Scott-Railton J, Arnold G, Vezina P. , Jan 1, 2006
Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA... more Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA). Because amphetamine, unlike emetic agents like LiCl, possesses appetitive properties that sensitize when it is administered repeatedly, the present study assessed the contribution of sensitization to this US pre-exposure effect (US-PEE). It was found that not all sensitizing regimens of systemic amphetamine injections produce a US-PEE. In addition, previous exposure to amphetamine in the VTA, where it acts to induce sensitization but not CTA, did not produce a US-PEE. It is concluded that amphetamine sensitization alone does not modulate this drug’s ability to produce CTA. Implications of these findings for anatomically based associative and non-associative models of CTA and the US-PEE are discussed.
The present experiments assessed the effect of the Group II-specific metabotropic glutamate recep... more The present experiments assessed the effect of the Group II-specific metabotropic glutamate receptor (mGluR) agonist, LY379268, on the expression of the locomotor sensitization observed following repeated exposure to amphetamine (AMPH). Rats in different groups were administered five injections of AMPH (1 mg/kg ip), one injection every 2-3 days. Two weeks after the last injection, rats were challenged with either AMPH (1 mg/kg ip) or AMPH coinjected with LY379268 (1 mg/kg ip). As expected, AMPH produced levels of locomotion that increased progressively from the first to the fifth injection. This locomotor sensitization was still evident 2 weeks later in rats challenged with AMPH. Rats challenged on this test with AMPH+LY379268, however, showed levels of locomotion similar to those observed following the first AMPH injection. These results indicate that Group II mGluRs can play an important role in the expression of locomotor sensitization by AMPH. The ability of Group II mGluR activ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction... more Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR ...
A novel version of the conditioned place preference (CPP) technique was used in an attempt to det... more A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS-). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS-, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most ...
Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological... more Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological underpinnings are not well characterized. As legal gambling increases in prominence in a growing number of casinos as well as on the internet, the potential for a rise in PG diagnoses warrants investigation of the disorder. The recent reclassification of PG as a behavioral addiction in the DSM-5 raises the possibility that similar cognitive and motivational phenotypes may underlie both gambling and substance use disorders. Indeed, in this Research Topic, Zack et al. (2014) tested the hypothesis that exposure to reward unpredictability can recruit brain dopamine (DA) systems in a similar way to chronic exposure to drugs of abuse (see also . Over the years a variety of models have proposed that alterations in DA signaling may mediate the transition from drug use to dependence; similarly, the hypothesis that aberrant DA responses may influence the transition from recreational, to problematic, and finally PG has only recently begun to be tested. The collection of articles in this Research Topic highlights the complexity of PG and posits several theories of how dopaminergic signaling may contribute to behavioral maladaptations that contribute to PG.
While the ventral striatum has long been implicated in the rewarding properties of psychomotor st... more While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self-administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions.
Addictions are commonly presaged by problems in childhood and adolescence. For many individuals t... more Addictions are commonly presaged by problems in childhood and adolescence. For many individuals this starts with the early expression of impulsive risk-taking, social gregariousness, and oppositional behaviors. Here we propose that these early diverse manifestations reflect a heightened ability of emotionally salient stimuli to activate dopamine pathways that foster behavioral approach. If substance use is initiated, these at-risk youth can also develop heightened responses to drug-paired cues. Through conditioning and drug-induced sensitization, these effects strengthen and accumulate, leading to responses that exceed those elicited by other rewards. At the same time, cues not paired with drug become associated with comparatively lower dopamine release, accentuating further the difference between drug and non-drug rewards. Together, these enhancing and inhibiting processes steer a pre-existing vulnerability toward a disproportionate concern for drugs and drugrelated stimuli. Implications for prevention and treatment are discussed. An integrative neurodevelopmental model of substance use disorders Drug addiction is the most prevalent neuropsychiatric disorder affecting society today. The social, medical, and economic costs are enormous, with drug use contributing to 12% of deaths worldwide [1] and costing the US government alone an estimated $400 billion per year .
