Patricia Di Ciano - Academia.edu (original) (raw)
Papers by Patricia Di Ciano
PloS one, 2015
Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no... more Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 7, 2015
Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorde... more Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here, we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission, in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12 h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (i.e. at steady state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016
Despite the existence of several treatment options for smoking cessation, the rate of relapse aft... more Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
Neuropsychopharmacology, 2015
There is considerable interest in blocking the dopamine D3 receptor (DRD3), versus the D2 recepto... more There is considerable interest in blocking the dopamine D3 receptor (DRD3), versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3 preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60 and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2 and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.Neuropsychopharmacology accepted article preview online, 19 June 2015. doi:10.1038/npp.2015.177.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 16, 2014
Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest ... more Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest in this receptor as a possible therapeutic target for drug addiction. The development of a D3 ligand suitable for use in humans has remained elusive, so the study of the function of the D3 receptor and its possible therapeutic efficacy has largely been restricted to animals. Pre-clinical studies have established that systemic administration of D3 ligands, particularly antagonists and partial agonists, can alter drug-seeking in animals. Despite over a decade of research, few studies have investigated the effects of intra-cerebral infusion of D3 ligands on drug-seeking. In the present review, these studies are summarized, which have largely focused on stimulus-controlled behaviors. Converging evidence from studies of D3 receptor expression, Fos and pharmacological Magnetic Resonance Imaging (phMRI) is also provided to delineate some of the D3 brain systems involved in drug-seeking and taki...
Advances in pharmacology (San Diego, Calif.), 2014
Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this... more Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this receptor in drug addiction, given the importance of dopamine in addiction. Like the D3 receptor, the D4 receptor has limited distribution within the brain, suggesting it may have a unique role in drug abuse. However, compared to the D3 receptor, few studies have evaluated the importance of the D4 receptor. This may be due, in part, to the relative lack of compounds selective for the D4 receptor; the early studies were mainly conducted in mice lacking the D4 receptor. In this review, we summarize the literature on the structure and localization of the D4 receptor before reviewing the data from D4 knockout mice that used behavioral models relevant to the understanding of stimulant use. We also present evidence from more recent pharmacological studies using selective D4 agonists and antagonists and animal models of drug-seeking and drug-taking. The data summarized here suggest a role for D...
Neuropharmacology, 2004
Conditioned environmental stimuli are known to be important determinants of drug seeking. Traditi... more Conditioned environmental stimuli are known to be important determinants of drug seeking. Traditional models of drug seeking under the control of conditioned stimuli have focused on the ability of conditioned reinforcers either to reinstate extinguished responding or to maintain prolonged chains of drug seeking under second-order schedules. These models have consistently suggested that it is the conditioned reinforcing, rather than other, effects of Pavlovian drug stimuli that most profoundly influence drug seeking. However, the impact of drug-associated conditioned reinforcers has not been studied directly and in isolation, not least because the instrumental seeking response is invariably the same as that which was previously reinforced with the drug itself. The purpose of the present study was, therefore, to investigate the conditioned reinforcing properties of drug-paired CSs using an acquisition of a new response procedure in which an animal learns to make a new instrumental response reinforced solely by the CS. It was found that CSs paired with either cocaine, heroin or sucrose supported the rapid acquisition of lever pressing for the CS that persisted over months of repeated, intermittent testing. Furthermore, rats did not acquire the lever press response when the CS was not paired with drug, suggesting that for this stimulus to acquire conditioned reinforcing properties, it must be predictively associated with the drug's effect. Moreover, lever pressing for the CS could not be explained as coincidental to an over-riding Pavlovian approach response to the location of the lever, since animals also acquired discriminated lever pressing when the CS was above the opposite, inactive lever. Extinction decreased responding with conditioned reinforcement, but only when the CS-US association was devalued prior to, and not after, acquisition of the lever press response, providing evidence for the establishment of habitual CS-maintained responding that may explain the persistence of drug-seeking responses in animal models of addiction and relapse.
