken together, the results of this dissertation advance our understanding of the functional neurocircuitry of sign-tracking behavior and how it is influenced by environmental and pharmacological manipulations of the motive circuit.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149891/1/cjfitzpa_1.pd

From the Cell to the Brain –Fear and Anxiety across the Levels of Neuroscience

The four studies presented in this thesis independently provided support for a dynamic multilevel account for anxiety-related phenomena (see Table 2). Study 1 showed how medial prefrontal cortex activity (i.e., Structure Level) measured with EEG was related to heart rate (PNS Level) and provided some evidence that this association was dynamically linked to trait anxiety: in conditions of negative but not positive feedback did trait anxiety increase the link between cortical and cardiac activity. This modulation is consistent with the functional definition of anxiety given that negative but not positive feedback is normally associated with increased danger in the future. Study 2 showed how dopaminergic genes (Molecule Level) and manipulations of dopamine (Synapse Level) presumably affected network states (Network Level), which then influenced brain activity at the AMC (Structure Level) and error-related behavior (Whole System Level). The unexpected finding that trait-anxiety was not related to error monitoring in that study can be explained post hoc by task characteristics (Olvet & Hajcak, 2009), again suggesting that some patterns of multilevel interactions are dynamically linked to anxiety. Study 3 tested individuals with GAD (manifest at the Whole System Level) using a neuropsychological test designed to measure future-orientation in patients with damage of the ventromedial prefrontal cortex (Structure Level) and resulting impairments in neurovisceral connectivity (Bechara et al., 1997) thus affecting the CNS and PNS-Levels. Consistent with (a) the assumed future-orientation of anxiety and (b) increased neurovisceral connectivity in anxiety (Study 1) individuals with GAD performed better in the IGT than non-anxious control participants. Finally, Study 4 manipulated intracellular signalling cascades (Molecule Level), thereby modulating synaptic learning and extinction learning (Synapse Level), which then affected fear-related reflex potentiation (CNS-Level and Whole Systems Level). In contrast to prior studies that found improved extinction learning of hippocampus-dependent fear memory (e.g., fear conditioned to a place), Study 4 found that rolipram disturbed extinction learning of presumably hippocampus independent fear-memory (e.g., fear conditioned to a sound). Together with these other studies, Study 4 thus provides further evidence that situational characteristics (place vs. sound as cue for present danger) may influence various levels (including the Molecule Level) with regard to fear processing. As can be seen in Table 2, some studies covered different levels than others. Of course, the herein proposed subdivision into eight levels of organization should be seen as a flexible framework used for illustrating the multilevel perspective rather than as a rigid model. Future research may uncover that much more levels of organization are needed to explain certain phenomena, and there may also be cases when good predictions can be made based on fewer than eight levels. However, Table 2 also shows that guesses for most empty cells can be made based on existing theories and research findings. A critical exception may be the network level, and it has been noted by others that this level is underrepresented in cognitive neuroscience research. However, the network level may be particularly critical for linking what we know about substances, cells, synapses and neurons (mostly based on in vitro work) to what we know about anxiety relevant structures (based on neuroimaging, EEG and lesion studies). From this perspective, future studies that include the neural network levels when investigating danger-reduction phenomena may be indispensable stations for achieving a wholistic understanding of fear and anxiety

The somatic marker theory in the context of addiction: contributions to understanding development and maintenance

Recent theoretical accounts of addiction have acknowledged that addiction to substances and behaviors share inherent similarities (eg, insensitivity to future consequences and self-regulatory deficits). This recognition is corroborated by inquiries into the neurobiological correlates of addiction, which has indicated that different manifestations of addictive pathology share common neural mechanisms. This review of the literature will explore the feasibility of the somatic marker hypothesis as a unifying explanatory framework of the decision-making deficits that are believed to be involved in addiction development and maintenance. The somatic marker hypothesis provides a neuroanatomical and cognitive framework of decision making, which posits that decisional processes are biased toward long-term prospects by emotional marker signals engendered by a neuronal architecture comprising both cortical and subcortical circuits. Addicts display markedly impulsive and compulsive behavioral patterns that might be understood as manifestations of decision-making processes that fail to take into account the long-term consequences of actions. Evidence demonstrates that substance dependence, pathological gambling, and Internet addiction are characterized by structural and functional abnormalities in neural regions, as outlined by the somatic marker hypothesis. Furthermore, both substance dependents and behavioral addicts show similar impairments on a measure of decision making that is sensitive to somatic marker functioning. The decision-making deficits that characterize addiction might exist a priori to addiction development; however, they may be worsened by ingestion of substances with neurotoxic properties. It is concluded that the somatic marker model of addiction contributes a plausible account of the underlying neurobiology of decision-making deficits in addictive disorders that is supported by the current neuroimaging and behavioral evidence. Implications for future research are outlined