In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display... more In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)... more Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.
Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to contribute to the expression o... more Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to contribute to the expression of psychostimulant sensitization by regulating dopamine (DA) overflow from DA neuron terminals in the nucleus accumbens (NAcc). The present experiments explored the contribution of CaMKII in NAcc neurons postsynaptic to these terminals where it is known to participate in a number of signaling pathways that regulate responding to psychostimulant drugs. Exposure to amphetamine transiently increased αCaMKII levels in the shell but not the core of the NAcc. Thus, HSV (herpes simplex viral) vectors were used to transiently overexpress αCaMKII in NAcc neurons in drug-naive rats, and behavioral responding to amphetamine was assessed. Transiently overexpressing αCaMKII in the NAcc shell led to long-lasting enhancement of amphetamine-induced locomotion and selfadministration manifested when αCaMKII levels were elevated and persisting long after they had returned to baseline. Enhanced locomotion was not observed after infection in the NAcc core or sites adjacent to the NAcc. Transient elevation of NAcc shell αCaMKII levels also enhanced locomotor responding to NAcc AMPA and increased phosphorylation levels of GluR1 (Ser831), a CaMKII site, both soon and long after infection. Similar increases in pGluR1 (Ser831) were observed both soon and long after exposure to amphetamine. These results indicate that the transient increase in αCaMKII observed in neurons of the NAcc shell after viral-mediated gene transfer and likely exposure to amphetamine leads to neuroadaptations in AMPA receptor signaling in this site that may contribute to the long-lasting maintenance of behavioral and incentive sensitization by psychostimulant drugs like amphetamine.
Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locom... more Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.
The effect of confinement during conditioning on subsequent test levels of locomotor activity and... more The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphinepaired floor cues (CS +) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS + and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.
Rationale and objectives: In order to assess directly the relationship between locomotor activity... more Rationale and objectives: In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. Methods: Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 µg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. Results: Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did salinepre-exposed rats. Conclusions: These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli as-sociated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed.
Environment-specific cross-sensitization between the locomotor activating effects of morphine and... more Environment-specific cross-sensitization between the locomotor activating effects of morphine and amphetamine. PHARMACOL BIOCHEM BEHAV 32(2) 581-584, 1989.-Groups of eight rats each were preexposed on four occasions to 10 or 20 mg/kg morphine sulfate, IP, either in activity boxes where activity was measured for two hours (COND, conditioning groups) or in their home cages (UNPAIRED groups). On alternate days these groups were administered saline in the other environment. Two groups of eight rats each served as CONTROL groups (one for each preexposure dose) and were administered saline in both environments. On the day following morphine preexposure, all animals were administered 0.5 mg/kg d-amphetamine sulfate, IP, prior to being tested in the activity boxes. On this test, the COND group preexposed to 10 mg/kg morphine showed higher levels of activity than either of its respective UNPAIRED or CONTROL groups. The COND group preexposed to 20 mg/kg morphine was significantly more active than its UNPAIRED group, but not more active than its CONTROL group. The implications of such environment-specific cross-sensitization between the activity effects of opiate and stimulant drugs are discussed.
VEZINA, P AND J. STEWART Condlttomng and pla~ e-,~pe~tfi~ sen~tttzatton o) tnctease~ m a~ ttvtty ... more VEZINA, P AND J. STEWART Condlttomng and pla~ e-,~pe~tfi~ sen~tttzatton o) tnctease~ m a~ ttvtty mduc ed by morphtne tn the VTA PHARMACOL BIOCHEM BEHAV 20(6) 925-934, 1984 --The condltionabdlty of increases in locomo-
3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) a... more 3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1-3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent 'reinforcement' (in its original meaning, like 'tolerance' or 'sensitization', a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more Abstract Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug's effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug's reinforcing effect, Zernig et al. Pharmacology 2007;80:65-119 66 often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals selfadministering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches.
Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 int... more Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 into the nucleus accumbens (NAcc) shell impairs expression of the sensitized locomotion and NAcc dopamine (DA) overflow normally observed in psychostimulant-exposed rats. Based on these results, we investigated the effect of NAcc shell KN-93 on the enhanced amphetamine (AMPH) intake normally observed in AMPH-relative to saline-exposed rats. Rats were administered five injections of either AMPH (1.5 mg/kg, i.p.) or saline, one injection every two-three days. Fourteen days following the last injection, they were trained to self-administer AMPH (200 μg/kg/infusion, i.v.) first on fixed ratio schedules (FR) and then on a progressive ratio schedule of reinforcement (PR). As expected, AMPH-exposed rats worked harder and obtained significantly more drug infusions than saline-exposed rats on the PR schedule. After four days of stable responding, all rats were bilaterally microinjected with KN-93 (1 or 10 nmol/0.5 μl/side) into the NAcc shell, two minutes prior to the beginning of the self-administration session. Inhibiting CaMKII in this site reduced the enhanced drug intake observed in AMPH-exposed rats to levels no longer significantly different from those of saline-exposed rats. Responding in these latter controls was not affected by KN-93 nor did KN-93 affect responding in AMPH-exposed rats when it was infused into the NAcc core. Thus, in a manner similar to what has been reported for sensitized locomotion and NAcc DA overflow, these results suggest that inhibiting CaMKII in the NAcc shell attenuates the enhanced motivation to obtain a drug reinforcer that is normally displayed in AMPH-exposed rats.
Acute administration of the psychostimulant amphetamine increases extracellular levels of dopamin... more Acute administration of the psychostimulant amphetamine increases extracellular levels of dopamine (DA) by reversing the DA transporter on ascending midbrain DA neurons. In vitro studies using striatal synaptosomal, slice and nucleus accumbens (NAcc) tissue preparations have implicated protein kinase C (PKC) in this effect. The present study further examined this effect in vivo by assessing the ability of the PKC inhibitor, Ro31-8220 (10 M), to inhibit acute amphetamine-induced DA overflow when applied with this drug to the NAcc via reverse dialysis. Amphetamine was applied at a concentration of 30 M, and the core and shell subregions of the NAcc were assayed separately in freely moving rats. These brain regions play a role in the acute locomotor-activating and motivational effects of amphetamine. Consistent with the findings of previous in vitro experiments, reverse dialysis of Ro31-8220 with amphetamine robustly attenuated the ability of this drug to increase extracellular levels of dopamine in both the core and shell subregions of the NAcc. These results confirm that amphetamine stimulates dopamine overflow via a PKC-dependent mechanism.
Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia ... more Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia have been known for some time to contribute importantly to the generation of motor behaviors. In particular, the role played by ionotropic glutamate receptors (iGluRs) in such interactions and in the production of locomotion has received considerable attention, particularly in brain areas such as the ventral tegmental area (VTA) where EAA afferants are known to modulate the activity of DA neurons and the nucleus accumbens (NAcc) where descending EAA projections and ascending DA mesencephalic projections come in close apposition to each other and co-innervate intrinsic neurons projecting to motor output regions. Recently, the growing importance of the metabotropic glutamate receptor (mGluR) in the generation of motor behaviors and various forms of plasticity has begun to emerge. The known coupling of the mGluR to second messenger systems and its demonstrated role in the long-term modulation of synaptic transmission make it a logical candidate not only for the generation of locomotion involving EAA-DA interactions, but also for the induction and expression of locomotor plasticity involving these neurotransmitters. In this review, we examine the evidence supporting a role for mGluRs in the generation of DA-dependent locomotion as well as in one form of locomotor plasticity: the sensitization of locomotor activity by psychomotor stimulant drugs.