Frontiers in Pharmacology, 2014
There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands f... more There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [(11)C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [(11)C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [(11)C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [(11)C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [(11)C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
NEURON, 2005
Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are ... more Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking. References Alberini, C.M. (2005). Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51-56. Arroyo, M., Markou, A., Robbins, T.W., and Everitt, B.J. (1998). Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology (Berl.) 140, 331-344. Bebien, M., Salinas, S., Becamel, C., Richard, V., Linares, L., and Hipskind, R.A. (2003). Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. Oncogene 22, 1836-1847. Cador, M., Robbins, T.W., and Everitt, B.J. (1989). Involvement of the amygdala in stimulus reward associations-Interaction with the ventral striatum. Neuroscience 30, 77-86. Childress, A.R., Mozley, P.D., McElgin, W., Fitzgerald, J., Reivich, M., and O'Brien, C.P. (1999). Limbic activation during cue-induced cocaine craving. Am. J. Psychiatry 156, 11-18. Ciccocioppo, R., Martin-Fardon, R., and Weiss, F. (2004). Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nat. Neurosci. 7, 495-496. Conklin, C.A., and Tiffany, S.T. (2002). Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97, 155-167. Corbit, L.H., and Balleine, B.W. (2005). Double dissociation of basolateral and central amygdala lesions on the general and outcomespecific forms of Pavlovian-instrumental transfer. J. Neurosci. 25, 962-970.
Current Topics in Behavioral Neurosciences, 2015
Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatri... more Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatric disorders. Notably, there is a high prevalence of smoking among those with dependence to other substances, schizophrenia, mood, or anxiety disorders. It has been difficult to understand how these phenomena interact with clinical populations as it is unclear what preceded what in most of the studies. These comorbidities may be best understood by using experimental approaches in well-controlled conditions. Notably, animal models represent advantageous approaches as the parameters under study can be controlled perfectly. This review will focus on evidence collected so far exploring how behavioral effects of nicotine are modified in animal models of psychiatric conditions. Notably, we will focus on behavioral responses induced by nicotine that are relevant for its addictive potential. Despite the clinical relevance and frequency of the comorbidity between psychiatric issues and tobacco smoking, very few studies have been done to explore this issue in animals. The available data suggest that the behavioral and reinforcing effects of nicotine are enhanced in animal models of these comorbidities, although much more experimental work would be required to provide certainty in this domain.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014
Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously s... more Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 μg/0.5 μl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 μg/0.5 μl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [(125)I]7-OH-PIPAT ...
Journal of Neuroscience, 2004
An insidious feature of drug craving and drug seeking in humans is that it can be induced and mai... more An insidious feature of drug craving and drug seeking in humans is that it can be induced and maintained by conditioned stimuli after a prolonged drug-free period. Understanding the neural basis of this control over addictive behavior may aid in the development of treatments targeting drug seeking and thereby be beneficial in preventing drug use. In the present study, we used a well established animal model to investigate the functional importance of amygdala-nucleus accumbens interactions in cocaine seeking under the control of drug-associated conditioned reinforcers. To probe the direct neuroanatomical relationship between these structures within a functional corticostriatal loop, we used a neuropharmacological disconnection procedure. Thus, infusing a dopamine receptor antagonist unilaterally into the basolateral amygdala (which had no effect on its own) and an AMPA-kainate (KA) receptor antagonist into the contralateral nucleus accumbens core (which also had no effect on its own) greatly reduced cocaine seeking. We also show that bilateral infusions of the DA receptor antagonist into the amygdala, but not nucleus accumbens, or of the AMPA-KA receptor antagonist in the nucleus accumbens, but not the amygdala, also greatly reduced cocaine seeking. The results of this study demonstrate an amygdalanucleus accumbens system that critically underlies stimulus-controlled cocaine seeking and indicate possible neurochemical targets for relapse-prevention medication.
Journal of Neuroscience, 2005
Through association with the interoceptive effects of drugs of abuse, neutral environmental stimu... more Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist alpha-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonist LY293558 (3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulus-response habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.
Psychopharmacology, 1996
Rats were prepared with jugular catheters and assigned randomly to one of three groups: intraveno... more Rats were prepared with jugular catheters and assigned randomly to one of three groups: intravenous (IV) self-administration of cocaine, yoked administration of cocaine or vehicle. Rats experienced intermittent administration of cocaine (0.75 mglkg per injection) or vehicle (0.1 ml/injection) for six test sessions, in accordance with the pattern of injections made by the self-administration group. Sensitization of motor activity between pre-and post-treatment challenges of cocaine (3 mg/kg, IV) was observed after both self-and yoked administration of cocaine but not in the yoked-vehicle group. These data indicate that sensitization as a consequence of drug self-administration may be an important factor in the etiology of addiction.
