Cocaine Self-administration Behavior In Rats Research Articles

Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats

According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D1-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.

Samidorphan, an opioid receptor antagonist, attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in male Wistar rats

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (μ), kappa- (κ), and delta- (δ) opioid receptors and functions as a μ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.

Cocaine addiction as a homeostatic reinforcement learning disorder.

Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record

Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats.

We have recently reported the expression of functional cannabinoid CB2 receptors (CB2 Rs) in midbrain dopamine (DA) neurons in mice. However, little is known whether CB2 Rs are similarly expressed in rat brain because significant species differences in CB2 R structures and expression are found. In situ hybridization and immunohistochemical assays detected CB2 gene and receptors in DA neurons of the ventral tegmental area (VTA), which was up-regulated in cocaine self-administration rats. Electrophysiological studies demonstrated that activation of CB2 Rs by JWH133 inhibited VTA DA neuronal firing in single dissociated neurons. Systemic administration of JWH133 failed to alter, while local administration of JWH133 into the nucleus accumbens inhibited cocaine-enhanced extracellular DA and i.v. cocaine self-administration. This effect was blocked by AM630, a selective CB2 R antagonist. These data suggest that CB2 Rs are expressed in VTA DA neurons and functionally modulate DA neuronal activities and cocaine self-administration behavior in rats.

Once is too much: conditioned aversion develops immediately and predicts future cocaine self-administration behavior in rats.

Rats emit aversive taste reactivity (TR) behavior (i.e., gapes) following intraoral delivery of a cocaine-paired taste cue and greater conditioned aversive TR at the end of training predicts greater drug-seeking and taking. Here, we examined the development of this conditioned aversive TR behavior on a trial-by-trial basis in an effort to determine when the change in behavior occurs and whether early changes in this behavior can be used to predict later drug taking. The results show that conditioned aversive TR to a cocaine-paired cue occurs very early in training (i.e., following as few as 1-2 taste-drug pairings) and, importantly, that it can be used to predict later drug seeking and drug taking in rats.

Impact of medial orbital cortex and medial subthalamic nucleus inactivation, individually and together, on the maintenance of cocaine self-administration behavior in rats

A reversible neuronal inactivation procedure was used to study the role of the medial orbital cortex (MO) and medial tip of the subthalamic nucleus (mSTN) in maintenance of cocaine self-administration studied under a second-order schedule of drug and cue presentation. Lidocaine or vehicle was infused 5-min before 1-h self-administration test sessions, using bilateral, asymmetric or unilateral manipulations. The results demonstrated that whether the MO was inactivated bilaterally, unilaterally or asymmetrically (with contralateral mSTN inactivation), cocaine seeking and cocaine intake were reduced. In contrast, bilateral mSTN inactivation did not impact cocaine seeking or cocaine intake, suggesting that the reductions in these measures following asymmetric inactivation may have been due to a unilateral influence of lidocaine in MO. Expression of c-Fos protein was measured in sites downstream of the STN to ensure that the lidocaine inactivation procedure was effective in selectively altering activity of neurons in mSTN. Cocaine-induced c-Fos protein expression was augmented only in the ipsilateral nucleus accumbens core after mSTN lidocaine pretreatment, consistent with the expectation that inactivation of mSTN would disinhibit nucleus accumbens core, but not shell, activity. The present investigation shows the critical importance of the MO for maintaining cocaine seeking and cocaine intake in rats, though its projections to mSTN appear to be unimportant for this purpose. Because cocaine seeking was impacted to such a great extent (45% of baseline, on average), it is likely that MO inactivation exerts its influence on maintenance of cocaine self-administration by interfering primarily with cue-controlled behavior rather than by modifying the reinforcing effects of cocaine.

Anti-Cocaine Vaccine Based on Coupling a Cocaine Analog to a Disrupted Adenovirus

The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans, we hypothesized that linking a cocaine hapten to Ad capsid proteins would elicit high-affinity, high-titer antibodies against cocaine, sufficient to sequester systemically administered cocaine and prevent access to the brain, thus suppressing cocaine-induced behaviors. Based on these concepts, we developed dAd5GNE, a disrupted E1-E3- serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In pre-clinical studies, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies, and was highly effective in blocking cocaine-induced hyperactivity and cocaine self-administration behavior in rats. Future studies will be designed to expand the efficacy studies, carry out relevant toxicology studies, and test dAd5GNE in human cocaine addicts.

D-cycloserine facilitates extinction of cocaine self-administration in rats.