Stimulant drugs such as amphetamine are readily selfadministered by humans and laboratory animals... more Stimulant drugs such as amphetamine are readily selfadministered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons of the midbrain. Repeated exposure to this drug systemically or exclusively in the cell body region of these neurons in the ventral tegmental area (VTA) leads to long-lasting changes in dopaminergic function that can be assessed by increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug. Three experiments were conducted to evaluate the possibility that this enduring sensitized reactivity underlies compulsive drug self-administration. In all experiments, rats were pre-exposed to amphetamine and, starting 10 d later, their intravenous self-administration of the drug was assessed. In the first experiment, rats previously exposed to amphetamine systemically or exclusively in the VTA subsequently worked harder than untreated animals to obtain the drug when the work required to obtain successive infusions was increased progressively. In the second experiment, this progressively increasing workload was found to decrease the magnitude of amphetamine-induced DA overflow observed with successive infusions until responding ceased. Rats previously exposed to amphetamine were more resistant to this decline and more apt to maintain responding. Finally, in experiment three, a noncontingent priming injection of the drug produced a greater NAcc DA response and a greater parallel increase in lever pressing in drug compared with saline preexposed rats. Together, these results demonstrate a direct relation between drug-induced sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and selfadministration of an abused substance.
Scott-Railton J, Arnold G, Vezina P. , Jan 1, 2006
Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA... more Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA). Because amphetamine, unlike emetic agents like LiCl, possesses appetitive properties that sensitize when it is administered repeatedly, the present study assessed the contribution of sensitization to this US pre-exposure effect (US-PEE). It was found that not all sensitizing regimens of systemic amphetamine injections produce a US-PEE. In addition, previous exposure to amphetamine in the VTA, where it acts to induce sensitization but not CTA, did not produce a US-PEE. It is concluded that amphetamine sensitization alone does not modulate this drug’s ability to produce CTA. Implications of these findings for anatomically based associative and non-associative models of CTA and the US-PEE are discussed.
The present experiments assessed the effect of the Group II-specific metabotropic glutamate recep... more The present experiments assessed the effect of the Group II-specific metabotropic glutamate receptor (mGluR) agonist, LY379268, on the expression of the locomotor sensitization observed following repeated exposure to amphetamine (AMPH). Rats in different groups were administered five injections of AMPH (1 mg/kg ip), one injection every 2-3 days. Two weeks after the last injection, rats were challenged with either AMPH (1 mg/kg ip) or AMPH coinjected with LY379268 (1 mg/kg ip). As expected, AMPH produced levels of locomotion that increased progressively from the first to the fifth injection. This locomotor sensitization was still evident 2 weeks later in rats challenged with AMPH. Rats challenged on this test with AMPH+LY379268, however, showed levels of locomotion similar to those observed following the first AMPH injection. These results indicate that Group II mGluRs can play an important role in the expression of locomotor sensitization by AMPH. The ability of Group II mGluR activ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction... more Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR ...
A novel version of the conditioned place preference (CPP) technique was used in an attempt to det... more A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS-). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS-, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most ...
Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological... more Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological underpinnings are not well characterized. As legal gambling increases in prominence in a growing number of casinos as well as on the internet, the potential for a rise in PG diagnoses warrants investigation of the disorder. The recent reclassification of PG as a behavioral addiction in the DSM-5 raises the possibility that similar cognitive and motivational phenotypes may underlie both gambling and substance use disorders. Indeed, in this Research Topic, Zack et al. (2014) tested the hypothesis that exposure to reward unpredictability can recruit brain dopamine (DA) systems in a similar way to chronic exposure to drugs of abuse (see also . Over the years a variety of models have proposed that alterations in DA signaling may mediate the transition from drug use to dependence; similarly, the hypothesis that aberrant DA responses may influence the transition from recreational, to problematic, and finally PG has only recently begun to be tested. The collection of articles in this Research Topic highlights the complexity of PG and posits several theories of how dopaminergic signaling may contribute to behavioral maladaptations that contribute to PG.
While the ventral striatum has long been implicated in the rewarding properties of psychomotor st... more While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self-administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions.