Neuropsychopharmacology, 2003
Conditioned stimuli paired with drugs of abuse can acquire motivational properties, and are capab... more Conditioned stimuli paired with drugs of abuse can acquire motivational properties, and are capable of inducing drug-seeking behavior and relapse to cocaine use. Converging evidence implicates the mesolimbic dopamine (DA) system, through interactions with limbic afferents to the nucleus accumbens, in behavior controlled by conditioned stimuli. The GABA(B) receptor agonist baclofen has been shown to decrease break points in rats responding for cocaine under progressive ratio schedules and also to attenuate activation of limbic cortical areas in human cocaine addicts. The purpose of the present study was therefore to investigate the effects of baclofen on drug-associated cue-controlled cocaine- or heroin-seeking behavior by rats. Under the second-order schedule of reinforcement used in the present study, cocaine or heroin were available after a fixed time interval, while high rates of responding during the interdrug intervals were maintained by the response-contingent presentations of drug-associated conditioned reinforcers. Baclofen decreased stimulus-maintained responding for either heroin or cocaine, but decreased only cocaine intake under an FR1 schedule. These results therefore support preliminary clinical findings and suggest that drugs with GABA(B) receptor agonist properties may aid abstinence in human drug addicts by decreasing the propensity to cue-induced drug-seeking and relapse.
Neuropsychopharmacology, 2008
Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providi... more Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providing a model of some aspects of longterm drug addiction. The purpose of the present study was to investigate the effects of inactivating the dorsal striatum (DStr), nucleus accumbens (NAcc) core, or NAcc shell on different types of responding, each maintained by drug-paired conditioned reinforcers. Inactivations were achieved by infusing a combination of baclofen and muscimol prior to (1) persistent responding for a drug-paired conditioned reinforcer, (2) reacquisition of this instrumental response after extinction by omission of the contingent conditioned stimulus (CS), or (3) CS (cue)-induced reinstatement of the original (and different) instrumental response that had previously delivered cocaine. Inactivation of the DStr attenuated persistent responding for a cocaine-paired conditioned reinforcer, as well as its reacquisition after extinction of this response, while the only effect of inactivation of the NAcc shell was to increase CS (cue)-induced reinstatement of the extinguished instrumental response that had previously delivered cocaine. Inactivation of the NAcc core affected all measures of responding maintained by drug-paired conditioned reinforcers. These results are discussed with reference to the neural systems involved in different aspects of responding maintained by drug-paired conditioned reinforcers.
European Journal of Neuroscience, 1998
In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents correspondin... more In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked-or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4-7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of µ 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were µ 5 nA above baseline by the fourth day of drug administration and reached µ 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of µ 6 nA. These data are discussed with relation to the neurochemistry of drug craving.
European Journal of Neuroscience, 2004
Stimuli paired with cocaine can maintain cocaine-seeking as conditioned reinforcers. Although con... more Stimuli paired with cocaine can maintain cocaine-seeking as conditioned reinforcers. Although converging evidence implicates a role for the ventral tegmental area (VTA) in the primary reinforcing effects of drugs of abuse, the role of the VTA in mediating associative influences over drug-seeking remains to be determined. The present study therefore investigated the contribution to CS-maintained cocaine-seeking under a second-order schedule of reinforcement of the VTA, and its terminal regions, the nucleus accumbens (NAcc) core and basolateral amygdala (BLA), previously shown to be critical for the acquisition of this behaviour. Inactivation of the VTA or NAcc core by direct infusion of a mixture of the GABA(A) and GABA(B) receptor agonists, baclofen and muscimol, decreased cocaine-seeking when rats were drug-free, while drug-seeking after self-administered cocaine was increased only when they were infused into the NAcc core. Inactivation of the BLA had no effect on drug-seeking. These results are discussed with reference to critical and distinct contributions of the VTA, NAcc core and BLA to drug-seeking maintained by conditioned reinforcers
European Journal of Neuroscience, 1998
Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the... more Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellullar dopamine.
