Adolescent-onset of cocaine use is associated with heightened stress-induced reinstatement of cocaine seeking.

Adolescent rats take cocaine more readily than adults, are more sensitive to lower doses of the drug and work harder for it. It remains unknown if adolescent-onset of cocaine use has long-term consequences on adult relapse liability. Therefore, we tested if self-administering cocaine during adolescence impacts subsequent stress-induced reinstatement to cocaine seeking and taking, after a prolonged drug-free period. Adolescent (~P42) or adult (P88) rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) for 7 or 10 days. Then, they underwent a prolonged drug-free period (21-40 days), after which they were tested for reinstatement of cocaine-seeking (i.e. responding in the absence of cocaine) induced by the stress hormone corticosterone, the pharmacological stressor yohimbine or electric footshock. Studies employed either single extinction session (within-session extinction/reinstatement) or repeated extinction prior to reinstatement (between-session extinction/reinstatement). Finally, in a separate set of experiments, rats underwent a prolonged drug-free period (~40 days) and were then allowed to self-administer cocaine again, using progressive-ratio procedures that appraise the reinforcing efficacy of cocaine. Rats with adolescent-onset of cocaine use showed greater stress-induced reinstatement of cocaine seeking than rats with adult-onset of cocaine use. This was observed across conditions, providing external validity to these results. Groups did not differ on drug taking in progressive-ratio tests. Our studies indicate that experiencing cocaine during adolescence renders subjects particularly responsive to the subsequent effects of stress on drug seeking. This heightened propensity for reinstatement puts adolescent-onset drug users at heightened risk for relapse.

Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence.

In humans, adolescence is a period of heightened propensity to develop cocaine addiction. It is unknown whether this is attributable to greater access and exposure to cocaine at this age, or whether the adolescent brain is particularly vulnerable to the addictive properties of cocaine. Here, we subjected male adolescent (P42) and adult (∼P88) rats to a wide range of cocaine self-administration procedures. In addition, to determine whether behavioral differences are associated with developmental differences in dopaminergic activity, we examined and manipulated the activity of dopamine neurons. Relative to adults, adolescent rats took cocaine more readily, were more sensitive to lower doses, showed greater escalation of cocaine intake, and were less susceptible to increases in price (i.e., were more "inelastic"). In parallel, adolescents also showed elevated activity of ventral tegmental area dopamine neurons, a feature known to be associated with increased self-administration behavior. Pharmacological manipulation of dopamine D2 receptor function with quinpirole (agonist) or eticlopride (antagonist), to alter dopamine neuron activity, eliminated age differences in cocaine self-administration. These data suggest a causal relationship between behavioral and electrophysiological determinants of cocaine addiction liability. In conclusion, adolescents show behavioral and electrophysiological traits of heightened addiction liability.

Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization.

It is well established that behavioral sensitization to cocaine is accompanied by increased spine density and AMPA receptor (AMPAR) transmission in the nucleus accumbens (NAc), but two major questions remain unanswered. Are these adaptations mechanistically coupled? And, given that they can be dissociated from locomotor sensitization, what is their functional significance? We tested the hypothesis that the guanine-nucleotide exchange factor Kalirin-7 (Kal-7) couples cocaine-induced AMPAR and spine upregulation and that these adaptations underlie sensitization of cocaine's incentive-motivational properties-the properties that make it "wanted." Rats received eight daily injections of saline or cocaine. On withdrawal day 14, we found that Kal-7 levels and activation of its downstream effectors Rac-1 and PAK were increased in the NAc of cocaine-sensitized rats. Furthermore, AMPAR surface expression and spine density were increased, as expected. To determine whether these changes require Kal-7, a lentiviral vector expressing Kal-7 shRNA was injected into the NAc core before cocaine exposure. Knocking down Kal-7 abolished the AMPAR and spine upregulation normally seen during cocaine withdrawal. Despite the absence of these adaptations, rats with reduced Kal-7 levels developed locomotor sensitization. However, incentive sensitization, which was assessed by how rapidly rats learned to self-administer a threshold dose of cocaine, was severely impaired. These results identify a signaling pathway coordinating AMPAR and spine upregulation during cocaine withdrawal, demonstrate that locomotor and incentive sensitization involve divergent mechanisms, and link enhanced excitatory transmission in the NAc to incentive sensitization.

Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving.

Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.

Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats.

Methylphenidate (MP) is commonly prescribed to treat attention-deficit hyperactivity disorder (ADHD). MP is also taken for non-medical purposes as a recreational drug or "cognitive enhancer". Combined exposure to MP and selective serotonin reuptake inhibitors such as fluoxetine (FLX) can also occur, such as in the treatment of ADHD with depression comorbidity or when patients taking FLX use MP for non-medical purposes. It is unclear if such exposure could subsequently increase the risk for relapse in former cocaine users. We investigated if an acute challenge with MP, FLX, or the combination of MP + FLX could trigger reinstatement of cocaine seeking behavior in a model for relapse in rats. Juvenile rats self-administered cocaine (600 µg/kg/infusion, 1-2 h/day, 7-8 days) and then underwent extinction and withdrawal during late adolescence-early adulthood. Reinstatement was tested at a low dose of MP (2 mg/kg, I.P., comparable to doses used therapeutically) or a high dose of MP (5 mg/kg, comparable to doses used recreationally or as a cognitive enhancer), with or without FLX (2.5-5 mg/kg, I.P.). An acute challenge with the high dose of MP (5 mg/kg), with or without FLX, reinstated cocaine seeking behavior to levels comparable to those seen after an acute challenge with cocaine (15 mg/kg, I.P.). The low dose of MP (2 mg/kg) with or without FLX did not reinstate cocaine seeking behavior. Our results suggest that acute exposure to a high dose of MP, with or without FLX, may increase the risk for relapse in individuals who used cocaine during the juvenile period.

Fluoxetine potentiates methylphenidate-induced behavioral responses: Enhanced locomotion or stereotypies and facilitated acquisition of cocaine self-administration.

The medical psychostimulant methylphenidate (MP) is used to treat attention-deficit hyperactivity disorder and recreationally as a "cognitive enhancer". MP is a dopamine reuptake inhibitor, but does not affect serotonin. Serotonin contributes to addiction-related gene regulation and behavior. Previously, we showed that enhancing serotonin action by adding a selective serotonin reuptake inhibitor, fluoxetine (FLX), to MP potentiates MP-induced gene regulation in striatum and nucleus accumbens, mimicking cocaine effects. Here, we investigated the behavioral consequences of MP+FLX treatment. Young adult male rats received MP (5 mg/kg, i.p.) or MP+FLX (5 mg/kg each) daily for 6-8 days. Behavioral effects were assessed in an open-field test during the repeated treatment. Two weeks later the motor response to a cocaine challenge (25 mg/kg) and the rate of acquisition of cocaine self-administration behavior were determined. Our results demonstrate that FLX potentiates effects of MP on open-field behavior. However, we found differential behavioral responses to MP+FLX treatment, as approximately half of the rats developed high rates of focal stereotypies (termed "MP+FLX/high reactivity" group), whereas the other half did not, and only showed increased locomotion ("MP+FLX/low reactivity" group). Two weeks later, cocaine-induced locomotion and stereotypies were positively correlated with MP+FLX-induced behavior seen at the end of the repeated MP+FLX treatment. Moreover, the MP+FLX/high reactivity group, but not the low reactivity group, showed facilitated acquisition of cocaine self-administration. These results demonstrate that repeated MP+FLX treatment can facilitate subsequent cocaine taking behavior in a subpopulation of rats. These findings suggest that MP+FLX exposure in some individuals may increase the risk for psychostimulant use later in life.

Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine.

