Cocaine-paired Cues Research Articles

Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats.

The action of serotonin (5-HT) at the 5-HT(2A) receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT(2A) receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior. This study examined the hypothesis that M100907, a 5-HT(2A) receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior. Rats trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10 mg/kg, i.p.) within 1 min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5 μg/0.2 μl/side) into the vmPFC. Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5 μg) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement. The results suggest that the blockade of 5-HT(2A) receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues.

Role of Dopamine D1 Receptors in the Activation of Nucleus Accumbens Extracellular Signal-Regulated Kinase (ERK) by Cocaine-Paired Contextual Cues

Exposure to drug-paired cues can trigger addicts to relapse into drug seeking. Although the molecular mechanisms underlying cue-elicited cocaine seeking are incompletely understood, the protein kinase extracellular signal-regulated kinase (ERK) is known to have an important role. Psychostimulants and their associated cues can activate ERK in medium spiny neurons of the nucleus accumbens core (AcbC). These medium spiny neurons can be classified according to their projections (to ventral pallidum and/or substantia nigra) and by their mRNA expression. The present experiments were designed to determine which distinct set of AcbC projection neurons expresses phosphorylated ERK (pERK) in response to cocaine-paired contextual cues. Combined use of the retrograde label Flurogold with immunohistochemical staining of pERK was used to show that the AcbC pERK accompanying preference for cocaine-paired contexts occurs in both the accumbens (Acb)-nigral and Acb-pallidal projections. The gene expression characteristics of the neurons expressing pERK in response to cocaine-paired cues was further investigated using combined in situ hybridization and immunocytochemistry to show that AcbC pERK+ cells correspond to D1, but not preproenkephalin, mRNA+ cells. Furthermore, intra-AcbC infusion of the D1-antagonist SCH23390 attenuated cue-induced AcbC pERK expression. In aggregate, these results indicate that (i) the D1-expressing AcbC neurons evidence long-term plasticity related to drug-cue memories and (ii) local dopamine D1 receptors are necessary for the expression of cocaine-paired cue-induced pERK in these AcbC neurons.

Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine.

Drug-associated cues and stress increase craving and lead to greater risk of relapse in abstinent drug users. Animal models of reinstatement of drug seeking have been utilized to study the neural circuitry by which either drug-associated cues or stress exposure elicit drug seeking. Recent evidence has shown a strong enhancing effect of yohimbine stress on subsequent cue-elicited reinstatement; however, there has been no examination of the neural substrates of this interactive effect. The current study examined whether inactivation of the bed nucleus of the stria terminalis (BNST), an area previously implicated in stress activation of drug seeking, would affect reinstatement of cocaine seeking caused by conditioned cues, yohimbine stress, or the combination of these factors. Male rats experienced daily IV cocaine self-administration, followed by extinction of lever responding in the absence of cocaine-paired cues. Reinstatement of responding was measured during presentation of cocaine-paired cues, following pretreatment with the pharmacological stressor, yohimbine (2.5mg/kg, IP), or the combination of cues and yohimbine. All three conditions led to reinstatement of cocaine seeking, with the highest responding seen after the combination of cues and yohimbine. Reversible inactivation of the BNST using the gamma-aminobutyric acid receptor agonists, baclofen + muscimol, significantly reduced all three forms of reinstatement. These results demonstrate a role for the BNST in cocaine seeking elicited by cocaine-paired cues, and suggest the BNST as a key mediator for the interaction of stress and cues for the reinstatement of cocaine seeking.

Stimulation of dopamine D2/D3 but not D1 receptors in the central amygdala decreases cocaine-seeking behavior

Alterations in dopamine output within the various subnuclei of the amygdala have previously been implicated in cocaine reinforcement, as well as cocaine-seeking behavior. To elucidate the potential for increased stimulation of D1- and D2-like receptors (D1Rs and D2Rs, respectively) specifically in the central nucleus of the amygdala (CeA) to modulate cue- and cocaine-elicited reinstatement of cocaine-seeking behavior, we infused either the D1R agonist, SKF-38393 (0–4.0 μg/side) or the D2R agonist, 7-OH-DPAT (0–4.0 μg/side) into the CeA immediately prior to tests for cue and cocaine-primed reinstatement. We also examined the effects of 7-OH-DPAT on cocaine self-administration as a positive behavioral control. 7-OH-DPAT decreased cue-and cocaine-primed reinstatement, and reduced the number of cocaine infusions obtained during self-administration; SKF-38393 produced no discernable effects. The results suggest that enhanced stimulation of D2Rs, but not D1Rs, in the CeA is sufficient to inhibit expression of the incentive motivational effects of cocaine priming and cocaine-paired cues. Together with previous findings that D1R blockade attenuates reinstatement of cocaine-seeking behavior, the results suggest that D1R stimulation may be necessary, but not sufficient, to modulate the incentive motivational effects of cues and cocaine priming.

Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior

Previous findings in rats suggest that the rostral basolateral amygdala (rBLA) and prelimbic prefrontal cortex (plPFC) are likely components of cue reinstatement circuitry based on bilateral inactivation of each site alone. In the present investigation, we examined whether the rBLA and plPFC interact to regulate reinstatement of cocaine-seeking behavior elicited by reexposure to a combination of discrete and contextual cocaine-paired cues. After establishing stable baseline responding under a second-order schedule of cocaine reinforcement and cue presentation, rats underwent response-extinction training in which cocaine and cocaine-paired cues were withheld. To test the interaction, rats with asymmetric cannulae placements in the rBLA and plPFC received vehicle or lidocaine infusions prior to reinstatement testing during which cocaine-paired cues were presented, in the absence of cocaine availability, under a second-order schedule. Asymmetric inactivation of the rBLA and plPFC significantly attenuated reinstatement of cocaine-seeking behavior relative to vehicle treatment. As expected, inactivation of the rBLA or plPFC in rats with unilateral cannulae placements did not disrupt reinstatement relative to vehicle treatment. Findings propose critical intrahemispheric interaction between the rBLA and plPFC in regulating reinstatement of cocaine-seeking behavior elicited by reexposure to drug-paired cues.

Footshock stress potentiates cue-induced cocaine-seeking in an animal model of relapse

Drug-associated cues and stress increase craving and lead to greater risk of relapse in abstinent drug addicts. This risk may be increased when these factors occur simultaneously. The current study examined whether the presentation of three different levels of intermittent footshock would trigger reinstatement or potentiate reinstatement of cocaine-seeking caused by conditioned cues. Male, Long Evans rats underwent daily i.v. cocaine self-administration, followed by extinction of lever responding in the absence of previously cocaine-paired cues. Reinstatement of cocaine-seeking was measured during presentation of cocaine-paired cues, following pretreatment with three levels of intermittent footshock (0.25, 0.5, and 0.75 mA), or after the combination of footshock and cues. Footshock at the 0.5 and 0.75 mA levels led to significant reinstatement when presented alone, and also potentiated the reinstatement triggered by the presentation of conditioned cues. These results demonstrate that while stress and drug-paired cues reinstate drug-seeking when presented in isolation, their interaction leads to potentiated reinstatement. Dual targeting of stress and cues is thus a critical consideration for treatment intervention in abstinent drug users.

Orexin/hypocretin signaling at the orexin 1 receptor regulates cue‐elicited cocaine‐seeking

The orexin/hypocretin system has recently been implicated in reward-processing and addiction. We examined the involvement of the orexin system in cue-induced reinstatement of extinguished cocaine-seeking by administering the orexin 1 receptor antagonist SB-334867 (SB) or the orexin 2 receptor antagonist 4-pyridylmethyl (S)-tert-leucyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4PT) prior to reinstatement testing. Male Sprague Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training. Reinstatement of cocaine-seeking was elicited by presentation of tone + light cues previously paired with cocaine infusions. SB (10, 20 and 30 mg/kg) dose-dependently decreased cue-induced reinstatement of cocaine-seeking without significantly affecting responding during late extinction. 4PT (10 and 30 mg/kg) did not significantly alter cue-induced reinstatement. In separate experiments, the highest doses of SB and 4PT had no significant effect on established cocaine self-administration, and 4PT reduced spontaneous activity in a locomotor test to a greater extent than SB. Finally, SB (30 mg/kg) had no effect on the acquisition of cocaine-paired cues during a Pavlovian cocaine-stimulus conditioning session in the operant chamber. Pretreatment with SB prior to the Pavlovian acquisition session had no effect on subsequent cue-induced reinstatement of cocaine-seeking elicited by those cues. However, pretreatment with SB prior to a second reinstatement session in the same animals significantly attenuated the expression of cue-induced reinstatement. These results show that orexin transmission at the orexin 1 receptor, but not the orexin 2 receptor, is necessary for the reinstatement of cocaine-seeking elicited by drug-paired cues and that orexin signaling is not critical for cocaine reinforcement or cocaine-stimulus conditioning.

Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model.

The serotonin 5-HT2A receptor (5-HT-sub(2A)R) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT-sub(2A)R antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naïve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT-sub(2A)R antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001-0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT-sub(2A)R attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse.

Certain or uncertain cocaine expectations influence accumbens dopamine responses to `self-administered cocaine and non-rewarded operant behavior

Uncertainty and errors in predicting natural rewards influence associative learning and dopamine activity. The present study was conducted to determine the influence of cue-induced cocaine uncertainty, certainty and prediction error on nucleus accumbens dopamine (NAcc DA) in rats. For Certainty training, distinctive sensory cues were present during cocaine availability and alternate cues were paired with non-reinforced (saline) operant sessions. For Uncertainty training, all cues were equally associated with both cocaine and non-reinforcement. After training, animals self-administered cocaine or saline in the presence of conditioned cues while NAcc DA responses were assessed using in vivo microdialysis. Findings revealed cocaine-stimulated NAcc DA increased significantly less in Certainty — compared to Uncertainty-trained animals, and cocaine-paired cues in the absence of cocaine (Negative Prediction Error) resulted in a significant depression of baseline NAcc DA. These findings provide support for enhanced DA activity during cocaine uncertainty or the development of conditioned cocaine tolerance in subjects certain of a cocaine outcome.

A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats

Studies on the reinstatement of drug-seeking after withdrawal from chronic drug self-administration have varied in terms of the procedures by which animals are initially trained to self-administer the drug. The current study directly compared whether prior operant training for food pellet reinforcement and/or maintained dietary restriction significantly altered the reinstatement of extinguished cocaine-seeking in the presence of cocaine-paired cues, a priming injection of cocaine (10 mg/kg; i.p.), and the pharmacological stressor, yohimbine (1.25 or 2.5 mg/kg, i.p.). Male Long Evans rats were divided into four groups as follows: a) trained to lever press for food pellets prior to cocaine self-administration and then maintained on a restricted diet, b) trained to lever press for food pellets prior to cocaine self-administration and then placed on an ad libitum diet, c) untrained and maintained on a restricted diet, or d) untrained and placed on ad libitum feeding. All rats readily self-administered cocaine (0.2 mg/50 μl/infusion) and were subsequently extinguished in the absence of cocaine or previously cocaine-paired cues (light + tone). Following extinction, rats experienced cue-, cocaine-, and yohimbine-induced reinstatement testing. No significant differences were seen between groups for lever responding during the maintenance phase and during extinction. Likewise, reinstatement of cocaine-seeking did not vary across groups for cue-, cocaine-, or yohimbine-induced reinstatement. Under these specific parameters, operant training prior to cocaine self-administration and/or dietary restriction do not significantly alter reinstatement of cocaine-seeking. The results arguably support the approach of not using prior lever training with a non-drug reinforcer and to limit the use of dietary restriction only to the acquisition phase of drug self-administration.

Neuroanatomical specificity of conditioned responses to cocaine versus food in mice

Neural circuits implicated in drug conditioning, craving and relapse overlap extensively with those involved in natural reward and reinforcement. To determine whether specificity could be detected in conditioned brain responses to drugs versus food, male outbred HSD:ICR mice were conditioned to a common environment using either 20 mg/kg cocaine (ip) or a familiar food (under food restriction). The mice were then re-exposed to the same environment without the reinforcer and patterns of brain activation were compared using immunohistochemical detection of Fos. Conditioned place preference tests were conducted first to establish relative potency of each reward and facilitate analysis of correlations between Fos and motivation. Place preference was stronger for cocaine than food. Food- but not cocaine-paired cues increased Fos in the paraventricular hypothalamic nucleus whereas the opposite occurred for prefrontal, cingulate and piriform cortices. Individual differences in cocaine place preference were negatively correlated with Fos in the prefrontal cortex. One difference between drugs and natural reinforcers may be lack of feedback from the periphery for drugs which may circumvent control from the hypothalamus in the development of reinforcement circuits.

Experience-dependent effects of cocaine self-administration/conditioning on prefrontal and accumbens dopamine responses.