Behavioural Pharmacology, 1995
PloS one, 2015
Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no... more Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 7, 2015
Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorde... more Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here, we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission, in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12 h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (i.e. at steady state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016
Despite the existence of several treatment options for smoking cessation, the rate of relapse aft... more Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
Neuropsychopharmacology, 2015
There is considerable interest in blocking the dopamine D3 receptor (DRD3), versus the D2 recepto... more There is considerable interest in blocking the dopamine D3 receptor (DRD3), versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3 preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60 and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2 and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.Neuropsychopharmacology accepted article preview online, 19 June 2015. doi:10.1038/npp.2015.177.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 16, 2014
Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest ... more Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest in this receptor as a possible therapeutic target for drug addiction. The development of a D3 ligand suitable for use in humans has remained elusive, so the study of the function of the D3 receptor and its possible therapeutic efficacy has largely been restricted to animals. Pre-clinical studies have established that systemic administration of D3 ligands, particularly antagonists and partial agonists, can alter drug-seeking in animals. Despite over a decade of research, few studies have investigated the effects of intra-cerebral infusion of D3 ligands on drug-seeking. In the present review, these studies are summarized, which have largely focused on stimulus-controlled behaviors. Converging evidence from studies of D3 receptor expression, Fos and pharmacological Magnetic Resonance Imaging (phMRI) is also provided to delineate some of the D3 brain systems involved in drug-seeking and taki...
Advances in pharmacology (San Diego, Calif.), 2014
Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this... more Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this receptor in drug addiction, given the importance of dopamine in addiction. Like the D3 receptor, the D4 receptor has limited distribution within the brain, suggesting it may have a unique role in drug abuse. However, compared to the D3 receptor, few studies have evaluated the importance of the D4 receptor. This may be due, in part, to the relative lack of compounds selective for the D4 receptor; the early studies were mainly conducted in mice lacking the D4 receptor. In this review, we summarize the literature on the structure and localization of the D4 receptor before reviewing the data from D4 knockout mice that used behavioral models relevant to the understanding of stimulant use. We also present evidence from more recent pharmacological studies using selective D4 agonists and antagonists and animal models of drug-seeking and drug-taking. The data summarized here suggest a role for D...
Neuropharmacology, 2004
Conditioned environmental stimuli are known to be important determinants of drug seeking. Traditi... more Conditioned environmental stimuli are known to be important determinants of drug seeking. Traditional models of drug seeking under the control of conditioned stimuli have focused on the ability of conditioned reinforcers either to reinstate extinguished responding or to maintain prolonged chains of drug seeking under second-order schedules. These models have consistently suggested that it is the conditioned reinforcing, rather than other, effects of Pavlovian drug stimuli that most profoundly influence drug seeking. However, the impact of drug-associated conditioned reinforcers has not been studied directly and in isolation, not least because the instrumental seeking response is invariably the same as that which was previously reinforced with the drug itself. The purpose of the present study was, therefore, to investigate the conditioned reinforcing properties of drug-paired CSs using an acquisition of a new response procedure in which an animal learns to make a new instrumental response reinforced solely by the CS. It was found that CSs paired with either cocaine, heroin or sucrose supported the rapid acquisition of lever pressing for the CS that persisted over months of repeated, intermittent testing. Furthermore, rats did not acquire the lever press response when the CS was not paired with drug, suggesting that for this stimulus to acquire conditioned reinforcing properties, it must be predictively associated with the drug's effect. Moreover, lever pressing for the CS could not be explained as coincidental to an over-riding Pavlovian approach response to the location of the lever, since animals also acquired discriminated lever pressing when the CS was above the opposite, inactive lever. Extinction decreased responding with conditioned reinforcement, but only when the CS-US association was devalued prior to, and not after, acquisition of the lever press response, providing evidence for the establishment of habitual CS-maintained responding that may explain the persistence of drug-seeking responses in animal models of addiction and relapse.