Repeated noncontingent cocaine injections, which lead to behavioral sensitization, increase AMPA receptor (AMPAR) transmission in the rodent nucleus accumbens (NAc) in a withdrawal-dependent manner. On withdrawal days (WD) 10-21, this is attributable to upregulation of GluA1A2-containing AMPARs. However, synaptic incorporation of GluA2-lacking/Ca(2+)-permeable AMPARs (CP-AMPARs) was observed after longer withdrawal (WD35) from repeated noncontingent cocaine injections in young mice (Mameli et al., 2009). CP-AMPARs had previously been observed in NAc synapses only after prolonged (WD30-WD47) withdrawal from extended-access cocaine self-administration. Our goal was to determine whether rats receiving repeated noncontingent cocaine injections during adulthood similarly exhibit CP-AMPARs in the NAc after prolonged withdrawal. For comparison, we began by evaluating CP-AMPARs on WD35-WD49 after extended-access cocaine self-administration. Confirming our previous results, whole-cell recordings revealed inwardly rectifying AMPAR EPSCs, a hallmark of CP-AMPARs. This was observed in both core and shell. Next, we conducted the same analysis in adult rats treated with eight daily noncontingent cocaine injections and recorded on WD35-WD49. AMPAR EPSCs in core and shell did not show inward rectification and were insensitive to 1-naphthylacetylspermine (a selective antagonist of CP-AMPARs). Locomotor sensitization could still be demonstrated after this long withdrawal period, although the upregulation of GluA1A2-containing AMPARs observed at earlier withdrawal times was no longer detected. In conclusion, in adult rats, accumulation of synaptic CP-AMPARs in the NAc occurs after prolonged withdrawal from extended-access cocaine self-administration but not after prolonged withdrawal from noncontingent cocaine injections.

Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism.

Following prolonged withdrawal from extended access cocaine self-administration in adult rats, high conductance Ca2+ -ermeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses and mediate the expression of "incubated" cue-induced cocaine craving. Using patch-clamp recordings from NAc slices prepared after extended access cocaine self-administration and >45 d of withdrawal, we found that group I metabotropic glutamate receptor (mGluR) stimulation using 3,5-dihydroxyphenylglycine (DHPG; 50 µm) rapidly eliminates the postsynaptic CP-AMPAR contribution to NAc synaptic transmission. This is accompanied by facilitation of Ca2+ -impermeable AMPAR (CI-AMPAR)-mediated transmission, suggesting that DHPG may promote an exchange between CP-AMPARs and CI-AMPARs. In saline controls, DHPG also reduced excitatory transmission but this occurred through a CB1 receptor-dependent presynaptic mechanism rather than an effect on postsynaptic AMPARs. Blockade of CB1 receptors had no significant effect on the alterations in AMPAR transmission produced by DHPG in the cocaine group. Interestingly, the effect of DHPG in the cocaine group was mediated by mGluR1 whereas its effect in the saline group was mediated by mGluR5. These results indicate that regulation of synaptic transmission in the NAc is profoundly altered after extended access cocaine self-administration and prolonged withdrawal. Furthermore, they suggest that activation of mGluR1 may represent a potential strategy for reducing cue-induced cocaine craving in abstinent cocaine addicts.

Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults.

Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.

Assessing SDG indicator 6.4.2 'level of water stress' at major basins level.

This paper describes a method to disaggregate indicator 6.4.2 (level of water stress) by major river basins. The analysis was performed using the GlobWat soil water balance model and global geospatial data consistent with national statistics published in AQUASTAT, the FAO's global information system on water and agriculture. When a river basin spans across more than one country, the water stress calculated by country can be very different from that calculated by the river basin as the counting of the renewable freshwater resources from one country to another is highly dependent on the official agreement and treaties that regulate the flow of those resources between countries. This problem is solved hydrologically once the accounting of the water resources is done on the major river basin as a whole. The disaggregation by the river basin allows the identification of hotspots where actions should be prioritised and reveals that the area affected by a high or critical water stress spans across all continents with the exception of Oceania. It also offers the possibility of an analysis of freshwater withdrawals by sector, which may become crucial for the definition of water management policies in the context of the economic development of a country.