Addictions are commonly presaged by problems in childhood and adolescence. For many individuals t... more Addictions are commonly presaged by problems in childhood and adolescence. For many individuals this starts with the early expression of impulsive risk-taking, social gregariousness, and oppositional behaviors. Here we propose that these early diverse manifestations reflect a heightened ability of emotionally salient stimuli to activate dopamine pathways that foster behavioral approach. If substance use is initiated, these at-risk youth can also develop heightened responses to drug-paired cues. Through conditioning and drug-induced sensitization, these effects strengthen and accumulate, leading to responses that exceed those elicited by other rewards. At the same time, cues not paired with drug become associated with comparatively lower dopamine release, accentuating further the difference between drug and non-drug rewards. Together, these enhancing and inhibiting processes steer a pre-existing vulnerability toward a disproportionate concern for drugs and drugrelated stimuli. Implications for prevention and treatment are discussed. An integrative neurodevelopmental model of substance use disorders Drug addiction is the most prevalent neuropsychiatric disorder affecting society today. The social, medical, and economic costs are enormous, with drug use contributing to 12% of deaths worldwide [1] and costing the US government alone an estimated $400 billion per year .
In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display... more In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)... more Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.
Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to contribute to the expression o... more Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to contribute to the expression of psychostimulant sensitization by regulating dopamine (DA) overflow from DA neuron terminals in the nucleus accumbens (NAcc). The present experiments explored the contribution of CaMKII in NAcc neurons postsynaptic to these terminals where it is known to participate in a number of signaling pathways that regulate responding to psychostimulant drugs. Exposure to amphetamine transiently increased αCaMKII levels in the shell but not the core of the NAcc. Thus, HSV (herpes simplex viral) vectors were used to transiently overexpress αCaMKII in NAcc neurons in drug-naive rats, and behavioral responding to amphetamine was assessed. Transiently overexpressing αCaMKII in the NAcc shell led to long-lasting enhancement of amphetamine-induced locomotion and selfadministration manifested when αCaMKII levels were elevated and persisting long after they had returned to baseline. Enhanced locomotion was not observed after infection in the NAcc core or sites adjacent to the NAcc. Transient elevation of NAcc shell αCaMKII levels also enhanced locomotor responding to NAcc AMPA and increased phosphorylation levels of GluR1 (Ser831), a CaMKII site, both soon and long after infection. Similar increases in pGluR1 (Ser831) were observed both soon and long after exposure to amphetamine. These results indicate that the transient increase in αCaMKII observed in neurons of the NAcc shell after viral-mediated gene transfer and likely exposure to amphetamine leads to neuroadaptations in AMPA receptor signaling in this site that may contribute to the long-lasting maintenance of behavioral and incentive sensitization by psychostimulant drugs like amphetamine.
Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locom... more Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.
The effect of confinement during conditioning on subsequent test levels of locomotor activity and... more The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphinepaired floor cues (CS +) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS + and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.
Rationale and objectives: In order to assess directly the relationship between locomotor activity... more Rationale and objectives: In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. Methods: Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 µg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. Results: Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did salinepre-exposed rats. Conclusions: These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli as-sociated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed.
Environment-specific cross-sensitization between the locomotor activating effects of morphine and... more Environment-specific cross-sensitization between the locomotor activating effects of morphine and amphetamine. PHARMACOL BIOCHEM BEHAV 32(2) 581-584, 1989.-Groups of eight rats each were preexposed on four occasions to 10 or 20 mg/kg morphine sulfate, IP, either in activity boxes where activity was measured for two hours (COND, conditioning groups) or in their home cages (UNPAIRED groups). On alternate days these groups were administered saline in the other environment. Two groups of eight rats each served as CONTROL groups (one for each preexposure dose) and were administered saline in both environments. On the day following morphine preexposure, all animals were administered 0.5 mg/kg d-amphetamine sulfate, IP, prior to being tested in the activity boxes. On this test, the COND group preexposed to 10 mg/kg morphine showed higher levels of activity than either of its respective UNPAIRED or CONTROL groups. The COND group preexposed to 20 mg/kg morphine was significantly more active than its UNPAIRED group, but not more active than its CONTROL group. The implications of such environment-specific cross-sensitization between the activity effects of opiate and stimulant drugs are discussed.