Previous research has indicated that D-cycloserine [DCS; a N-methyl-D-aspartate (NMDA) partial agonist] facilitates the extinction of conditioned fear as well as the extinction of cocaine conditioned place preference. Sprague Dawley rats were first trained to self-administer cocaine and then we compared their extinction behavior (lever pressing) following treatment with vehicle; 15 mg/kg DCS; or 30 mg/kg DCS. We showed that 30 mg/kg DCS, but not 15 mg/kg significantly accelerated extinction of cocaine self-administration behavior when compared with saline by almost half (4 days vs. 9 days). At 2 weeks when all animals had extinguished, there were no longer differences between the groups. The present findings support of the potential of NMDA partial agonists as prospectively valuable in facilitating the extinction of cocaine-seeking behavior. More specifically, we demonstrate that 30 mg/kg DCS was effective at significantly accelerating the extinction of cocaine self-administration behavior in rats. These results provide further support for the potential of DCS as a treatment strategy for addiction.

A molecular model for cocaine binding by the immunotherapeutic human/mouse chimeric monoclonal antibody 2E2

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (γ 1 heavy chain)/murine (λ light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2's ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its F v fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2's cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2's cocaine binding properties.

Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats

There is considerable interest in elucidating neurocognitive mechanisms of cocaine addiction. This report focuses on the hippocampal memory system. Using food reward, two cognitive tasks were examined after lidocaine inactivation of the dorsal (dSUB) or ventral (vSUB) subiculum, the primary hippocampal output regions in rats. These tasks were conducted to first identify functionally relevant stereotaxic coordinates within the hippocampal memory system, in order to then examine its role in regulating drug-seeking and drug-taking behavior studied under a contextually discriminable FI 5-min(FR5:S) second-order schedule of cocaine and brief stimulus delivery. Inactivation of the dSUB and vSUB with 10 μg lidocaine impaired hippocampal-dependent win-shift performance. Amygdalar-dependant conditioned cue preference, used as a test for behavioral specificity of lidocaine, was not affected following inactivation of either site. Inactivation of the dSUB with 100 μg lidocaine significantly reduced drug-seeking and drug-taking behavior studied during the cocaine self-administration maintenance phase. Following extinction, inactivation of neither the dSUB nor vSUB influenced reinstatement of drug-seeking behavior induced by drug-paired cues presented alone or with a cocaine priming injection. The impairments in win-shift performance are consistent with the spatial processing functions of the dSUB and vSUB, and the reduction in drug-taking behavior is consistent with the non-spatial temporal processing functions of the dSUB. The lack of an effect of dSUB and vSUB inactivation on reinstatement of drug-seeking behavior may relate to the fact that the contextual associations with cocaine were well-practiced at the time of cue reinstatement testing, and therefore, drug-seeking behavior was likely regulated by nonhippocampal-dependent mechanisms.

Dopaminergic Mechanism for Caffeine-Produced Cocaine Seeking in Rats

Systemic administration of caffeine reinstates extinguished cocaine self-administration behavior in rats, but the mechanism mediating this behavioral effect has not been established. The present study examined the role of adenosinergic A2 and dopaminergic mechanisms in caffeine-produced cocaine seeking. Following extinction of cocaine self-administration, experimenter-administered injections of caffeine (1.25–20 mg/kg) and theophylline (1–10 mg/kg) dose-dependently reinstated extinguished cocaine-seeking behavior. Administration of the adenosinergic A2 antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX; 0.546–2.18 μg/kg), failed to produce cocaine seeking. Pretreatment with doses of the adenosine A1/A2 agonist 5′-N-ethylcarboxamidoadenosine (NECA; 0.003–0.03 mg/kg) that were below those that produced marked sedation failed to block reinstatement. These data suggest that methylxanthine-produced cocaine seeking is not due to adenosine A2 receptor antagonism. In contrast, pretreatment with the dopaminergic D1-like antagonist SCH 23390 (0.005–0.02 mg/kg) or the D2-like antagonist eticlopride (0.03–0.3 mg/kg) produced a dose-dependent attenuation of caffeine-produced reinstatement at doses that did not decrease cocaine self-administration. These findings suggest that dopaminergic mechanisms underlie the ability of caffeine to reinstate extinguished cocaine-taking behavior.

Time course of changes in cocaine self-administration behavior in rats during immunization with the cocaine vaccine IPC-1010.