Long-term effects of social stress exposure during adolescence in impulsivity : toward a new model of aggression

Adolescent male hamsters exposed to chronic social stress become themselves aggressive adults, evidenced by increased frequency of attacks and shorter latencies to attack opponents. Perhaps, this enhanced aggression is associated with a lack of impulse control, in particular with the ability to inhibit responses (i.e. action inhibition) and wait to respond (i.e. waiting impulsivity). Male golden hamsters were exposed daily to aggressive adults from postnatal day 28 to 42. Later, the animals were trained in conditioning chambers and tested in a Go-NoGo task to evaluate action inhibition. Overall, previously stressed hamsters were less likely to inhibit a conditioned lever pressing response during NoGo trials. These results show that animals exposed to social stress in early adolescence, have a decrease ability to withhold responses, which could possible explain why as adults, they have higher frequency of attacks. To test waiting impulsivity, animals learned to respond to a main house-light by nose-poking in any of two, adjacent illuminated ports in a modified version of a 5-choice-serial-reaction-time task (5-CSRTT). During testing, random and varying delays were introduced between the main house-light presentation and illumination of the ports, and premature nose-poking responses, (i.e. responses before the ports were illuminated) were considered an indicator of waiting impulsivity. As delays grew longer, animals performed more premature responses. However, previously stressed animals were 25% less likely to perform such actions by the longest delay. These studies show that early stress exposure enhanced the capacity to wait to perform a response, which is unrelated to aggression. Aspects of perseverance were tested in additional studies. In summary, chronic social stress exposure in early adolescence causes a variety of behavioral changes including enhanced aggression, decreased action inhibition and improved waiting impulsivity. This ambiguous relation between aggressive and impulsive behaviors suggests that perhaps there are multiple types of impulsive-aggression profiles related to different brain mechanisms. Thus, it is proposed that the concept of aggression should be reconsidered as a multidimensional construct mediating aspects of personality.Psycholog

Neurochemical modulation of affective and behavioural control: Models and applications for psychiatry