VEZINA, P AND J. STEWART Condlttomng and pla~ e-,~pe~tfi~ sen~tttzatton o) tnctease~ m a~ ttvtty ... more VEZINA, P AND J. STEWART Condlttomng and pla~ e-,~pe~tfi~ sen~tttzatton o) tnctease~ m a~ ttvtty mduc ed by morphtne tn the VTA PHARMACOL BIOCHEM BEHAV 20(6) 925-934, 1984 --The condltionabdlty of increases in locomo-
3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) a... more 3) reward allostasis, (4) an increase in the incentive salience of drug-associated stimuli, (5) an increase in the reinforcing strength of the drug reinforcer relative to alternative reinforcers, or (6) habit formation. From the pharmacological perspective, models 1-3 allow predictions about the change in the shape of drug dose-effect curves that are based on mathematically defined models governing receptor-ligand interaction and signal transduction. These predictions are tested in the present review, which also describes the other currently championed models for drug use escalation and other components of apparent 'reinforcement' (in its original meaning, like 'tolerance' or 'sensitization', a purely descriptive term). It evaluates the animal experimental approaches employed to support or prove the existence of each of the models and reinforcement components, and recapitulates the clinical evidence, which strongly suggests that escalation of drug use is predominantly based on an increase in the frequency of intoxication events rather than an increase in the dose taken at each intoxication event. Two apparent discrepancies in animal experiments are that (a) sensitization to overall reinforcement has been found more Abstract Escalation of drug use, a hallmark of drug dependence, has traditionally been interpreted as reflecting the development of tolerance to the drug's effects. However, on the basis of animal behavioral data, several groups have recently proposed alternative explanations, i.e. that such an escalation of drug use might not be based on (1) tolerance, but rather be indicative of (2) sensitization to the drug's reinforcing effect, Zernig et al. Pharmacology 2007;80:65-119 66 often for psychostimulants than for opioids, and that (b) tolerance to the reinforcing and other effects has been observed more often for opioids than for cocaine. These discrepancies are resolved by the finding that cocaine levels seem to be more tightly regulated at submaximum reinforcing levels than opioid levels are. Consequently, animals selfadministering opioids are more likely to expose themselves to higher above-threshold doses than animals self-administering psychostimulants, rendering the development of tolerance to opioids more likely than tolerance to psychostimulants. The review concludes by making suggestions on how to improve the current behavioral experimental approaches.
Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 int... more Microinjection of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 into the nucleus accumbens (NAcc) shell impairs expression of the sensitized locomotion and NAcc dopamine (DA) overflow normally observed in psychostimulant-exposed rats. Based on these results, we investigated the effect of NAcc shell KN-93 on the enhanced amphetamine (AMPH) intake normally observed in AMPH-relative to saline-exposed rats. Rats were administered five injections of either AMPH (1.5 mg/kg, i.p.) or saline, one injection every two-three days. Fourteen days following the last injection, they were trained to self-administer AMPH (200 μg/kg/infusion, i.v.) first on fixed ratio schedules (FR) and then on a progressive ratio schedule of reinforcement (PR). As expected, AMPH-exposed rats worked harder and obtained significantly more drug infusions than saline-exposed rats on the PR schedule. After four days of stable responding, all rats were bilaterally microinjected with KN-93 (1 or 10 nmol/0.5 μl/side) into the NAcc shell, two minutes prior to the beginning of the self-administration session. Inhibiting CaMKII in this site reduced the enhanced drug intake observed in AMPH-exposed rats to levels no longer significantly different from those of saline-exposed rats. Responding in these latter controls was not affected by KN-93 nor did KN-93 affect responding in AMPH-exposed rats when it was infused into the NAcc core. Thus, in a manner similar to what has been reported for sensitized locomotion and NAcc DA overflow, these results suggest that inhibiting CaMKII in the NAcc shell attenuates the enhanced motivation to obtain a drug reinforcer that is normally displayed in AMPH-exposed rats.