Following a 6-week immunization period consisting of three biweekly injections of the cocaine vaccine IPC-1010, the reacquisition of cocaine self-administration behavior in rats was previously shown to be reduced in a manner that was dependant on serum antibody level. The present studies were conducted to examine additional issues relevant to the clinical use of the vaccine. One experiment was conducted to address the issue of whether exposure to cocaine during the immunization period would influence the ability of the vaccine to block cocaine self-administration. A second experiment was conducted to determine if the reductions in drug-seeking behavior and drug intake by the vaccine were behaviorally specific, or if behavior maintained by a non-drug reinforcer would be similarly affected. Identical second-order schedules of cocaine (1 mg/kg) or food pellet (45 mg) delivery were used in rats. In both studies, the time course of changes in behavior during the 6-week immunization period was examined in vaccine and alum-treated control rats following baseline and extinction conditions. The cocaine vaccine IPC-1010 induced average serum antibody levels of 0.07 mg/ml and significantly reduced self-administration behavior during the 2-week period following the third vaccine boost in a subgroup of rats with serum antibody levels greater than the average value. Cocaine self-administration behavior at this time point significantly correlated with serum antibody level. IPC-1010 did not alter responding maintained by food throughout the immunization period although serum antibody levels reached a similar average of 0.06 mg/ml in this group of rats. These findings suggest that the reductions in drug-seeking behavior and drug intake after immunization with IPC-1010 did not result from a reduced ability of the rats to respond on the lever. Furthermore, daily exposure to cocaine during the immunization period did not influence the ability of the vaccine to reduce cocaine self-administration behavior that emerged gradually over time. These findings also confirm the need for a sufficiently high antibody level to blunt the reinforcing effects of cocaine.

Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats

Electrophysiological recording procedures were used to examine nucleus accumbens (Acb) cell firing in rats ( N=13) during cocaine self-administration sessions consisting of three phases. In phase one (maintenance), each lever press resulted in an intravenous cocaine infusion (0.33 mg, 6 s) paired with a tone-houselight stimulus (20 s). Of 144 Acb cells recorded during maintenance, 39 neurons (27%) exhibited phasic firing relative to the cocaine-reinforced response [4–8]. Briefly, Acb neurons showed increases in firing rate within seconds preceding the reinforced response and/or changes (increases or decreases) in activity within seconds following response completion. In phase two (extinction), saline was substituted for cocaine in the task. Results indicated that cells displaying exclusively anticipatory discharges during maintenance exhibited similar phasic activity during extinction. However, neurons that displayed post-response activity during the maintenance phase typically showed significant attenuation of phasic firing rates during extinction. After 30 min of no responding, animals were ‘primed’ with an intravenous infusion of cocaine, and self-administration was reestablished during phase three (reinstatement). Results showed that pre-response discharge patterns remained relatively intact while post-response cells typically exhibited a partial recovery of phasic activity. Similar findings were observed during other extinction experiments in which the stimulus only was removed (CS extinction). These findings support the notion that specific factors operating within the self-administration context differentially control pre- versus post-response discharge patterns of Acb neurons.

Modulation of drug-conditioned responses by NMDA receptor antagonists

High-speed chronoamperometry with Nafion-coated monoamine-sensitive carbon fiber electrodes was used to estimate changes in extracellular dopamine concentration in the nucleus accumbens during cocaine self-administration behavior in rats. In trained animals, time-locked biphasic fluctuations in dopamine-dependent electrochemical signal were found to accompany cocaine self-injections (0.8−0.9 mg/kg/inj). The mean signal gradually increased by the equivalent of 20–30 nM of dopamine during the 60 s preceding the injection, reached a peak value at the lever-press and decreased abruptly by about 20–30 nM for 40–60 s after the injection. This cyclic pattern was repeated with the next lever-press. The post-cocaine signal decreases were most pronounced during the first 30 min of each session, when self-administration behavior was highest (eight to 16 injections), and gradually diminished during the session. In contrast, the pre-injection signal increases became enhanced over time. Lever-presses reinforced by a double cocaine dose were followed by significantly larger and longer lasting signal decreases. These biphasic fluctuations quickly disappeared after several non-reinforced lever-presses. Although experimenter-delivered cocaine injections paced to mimic the pattern of self-administration also induced biphasic signal fluctuations, both the post-drug signal decreases and subsequent pre-injection increases were significantly smaller.It is hypothesized that the increases in signal seen in trained animals are a consequence of cocaine-induced dopamine uptake inhibition following behavior-associated dopamine cell activation. In contrast, the post-cocaine abrupt transient signal depression may be related to a decrease in mesolimbic dopamine release due to inhibition of dopamine cell activity. Signal decreases seen after self-administered procaine suggest that cocaine's local anesthetic action may contribute to this decrease in dopamine release. Additionally, while the latency of response differed somewhat, since apomorphine administration also led to a reduction in signal, autoreceptor activation may also have contributed to the cocaine-induced signal depression. That learning and behavioral mechanisms are also important determinants of the observed cocaine-induced signal changes is suggested by the signal decreases after the first non-reinforced responses, signal differences between self- and passively-administered cocaine and signal increases caused by cocaine-related cues.In light of numerous neuropharmacological studies implicating the significance of the mesolimbic dopamine system in the organization and regulation of goal-directed behaviors, these data suggest that mesolimbic dopamine system activation may mediate motivational and activational components of drug-seeking and drug-taking behavior, while the transient, reward-associated inhibition of the system may be involved in regulating these behaviors. The co-existence of two functionally antagonistic actions of cocaine on mesolimbic dopamine release and accumulation may be important in mediating the drug's unique psychogenic properties, including the ability to drive and maintain compulsive drug-taking behavior.