Frontiers in Pharmacology, 2014
There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands f... more There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [(11)C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [(11)C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [(11)C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [(11)C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [(11)C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
NEURON, 2005
Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are ... more Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking. References Alberini, C.M. (2005). Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51-56. Arroyo, M., Markou, A., Robbins, T.W., and Everitt, B.J. (1998). Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology (Berl.) 140, 331-344. Bebien, M., Salinas, S., Becamel, C., Richard, V., Linares, L., and Hipskind, R.A. (2003). Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. Oncogene 22, 1836-1847. Cador, M., Robbins, T.W., and Everitt, B.J. (1989). Involvement of the amygdala in stimulus reward associations-Interaction with the ventral striatum. Neuroscience 30, 77-86. Childress, A.R., Mozley, P.D., McElgin, W., Fitzgerald, J., Reivich, M., and O'Brien, C.P. (1999). Limbic activation during cue-induced cocaine craving. Am. J. Psychiatry 156, 11-18. Ciccocioppo, R., Martin-Fardon, R., and Weiss, F. (2004). Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking. Nat. Neurosci. 7, 495-496. Conklin, C.A., and Tiffany, S.T. (2002). Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97, 155-167. Corbit, L.H., and Balleine, B.W. (2005). Double dissociation of basolateral and central amygdala lesions on the general and outcomespecific forms of Pavlovian-instrumental transfer. J. Neurosci. 25, 962-970.
Current Topics in Behavioral Neurosciences, 2015
Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatri... more Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatric disorders. Notably, there is a high prevalence of smoking among those with dependence to other substances, schizophrenia, mood, or anxiety disorders. It has been difficult to understand how these phenomena interact with clinical populations as it is unclear what preceded what in most of the studies. These comorbidities may be best understood by using experimental approaches in well-controlled conditions. Notably, animal models represent advantageous approaches as the parameters under study can be controlled perfectly. This review will focus on evidence collected so far exploring how behavioral effects of nicotine are modified in animal models of psychiatric conditions. Notably, we will focus on behavioral responses induced by nicotine that are relevant for its addictive potential. Despite the clinical relevance and frequency of the comorbidity between psychiatric issues and tobacco smoking, very few studies have been done to explore this issue in animals. The available data suggest that the behavioral and reinforcing effects of nicotine are enhanced in animal models of these comorbidities, although much more experimental work would be required to provide certainty in this domain.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014
Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously s... more Dopamine D3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D3 antagonist SB-277011-A (0.01-1 μg/0.5 μl/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 μg/0.5 μl/side) into the basolateral amygdala or lateral habenula had no effect on food self-administration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [(125)I]7-OH-PIPAT ...
Journal of Neuroscience, 2004
An insidious feature of drug craving and drug seeking in humans is that it can be induced and mai... more An insidious feature of drug craving and drug seeking in humans is that it can be induced and maintained by conditioned stimuli after a prolonged drug-free period. Understanding the neural basis of this control over addictive behavior may aid in the development of treatments targeting drug seeking and thereby be beneficial in preventing drug use. In the present study, we used a well established animal model to investigate the functional importance of amygdala-nucleus accumbens interactions in cocaine seeking under the control of drug-associated conditioned reinforcers. To probe the direct neuroanatomical relationship between these structures within a functional corticostriatal loop, we used a neuropharmacological disconnection procedure. Thus, infusing a dopamine receptor antagonist unilaterally into the basolateral amygdala (which had no effect on its own) and an AMPA-kainate (KA) receptor antagonist into the contralateral nucleus accumbens core (which also had no effect on its own) greatly reduced cocaine seeking. We also show that bilateral infusions of the DA receptor antagonist into the amygdala, but not nucleus accumbens, or of the AMPA-KA receptor antagonist in the nucleus accumbens, but not the amygdala, also greatly reduced cocaine seeking. The results of this study demonstrate an amygdalanucleus accumbens system that critically underlies stimulus-controlled cocaine seeking and indicate possible neurochemical targets for relapse-prevention medication.
Journal of Neuroscience, 2005
Through association with the interoceptive effects of drugs of abuse, neutral environmental stimu... more Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist alpha-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonist LY293558 (3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulus-response habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.
Psychopharmacology, 1996
Rats were prepared with jugular catheters and assigned randomly to one of three groups: intraveno... more Rats were prepared with jugular catheters and assigned randomly to one of three groups: intravenous (IV) self-administration of cocaine, yoked administration of cocaine or vehicle. Rats experienced intermittent administration of cocaine (0.75 mglkg per injection) or vehicle (0.1 ml/injection) for six test sessions, in accordance with the pattern of injections made by the self-administration group. Sensitization of motor activity between pre-and post-treatment challenges of cocaine (3 mg/kg, IV) was observed after both self-and yoked administration of cocaine but not in the yoked-vehicle group. These data indicate that sensitization as a consequence of drug self-administration may be an important factor in the etiology of addiction.