Impairments in emotional reactivity and behavioural flexibility are pervasive across disparate psychiatric conditions as traditionally defined. Here, I provide new evidence on how these processes are altered by neuromodulators in humans, with a primary focus on serotonin (5- HT; 5-hydroxytryptamine). Emotional reactions prepare the body for action. Some emotion is primitive, implicit, and critical for surviving threats, yet can inappropriately persist in times of safety. Other emotions are more complex, self-conscious and important in maintaining harmonious interpersonal relationships. At the same time, learned behaviours that are adaptive in the first instance, may become irrelevant or even disadvantageous as circumstances change. In Chapters 3 through 6, I report on experiments in healthy human volunteers that employed the dietary technique acute tryptophan depletion (ATD). ATD temporarily lowers serotonin synthesis and release by depleting its biosynthetic precursor tryptophan. Chapter 3 is a study of self-reported social emotion. ATD enhanced emotion in response to social injustice non-specifically; however, consideration of personality traits revealed that highly empathic participants reported more guilt under ATD, whereas individuals high in trait psychopathy demonstrated more annoyance. Chapter 4, in contrast, considers evolutionarily ancient automatic emotional reactions to threats. This was assayed instead by an objective measure, the skin conductance response (SCR). Here, ATD conversely attenuated the retention of Pavlovian conditioned emotional memory to threat. Traits again influenced this response: individuals more intolerant of uncertainty displayed the greatest attenuation of emotional reactions. Chapter 5 both extends the studies on emotion and bridges to the remaining empirical work by investigating reversal learning, an index of cognitive flexibility, in two experiments. Individuals again underwent Pavlovian (stimulus-outcome) threat conditioning, whereby one stimulus predicted threat, and another was safe. These contingencies then swapped (reversed). In a separate experiment, participants underwent instrumental (stimulus-response-outcome) conditioning on a deterministic schedule (the correct option was always correct), followed by reversal of the contingencies. ATD impaired both Pavlovian and instrumental reversal learning. Chapters 6 through 8 instead examine instrumental reversal learning that was probabilistic (the correct option was correct most but not all of the time), rather than deterministic. Chapter 6 expands on previous ATD studies of probabilistic reversal learning (PRL) in the literature, which had not found effects on choice behaviour. Despite nearly tripling the sample size, behaviour here assessed by conventional methods was unaffected, replicating previously published null results. Applying reinforcement learning (RL) models, however, revealed ATD elevated a basic perseverative tendency, referred to as “stimulus stickiness”; behaviour was more stimulus-bound and insensitive to the outcome of actions, consistent with the deterministic instrumental reversal impairment following ATD. Chapters 7 and 8 apply RL models as well, to existing datasets on PRL for comparison. Chapter 7 shows that healthy volunteers under lysergic acid diethylamide (LSD), which acts both at serotonin but also dopamine receptors, showed enhanced learning from positive feedback in particular, which was related to perseveration. Chapter 8 applies computational methods to PRL in clinical populations. RL modelling revealed a computational signature that dissociated PRL in stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD): Individuals with SUD showed heightened stimulus stickiness, as occurred following ATD in healthy volunteers, whereas the OCD group (under serotonergic medication) demonstrated lower stimulus stickiness than healthy controls. Dopaminergic agents remediated a reward learning deficit in SUD, among other measures. The general discussion considers these various findings in terms of theories of central serotonin function, in relation to the animal literature, and its relevance to mental disorder. These results, collectively, advance knowledge of neurochemical and computational mechanisms underlying psychiatric conditions trans-diagnostically, with implications for revised psychiatric classifications in line with the Research Domain Criteria (RDoC).Gates Cambridge Trust Wellcome Trus

Effects of the Abused Inhalant Toluene on mPFC-Dependent Cognitive Behaviors and Associated Neural Activity

Volatile organic solvents like toluene induce euphoria and intoxication when inhaled at high concentrations. Inhalant misuse is linked to behavioral, cognitive, and anatomical deficits in humans leading to a reduced productivity and quality of life. Yet, preclinical studies on the effect of inhalants on executive control in animal models are limited. We address this gap in knowledge using rodent models in two ways: first, by examining the long-lasting effects of repeated toluene inhalation during adolescence on several measures of executive function in adulthood and second, by studying the effects of acute toluene inhalation on risk/reward decision making and related neurocircuitry. Repeated inhalation of toluene during adolescence blunted acquisition of operant and Pavlovian learning in adulthood without affecting probabilistic discounting, progressive ratio breakpoint, latent inhibition or reversal learning. Acute toluene vapor inhalation, however, caused a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting, a pattern that implicates dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients during during task performance using in vivo fiber photometry. Peaks in GCaMP6f activity shifted from pre-risky to pre-safe choice during contingency updating, an effect that was eliminated by acute toluene exposure. mPFC activity in toluene-treated animals also did not distinguish between risky/large wins and safe/small wins. Interestingly, previous studies from our lab demonstrated a toluene-induced long-term depression of AMPA-mediated synaptic activity in deep-layer mPFC neurons. This effect was dependent on endocannabinoids (EC) synthesis and presynaptic cannabinoid receptor (CB1R) function. Here, we found that pharmacological inhibition of CB1Rs in the mPFC or systemically did not mitigate toluene’s effect on probabilistic discounting. Behavioral flexibility in this task also depends on functional mPFC-basolateral amygdala (BLA) neurocircuitry. Electrophysiological interrogation of BLA neurons innervated by the mPFC using ex vivo slice electrophysiology and optogenetics revealed a CB1R-dependent decrease in excitatory synaptic transmission following toluene application. These data elucidate learning and behavioral flexibility deficits caused by toluene, including insights on potential mPFC-BLA- and CB1R-dependent mechanisms