Acute administration of the psychostimulant amphetamine increases extracellular levels of dopamin... more Acute administration of the psychostimulant amphetamine increases extracellular levels of dopamine (DA) by reversing the DA transporter on ascending midbrain DA neurons. In vitro studies using striatal synaptosomal, slice and nucleus accumbens (NAcc) tissue preparations have implicated protein kinase C (PKC) in this effect. The present study further examined this effect in vivo by assessing the ability of the PKC inhibitor, Ro31-8220 (10 M), to inhibit acute amphetamine-induced DA overflow when applied with this drug to the NAcc via reverse dialysis. Amphetamine was applied at a concentration of 30 M, and the core and shell subregions of the NAcc were assayed separately in freely moving rats. These brain regions play a role in the acute locomotor-activating and motivational effects of amphetamine. Consistent with the findings of previous in vitro experiments, reverse dialysis of Ro31-8220 with amphetamine robustly attenuated the ability of this drug to increase extracellular levels of dopamine in both the core and shell subregions of the NAcc. These results confirm that amphetamine stimulates dopamine overflow via a PKC-dependent mechanism.
Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia ... more Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia have been known for some time to contribute importantly to the generation of motor behaviors. In particular, the role played by ionotropic glutamate receptors (iGluRs) in such interactions and in the production of locomotion has received considerable attention, particularly in brain areas such as the ventral tegmental area (VTA) where EAA afferants are known to modulate the activity of DA neurons and the nucleus accumbens (NAcc) where descending EAA projections and ascending DA mesencephalic projections come in close apposition to each other and co-innervate intrinsic neurons projecting to motor output regions. Recently, the growing importance of the metabotropic glutamate receptor (mGluR) in the generation of motor behaviors and various forms of plasticity has begun to emerge. The known coupling of the mGluR to second messenger systems and its demonstrated role in the long-term modulation of synaptic transmission make it a logical candidate not only for the generation of locomotion involving EAA-DA interactions, but also for the induction and expression of locomotor plasticity involving these neurotransmitters. In this review, we examine the evidence supporting a role for mGluRs in the generation of DA-dependent locomotion as well as in one form of locomotor plasticity: the sensitization of locomotor activity by psychomotor stimulant drugs.
Stimulant drugs such as amphetamine are readily selfadministered by humans and laboratory animals... more Stimulant drugs such as amphetamine are readily selfadministered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons of the midbrain. Repeated exposure to this drug systemically or exclusively in the cell body region of these neurons in the ventral tegmental area (VTA) leads to long-lasting changes in dopaminergic function that can be assessed by increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug. Three experiments were conducted to evaluate the possibility that this enduring sensitized reactivity underlies compulsive drug self-administration. In all experiments, rats were pre-exposed to amphetamine and, starting 10 d later, their intravenous self-administration of the drug was assessed. In the first experiment, rats previously exposed to amphetamine systemically or exclusively in the VTA subsequently worked harder than untreated animals to obtain the drug when the work required to obtain successive infusions was increased progressively. In the second experiment, this progressively increasing workload was found to decrease the magnitude of amphetamine-induced DA overflow observed with successive infusions until responding ceased. Rats previously exposed to amphetamine were more resistant to this decline and more apt to maintain responding. Finally, in experiment three, a noncontingent priming injection of the drug produced a greater NAcc DA response and a greater parallel increase in lever pressing in drug compared with saline preexposed rats. Together, these results demonstrate a direct relation between drug-induced sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and selfadministration of an abused substance.
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Papers by Paul Vezina