Experiments were performed to examine the effects of cocaine self-administration and conditioning experience on operant behavior, locomotor activity, and nucleus accumbens (NAcc) and prefrontal cortex (PFC) dopamine (DA) responses. Sensory cues were paired with alternating cocaine and nonreinforcement during 12 (limited training) or 40 (long-term training) daily operant sessions. After limited training, NAcc DA responses to cocaine were significantly enhanced in the presence of cocaine-associated cues compared with nonreward cues and significantly depressed after cocaine-paired cues accompanied a nonreinforced lever response. PFC DA levels were generally nonresponsive to cues after the same training duration. However, after long-term training, cocaine-associated cues increased the magnitude of cocaine-stimulated PFC DA levels significantly over levels observed with nonreinforcement cues. Conversely, conditioned cues no longer influenced NAcc DA levels after long-term training. In addition, cocaine-stimulated locomotor activity was enhanced by cocaine-paired cues after long-term, but not after limited, training. Findings demonstrate that cue-induced cocaine expectation exerts a significant impact on dopaminergic and behavioral systems, progressing from mesolimbic to mesocortical regions and from latent to patent behaviors as cocaine and associative experiences escalate.

Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats

Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated. The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking. Male, Sprague-Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking. Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions. Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditioned-cued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.

AMPA-Receptor GluR1 Subunits are Involved in the Control Over Behavior by Cocaine-Paired Cues

The learning processes underlying the formation of drug-cue associations involve changes in synaptic transmission mediated by AMPA receptors. Here, we examine the consequences of targeted deletion of the gene encoding GluR1 subunits of AMPA receptors (gria1 knockouts (KO)) on cocaine self-administration and on the ability of cocaine-paired cues to affect cocaine-seeking in mice. Cocaine self-administration was unaffected by gria1 deletion, as was the ability of a cocaine-paired cue to reinstate responding following extinction, following either a 3 or a 66 day delay. However, gria1 KOs over-responded during extinction. The KOs were unable initially to learn a new response to access a cue previously conditioned to cocaine (conditioned reinforcement (CR)), although a second test 2 months later revealed that this was a transient deficit. These studies indicate that GluR1-containing AMPA-receptors are not involved in cocaine self-administration, cue-induced reinstatement of cocaine seeking, or incubation of the cocaine seeking response. In order to understand the specificity of the deficits in CR responding, a parallel study was performed with food reward. As with cocaine, there were no effects of gria1 deletion on food self-administration or cue-induced reinstatement, and KOs over-responded during extinction. However, even immediately after instrumental training for food, KO mice demonstrated responding for CR, suggesting that the CR deficit observed with a cocaine cue is specific to drug reward. These data indicate that GluR1-containing AMPA receptors are important in stimulus reward learning, though the method of cue-reward association formation, the reward class, and the behavioral end point are critical variables in determining their involvement.

Changes in extracellular dopamine during cocaine self‐administration in squirrel monkeys

Environmental cues are thought to play a role in drug craving, leading to the high relapse rate observed in cocaine abusers. Cocaine-paired cues can reinstate cocaine-maintained behavior in rodents and nonhuman primates and can induce changes in dopamine levels in the rodent striatum. In the present study, squirrel monkeys were trained to self-administer cocaine under a second-order schedule, and then were implanted with guide cannulae targeted at the caudate nucleus. Caudate dopamine levels were measured while the animals performed the behavioral task, self-administering cocaine or saline under extinction conditions. In addition, animals received noncontingent (passive) cocaine infusions yoked to the drug self-administration sessions. Cocaine administration increased dopamine levels 2-fold, but a leftward shift was seen in the peak effect in animals self-administering cocaine as compared to animals passively receiving cocaine. Moreover, dopamine levels began to decline during the experimental session when animals were self-administering cocaine, even though they continued to receive cocaine injections. In contrast, dopamine levels declined below baseline during the session when animals were given access to saline. The results suggest that the environmental context associated with drug self-administration can modulate cocaine-induced elevations in extracellular dopamine.

Effects of a dopamine D3 receptor ligand, BP 897, on acquisition and expression of food-, morphine-, and cocaine-induced conditioned place preference, and food-seeking behavior in rats.