The Effects of Acute Stress and Adolescent Alcohol Exposure on Behavioral Flexibility in Adulthood

The prefrontal cortex (PFC) is critical for executive functions that underlie behavioral flexibility, but is especially vulnerable to environmental insults during development, which concludes after adolescence. Adolescence is a time of neural development, and is marked by increased risk-taking and impaired judgment. Adolescence is often associated with engagement in risky behaviors such as experimentation with drugs of abuse, including alcohol. Alcohol is particularly damaging to the PFC, and leads to negative impacts on executive functions. Traumatic stress has also been shown to negatively impact executive functions, and alcohol use and stress disorders frequently occur co-morbidly. Additionally, deficits in executive functions following adolescent alcohol or traumatic stress exposure in rats may differentially affect different strains of rats. This dissertation addressed the overarching hypothesis that binge-like adolescent alcohol (AIE) and a model of traumatic stress (SPS) negatively impact executive functions in adulthood, and that two strains of rats (Long-Evans, LE, and Sprague-Dawley, SD) may respond differentially to these exposures. First, the effects of AIE and SPS in adulthood on probabilistic reversal learning (PRL) were examined. AIE impaired discrimination learning with probabilistic reinforcement in LE rats on day one of the PRL task, and led to decreased reward and negative feedback sensitivity in SD rats over extended testing. SPS exposure following AIE led to increased negative feedback and reward sensitivity in LE rats. The second component of this dissertation addressed the effects of AIE and SPS on the probabilistic decision-making task. AIE led to increased choice latency and impaired mastery of the task in SD rats during initial training sessions. SPS exposure following AIE led to decreased risky choice compared to SPS exposure alone in SD rats. The third component of this dissertation addressed the effects of AIE and SPS on fear-related behaviors. AIE and SPS exposure led to faster acquisition of associative fear conditioning in LE rats, and increased resistance to extinction. Taken together, this dissertation demonstrates that AIE leads to persistent deficits in behavioral flexibility in adulthood, and that SPS exacerbates these deficits

METHYLPHENIDATE AND ATOMOXETINE TREATMENT DURING ADOLESCENCE IN THE SPONTANEOUSLY HYPERTENSIVE RAT: MECHANISMS UNDERLYING HIGH COCAINE ABUSE LIABILITY IN ATTENTION DEFICIT/HYPERACTIVITY DISORDER

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action. In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 mg/kg/day, i.p.) or vehicle during adolescence (postnatal day 28-55). During adulthood (\u3e77 days), DAT and NET functions in mPFC and OFC were determined as neurochemical mechanisms and locomotor sensitization to cocaine, and impulsivity under differential reinforcement of low rates 30-second (DRL30) schedule were evaluated as behavioral mechanisms associated with greater cocaine self-administration in methylphenidate-treated SHRs. Maximal velocity of [3H]dopamine uptake (Vmax) by DAT and DAT cellular distribution in mPFC and OFC did not differ between vehicle-control, adult SHR, Wistar-Kyoto and Wistar. Methylphenidate increased DAT Vmax, but not cell-surface expression, in SHR mPFC. In contrast, atomoxetine decreased Vmax and cell-surface expression in SHR OFC. Compared to control strains, norepinephrine uptake by NET in the OFC was increased in vehicle-administered SHR; methylphenidate during adolescence normalized NET function in SHR OFC. Locomotor sensitization was greater in SHR compared to control, and was not altered by methylphenidate. Under DRL30, methylphenidate increased burst responses in adult SHR compared to vehicle control as well as methylphenidate-treated Wistar-Kyoto and Wistar, indicating increased impulsivity. Increased OFC NET function, increased impulsivity and cocaine sensitivity may be the neurobehavioral mechanisms associated with the increased cocaine self-administration in SHR. Increased mPFC DAT function may underlie the enhanced impulsivity and cocaine self-administration in SHR administered methylphenidate during adolescence. Decreased OFC DAT function from atomoxetine-treated SHR may explain the reduced cocaine self-administration relative to methylphenidate. Thus, methylphenidate during adolescence in ADHD may increase risk for cocaine abuse, while atomoxetine may represent a therapeutic alternative for at-risk adolescents with ADHD