Neuropsychopharmacology, 2003
Conditioned stimuli paired with drugs of abuse can acquire motivational properties, and are capab... more Conditioned stimuli paired with drugs of abuse can acquire motivational properties, and are capable of inducing drug-seeking behavior and relapse to cocaine use. Converging evidence implicates the mesolimbic dopamine (DA) system, through interactions with limbic afferents to the nucleus accumbens, in behavior controlled by conditioned stimuli. The GABA(B) receptor agonist baclofen has been shown to decrease break points in rats responding for cocaine under progressive ratio schedules and also to attenuate activation of limbic cortical areas in human cocaine addicts. The purpose of the present study was therefore to investigate the effects of baclofen on drug-associated cue-controlled cocaine- or heroin-seeking behavior by rats. Under the second-order schedule of reinforcement used in the present study, cocaine or heroin were available after a fixed time interval, while high rates of responding during the interdrug intervals were maintained by the response-contingent presentations of drug-associated conditioned reinforcers. Baclofen decreased stimulus-maintained responding for either heroin or cocaine, but decreased only cocaine intake under an FR1 schedule. These results therefore support preliminary clinical findings and suggest that drugs with GABA(B) receptor agonist properties may aid abstinence in human drug addicts by decreasing the propensity to cue-induced drug-seeking and relapse.
Neuropsychopharmacology, 2008
Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providi... more Drug-paired conditioned reinforcers can maintain persistent instrumental responding, thus providing a model of some aspects of longterm drug addiction. The purpose of the present study was to investigate the effects of inactivating the dorsal striatum (DStr), nucleus accumbens (NAcc) core, or NAcc shell on different types of responding, each maintained by drug-paired conditioned reinforcers. Inactivations were achieved by infusing a combination of baclofen and muscimol prior to (1) persistent responding for a drug-paired conditioned reinforcer, (2) reacquisition of this instrumental response after extinction by omission of the contingent conditioned stimulus (CS), or (3) CS (cue)-induced reinstatement of the original (and different) instrumental response that had previously delivered cocaine. Inactivation of the DStr attenuated persistent responding for a cocaine-paired conditioned reinforcer, as well as its reacquisition after extinction of this response, while the only effect of inactivation of the NAcc shell was to increase CS (cue)-induced reinstatement of the extinguished instrumental response that had previously delivered cocaine. Inactivation of the NAcc core affected all measures of responding maintained by drug-paired conditioned reinforcers. These results are discussed with reference to the neural systems involved in different aspects of responding maintained by drug-paired conditioned reinforcers.
European Journal of Neuroscience, 1998
In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents correspondin... more In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked-or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4-7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of µ 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were µ 5 nA above baseline by the fourth day of drug administration and reached µ 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of µ 6 nA. These data are discussed with relation to the neurochemistry of drug craving.
European Journal of Neuroscience, 2004
Stimuli paired with cocaine can maintain cocaine-seeking as conditioned reinforcers. Although con... more Stimuli paired with cocaine can maintain cocaine-seeking as conditioned reinforcers. Although converging evidence implicates a role for the ventral tegmental area (VTA) in the primary reinforcing effects of drugs of abuse, the role of the VTA in mediating associative influences over drug-seeking remains to be determined. The present study therefore investigated the contribution to CS-maintained cocaine-seeking under a second-order schedule of reinforcement of the VTA, and its terminal regions, the nucleus accumbens (NAcc) core and basolateral amygdala (BLA), previously shown to be critical for the acquisition of this behaviour. Inactivation of the VTA or NAcc core by direct infusion of a mixture of the GABA(A) and GABA(B) receptor agonists, baclofen and muscimol, decreased cocaine-seeking when rats were drug-free, while drug-seeking after self-administered cocaine was increased only when they were infused into the NAcc core. Inactivation of the BLA had no effect on drug-seeking. These results are discussed with reference to critical and distinct contributions of the VTA, NAcc core and BLA to drug-seeking maintained by conditioned reinforcers
European Journal of Neuroscience, 1998
Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the... more Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellullar dopamine.
Behavioural Pharmacology, 1995