The present study addressed the role of dopaminergic D(3) receptors (D(3)R) in motivational processes in rats. The effects of the selective D(3)R partial agonist, BP 897 (0.25-1 mg/kg, i.p.), on the establishment and the expression of conditioned place preference (CPP) supported by food, morphine (4 mg/kg, s.c.), or cocaine (2 mg/kg, s.c.) were investigated using an unbiased, one-compartment, place-conditioning procedure. When administered alone, BP 897 (0.05-2 mg/kg, i.p.) did not support CPP; on the contrary, conditioned place avoidance (CPA) was observed at 1 mg/kg, suggesting that this dose of BP 897 could be perceived as aversive. When given before each cocaine injection during the conditioning phase, BP 897 (1 mg/kg) prevented the establishment of CPP, and a single administration of BP 897 (0.5 and 1 mg/kg) before the test session impaired the expression of cocaine CPP. In contrast, neither the establishment nor the expression of food- and morphine-CPP were significantly altered by BP 897 (up to 1 mg/kg), whereas the full but less selective D(3)/D(2)R agonists, 7-OH-DPAT (0.5-2 mug/kg, s.c.) and quinelorane (1 mug/kg, s.c.), prevented the acquisition of food CPP. In a within-session extinction schedule of lever pressing for food, BP 897 (0.06-2 mg/kg) was ineffective in potentiating response reinstatement induced by the noncontingent delivery of two food pellets, in contrast with quinelorane and 7-OH-DPAT where previous studies showed to be efficient in this respect (Duarte et al, 2003). These results indicate that BP 897 has no positive appetitive value on its own, and that a moderate degree of stimulation of D(3)R is not sufficient to modulate food-primed food-seeking behavior or alter incentive motivation for food, morphine, and/or their associated cues. However, D(3)R are likely involved in the perception of the rewarding value of cocaine and cocaine-paired cues. This suggests that the appetitive effects of cocaine are subserved by mechanisms different, at least in part, from those of morphine and food, and that D(3)R play a role only in the former.

Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats

Recent evidence has demonstrated a critical role for the basolateral amygdala complex in the reinstatement of extinguished drug-seeking behavior produced by drug-paired cues. In the current study, we utilized a model of the acquisition and expression of cocaine-stimulus associative pairing in order to study the role of cholinergic input to the basolateral amygdala in mediating conditioned-cued reinstatement. Male, Sprague–Dawley rats were first trained daily to self-administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused into the basolateral amygdala prior to: a) classically conditioned pairing of a tone+light stimulus with cocaine infusions (acquisition), or b) testing of conditioned-cued reinstatement following a period of withdrawal from cocaine and extinction of cocaine-paired lever responding. Infusion of scopolamine just prior to the classical conditioning trial produced a dose-dependent disruption of cocaine-seeking behavior maintained by cocaine-paired cues during the reinstatement test. In contrast, infusion of scopolamine prior to the reinstatement test had no effect on conditioned-cued reinstatement of cocaine-seeking behavior. These results indicate a crucial role for cholinergic innervation of muscarinic acetylcholine receptors in the basolateral amygdala during the formation, but not the expression, of stimulus–reward associations that mediate cue-induced cocaine-seeking behavior.

Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats.

Serotonin (5-HT) systems may play a role in modulating cocaine-seeking behavior. The present study examined the effects of acute administration of the 5-HT reuptake inhibitor (SRI) fluoxetine, and the SRI/releaser d-fenfluramine, on reinstatement of extinguished cocaine-seeking behavior elicited by either response-contingent presentations of cocaine-paired cues or cocaine priming. Separate groups of rats that had been trained to press a lever for a cocaine reinforcer (0.75 mg/kg per 0.1 ml, IV) with a light/tone stimulus complex paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e. neither cocaine nor the stimulus complex was available). Subsequently, the effects of fluoxetine (0-10.0 mg/kg, IP) on extinction and cue reinstatement of extinguished cocaine-seeking behavior were examined, as well as the effects of d-fenfluramine (0-3.0 mg/kg, IP) on cue reinstatement. Additionally, dose-dependent effects of fluoxetine (0-10.0 mg/kg, IP) and d-fenfluramine (0-1.0 mg/kg, IP) on cocaine-primed (0-15.0 mg/kg, IP) reinstatement of extinguished cocaine-seeking behavior were examined. Fluoxetine dose-dependently attenuated cocaine-seeking behavior during extinction. Both fluoxetine and d-fenfluramine dose-dependently attenuated cue-reinstated cocaine-seeking behavior. In contrast, neither drug reliably altered cocaine-seeking behavior reinstated by cocaine priming. These findings suggest that 5-HT indirect agonists effectively attenuate cocaine-seeking behavior elicited by cocaine-associated stimuli, but are much less effective in attenuating cocaine-seeking behavior elicited by cocaine priming.

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats.

D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.

Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats.

Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.