Effect of (-)-DS 121 and (+)-UH 232 on cocaine self-administration in rats.

The novel dopamine autoreceptor antagonists (-)-DS 121 and (+)-UH 232 were tested for their ability to alter cocaine self-administration behavior in rats reinforced on a progressive ratio (PR) schedule. (-)-DS 121 (15 mg/kg) and (+)-UH 232 (30 mg/kg) produced significant decreases in breaking point. (-)-DS 121 produced variable results on rate of cocaine intake on an FR1 schedule, indicating that rate may on occasion be insensitive to changes in cocaine reinforcement. In animals previously trained to self-administer cocaine, (-)-DS 121 failed to maintain responding when substituted for cocaine. This profile suggests that (-)-DS 121 is a promising new candidate for the treatment of cocaine abuse.

Fluctuations in nucleus accumbens dopamine during cocaine self-administration behavior: An in vivo electrochemical study

High-speed chronoamperometry with Nafion-coated monoamine-sensitive carbon fiber electrodes was used to estimate changes in extracellular dopamine concentration in the nucleus accumbens during cocaine self-administration behavior in rats. In trained animals, time-locked biphasic fluctuations in dopamine-dependent electrochemical signal were found to accompany cocaine self-injections (0.8-0.9 mg/kg/inj). The mean signal gradually increased by the equivalent of 20-30 nM of dopamine during the 60 s preceding the injection, reached a peak value at the lever-press and decreased abruptly by about 20-30 nM for 40-60 s after the injection. This cyclic pattern was repeated with the next lever-press. The post-cocaine signal decreases were most pronounced during the first 30 min of each session, when self-administration behavior was highest (eight to 16 injections), and gradually diminished during the session. In contrast, the pre-injection signal increases became enhanced over time. Lever-presses reinforced by a double cocaine dose were followed by significantly larger and longer lasting signal decreases. These biphasic fluctuations quickly disappeared after several non-reinforced lever-presses. Although experimenter-delivered cocaine injections paced to mimic the pattern of self-administration also induced biphasic signal fluctuations, both the post-drug signal decreases and subsequent pre-injection increases were significantly smaller. It is hypothesized that the increases in signal seen in trained animals are a consequence of cocaine-induced dopamine uptake inhibition following behavior-associated dopamine cell activation. In contrast, the post-cocaine abrupt transient signal depression may be related to a decrease in mesolimbic dopamine release due to inhibition of dopamine cell activity. Signal decreases seen after self-administered procaine suggest that cocaine's local anesthetic action may contribute to this decrease in dopamine release. Additionally, while the latency of response differed somewhat, since apomorphine administration also led to a reduction in signal, autoreceptor activation may also have contributed to the cocaine-induced signal depression. That learning and behavioral mechanisms are also important determinants of the observed cocaine-induced signal changes is suggested by the signal decreases after the first non-reinforced responses, signal differences between self- and passively-administered cocaine and signal increases caused by cocaine-related cues. In light of numerous neuropharmacological studies implicating the significance of the mesolimbic dopamine system in the organization and regulation of goal-directed behaviors, these data suggest that mesolimbic dopamine system activation may mediate motivational and activational components of drug-seeking and drug-taking behavior, while the transient, reward-associated inhibition of the system may be involved in regulating these behaviors.(ABSTRACT TRUNCATED AT 400 WORDS)

Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment

Intravenous cocaine self-administration behavior in rats was investigated using a progressive ratio (PR) schedule of reinforcement. The first response on the lever each day produced a drug infusion, whereupon the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed each day was found to be relatively stable, sensitive to changes in dose, and drastically reduced by pretreatment with haloperidol (0.05 mg/kg). We conclude that self-administration behavior of rats reinforced on a progressive ratio schedule can provide useful information about changes in the reinforcing efficacy of specific drugs.