Dopamine scales performance in the absence of new learning.

Learning and motivation are integral in shaping an organism's adaptive behavior. The dopamine system has been implicated in both processes; however, dissociating the two, both experimentally and conceptually, has posed significant challenges. We have developed an animal model that dissociates expression or scaling of a learned behavior from learning itself. An inducible dopamine transporter (DAT) knockdown mouse line has been generated, which exhibits significantly slower reuptake of released dopamine and increased tonic firing of dopamine neurons without altering phasic burst firing. Mice were trained in experimental tasks prior to inducing a hyperdopaminergic tone and then retested. Elevated dopamine enhanced performance in goal-directed operant responses. These data demonstrate that alterations in dopaminergic tone can scale the performance of a previously learned behavior in the absence of new learning.

Leptin receptor signaling in midbrain dopamine neurons regulates feeding.

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.

Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum.

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.

The Lateral Preoptic Area and Its Projection to the VTA Regulate VTA Activity and Drive Complex Reward Behaviors.

The ventral tegmental area (VTA) underlies motivation and reinforcement of natural rewards. The lateral preoptic area (LPO) is an anterior hypothalamic brain region that sends direct projections to the VTA and to other brain structures known to regulate VTA activity. Here, we investigated the functional connection between the LPO and subpopulations of VTA neurons and explored the reinforcing and valence qualities of the LPO in rats. We found that the LPO and the LPO→VTA pathway inhibit the activity of VTA GABA neurons and have mixed effects on VTA dopamine neurons. Furthermore, we found that the LPO supports operant responding but drives avoidance, and we explored the apparent discrepancy between these two results. Finally, using fiber photometry, we show that the LPO signals aversive events but not rewarding events. Together, our findings demonstrate that the LPO modulates the activity of the VTA and drives motivated behavior and represents an overlooked modulator of reinforcement.

Age matters.

The age of an experimental animal can be a critical variable, yet age matters are often overlooked within neuroscience. Many studies make use of young animals, without considering possible differences between immature and mature subjects. This is especially problematic when attempting to model traits or diseases that do not emerge until adulthood. In this commentary we discuss the reasons for this apparent bias in age of experimental animals, and illustrate the problem with a systematic review of published articles on long-term potentiation. Additionally, we review the developmental stages of a rat and discuss the difficulty of using the weight of an animal as a predictor of its age. Finally, we provide original data from our laboratory and review published data to emphasize that development is an ongoing process that does not end with puberty. Developmental changes can be quantitative in nature, involving gradual changes, rapid switches, or inverted U-shaped curves. Changes can also be qualitative. Thus, phenomena that appear to be unitary may be governed by different mechanisms at different ages. We conclude that selection of the age of the animals may be critically important in the design and interpretation of neurobiological studies.

The Lateral Preoptic Area: A Novel Regulator of Reward Seeking and Neuronal Activity in the Ventral Tegmental Area.

The lateral preoptic area (LPO) is a hypothalamic region whose function has been largely unexplored. Its direct and indirect projections to the ventral tegmental area (VTA) suggest that the LPO could modulate the activity of the VTA and the reward-related behaviors that the VTA underlies. We examined the role of the LPO on reward taking and seeking using operant self-administration of cocaine or sucrose. Rats were trained to self-administer cocaine or sucrose and then subjected to extinction, whereby responding was no longer reinforced. We tested if stimulating the LPO pharmacologically with bicuculline or chemogenetically with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) modifies self-administration and/or seeking. In another set of experiments, we tested if manipulating the LPO influences cocaine self-administration during and after punishment. To examine the functional connectivity between the LPO and VTA, we used in vivo electrophysiology recordings in anesthetized rats. We tested if stimulating the LPO modifies the activity of GABA and dopamine neurons of the VTA. We found that stimulating the LPO reinstated cocaine and sucrose seeking behavior but had no effect on reward intake. Furthermore, both stimulating and inhibiting the LPO prevented the sustained reduction in cocaine intake seen after punishment. Finally, stimulating the LPO inhibited the activity of VTA GABA neurons while enhancing that of VTA dopamine neurons. These findings indicate that the LPO has the capacity to drive reward seeking, modulate sustained reductions in self-administration following punishment, and regulate the activity of VTA neurons. Taken together, these findings implicate the LPO as a previously overlooked member of the reward circuit.

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes.

RATIONALE: Adolescence is a period of considerable development of brain and behavior and is the time during which most drug use is initiated. OBJECTIVE: Age-dependent differences in motivated behaviors may be one of the factors that contribute to heightened vulnerability to developing substance use disorders, so we sought to compare age differences in methamphetamine (METH) and saccharin seeking. METHODS: Beginning during adolescence or adulthood, male and female Sprague-Dawley rats were trained to self-administer 0.1% saccharin (via liquid dipper cup) or intravenous METH at one of three doses (0.02, 0.05, 0.08 mg/kg/inf) under increasing fixed ratio schedules of reinforcement. Subsequently, responding for METH (0.02, 0.05, 0.08, or 0.1 mg/kg/inf) under progressive ratio response requirements was assessed in rats that acquired METH self-administration at the highest dose (0.08 mg/kg/inf). RESULTS: We found that adult-onset rats acquired METH self-administration more readily and exhibited higher motivation compared to adolescent-onset rats, although there were no differences in METH intake during acquisition. Adult rats also acquired saccharin self-administration more readily, but in contrast to METH, there were age and sex differences in saccharin intake driven by high levels of responding in adult females. CONCLUSIONS: These findings challenge the prevailing notion that adolescents are hypersensitive to reward and instead raise questions about the potential role of methodological factors on which rodent studies often differ.

The many facets of the locomotor response to a novel environment test: theoretical comment on Mitchell, Cunningham, and Mark (2005).

Several animal studies have shown that there is a positive correlation between locomotor activity in response to a novel environment and acquisition of drug self-administration behavior. This finding led to the assumption that animals with heightened reactivity to novel environments are more sensitive to the rewarding effects of drugs compared with animals with reduced reactivity. But are these individuals really more responsive to drugs, or could they have enhanced sensitivity to rewards in general or even simply be better learners? In the previous issue of this journal, J. M. Mitchell, C. L. Cunningham, and G. P. Mark (2005), investigated these important matters. They reported that the locomotor response to a novel environment does not predict responding for cocaine but reflects overall differences in the ability to learn operant tasks. ((c) 2005 APA, all rights reserved).

Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons.

BACKGROUND: Methylphenidate is commonly used to treat children and adolescents with attention-deficit/hyperactivity disorder. A health concern is its long-term effects with respect to later stimulant exposure. We reported that repeated exposure to a low dose of methylphenidate during adolescence increases self-administration of a low, typically nonreinforcing dose of cocaine in adult rats. We also showed that enhanced vulnerability to cocaine is associated with elevated impulse and bursting activity of midbrain dopamine neurons in drug-naïve adult rats and might constitute a substrate critically associated with abuse liability. Thus we sought to determine whether repeated exposure to low-dose methylphenidate in adolescence alters dopamine neuronal excitability in adulthood. METHODS: After 3-day and 2-week withdrawal from repeated low-dose adolescent exposure to methylphenidate, we used extracellular single-unit recording in chloral hydrate-anesthetized rats to determine basal firing and bursting activity of midbrain dopamine neurons and dopamine autoreceptor sensitivity to the D2-class direct receptor agonist quinpirole. RESULTS: Dopamine neuronal impulse activity was increased after 3 days and decreased after 2 weeks' withdrawal from methylphenidate given in adolescence. No difference between groups was evident with respect to autoreceptor sensitivity to quinpirole. CONCLUSIONS: Adolescent exposure to methylphenidate induces neuronal changes associated with increased addiction liability in rats.