Effects of Chronic Varenicline Treatment on Nicotine,Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.     

Adolescent Atomoxetine Treatment in a Rodent Model of ADHD: Effects on Cocaine Self-Administration and Dopamine Transporters in Frontostriatal Regions

Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar–Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar–Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar–Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased V_max and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern.     

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.     

Long-Term Reduction of Cocaine Self-Administration in Rats Treated with Adenoviral Vector-Delivered Cocaine Hydrolase: Evidence for Enzymatic Activity

A new pharmacokinetic approach treating cocaine addiction involves rapidly metabolizing cocaine before it reaches brain reward centers using mutated human butyrylcholinesterase (BChE) or cocaine hydrolase (CocH). Recent work has shown that helper-dependent adenoviral (hdAD) vector-mediated plasma CocH reduced the locomotor-activating effects of cocaine and prevented reinstatement of cocaine-seeking behavior up to 6 months in rats. The present study investigated whether hdAD-CocH could decrease ongoing intravenous cocaine (0.4 mg/kg) self-administration. The hdAD-CocH vector was injected into self-administering rats, and after accumulation of plasma CocH, there was a dramatic reduction in cocaine infusions earned under a fixed ratio 1 schedule of reinforcement that lasted for the length of the study (>2 months). Pretreatment with the selective BChE and CocH inhibitor iso-OMPA (1.5 mg/kg) restored cocaine intake; therefore, the decline in self-administration was likely due to rapid CocH-mediated cocaine metabolism. Direct measurements of cocaine levels in plasma and brain samples taken after the conclusion of behavioral studies provided strong support for this conclusion. Further, rats injected with hdAD-CocH did not experience a deficit in operant responding for drug reinforcement and self-administered methamphetamine (0.05 mg/kg) at control levels. Overall, these outcomes suggest that viral gene transfer can yield plasma CocH levels that effectively diminish long-term cocaine intake and may have potential treatment implications for cocaine-dependent individuals seeking to become and remain abstinent.     

Drug Intake is Sufficient,but Conditioning is not Necessary for the Emergence of Compulsive Cocaine Seeking After Extended Self-Administration

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decision-making circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.     

Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF₉₋₄₁ (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF''s reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use.     

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.     

Methylphenidate Treatment in Adolescent Rats with an Attention Deficit/Hyperactivity Disorder Phenotype: Cocaine Addiction Vulnerability and Dopamine Transporter Function

Appropriate animal models of attention deficit/hyperactivity disorder (ADHD) and drug reinforcement allow investigation of possible underlying biological bases of ADHD and its comorbidity with cocaine addiction. Toward this end, spontaneously hypertensive rats (SHRs) exhibiting an ADHD phenotype were compared with Wistar-Kyoto (WKY) and Wistar (WIS) rats. Initially, 1.5 mg/kg oral methylphenidate or vehicle was administered between postnatal days 28 and 55, and acquisition of visual discrimination learning was examined. After discontinuing adolescent treatments, adult rats were evaluated for cocaine self-administration and dopamine transporter (DAT) function in the prefrontal cortex (PFC) and striatum. During adolescence, SHRs showed deficits in visual discrimination relative to WKY and WIS rats when non-medicated. Methylphenidate improved visual discrimination only in SHRs. Compared with WKY and WIS rats, SHRs with previous methylphenidate treatment acquired cocaine self-administration faster, identified cocaine as a highly efficacious reinforcer by displaying an upward shift in the cocaine dose–response function, and showed the greatest motivation to self-administer cocaine by exhibiting the highest progressive ratio breakpoints. In the PFC, the maximal dopamine uptake (V_max) at DAT was decreased in SHRs and increased in WKY and WIS rats by previous methylphenidate treatment. The affinity (K_m) for dopamine at DAT in the PFC was not different between strains, nor was V_max or K_m altered in the striatum by previous methylphenidate treatment in any strain. Methylphenidate-induced decreases in dopamine clearance by DAT in the PFC may underlie increased cocaine self-administration in SHRs. These preclinical findings suggest that caution should be exercised when methylphenidate is prescribed for first-time treatment of ADHD in adolescent patients, as cocaine addiction vulnerability may be augmented.     

fMRI of Cocaine Self-Administration in Macaques Reveals Functional Inhibition of Basal Ganglia

Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion.     

Cocaine-Induced Membrane Adaptation in the Central Nucleus of Amygdala

Exposure to drugs of abuse lead to both rewarding effects and the subsequent development of negative affects. The progressive dysregulation of both processes is thought to critically contribute to the addictive state. Whereas cocaine-induced maladaptations in reward circuitry have been extensively examined, the cellular substrates underlying negative affect remain poorly understood. This study focuses on the central nucleus of the amygdala (CeA), a brain region that has been implicated in negative affective states upon withdrawal from chronic cocaine use. We observed that the two major types of CeA neurons, low-threshold bursting (LTB) neurons and regular spiking (RS) neurons, exhibited different sensitivity to corticotrophin-releasing factor (CRF), a stress hormone that has been implicated in negative affect during drug withdrawal. Furthermore, LTB and RS neurons developed opposite membrane adaptations following short-term (5 day) cocaine self-administration; the membrane excitability was increased in LTB neurons but decreased in RS neurons. These short-term exposure-induced effects were transient as they were present on withdrawal day 1 but disappeared on withdrawal day 21. However, extended exposure (21 day) led to sustained increase in the membrane excitability of LTB neurons such that it lasted over 21 days into the withdrawal period. These results suggest that CeA neurons can be a cellular target for cocaine to reshape the circuitry mediating negative affects during withdrawal, and that the long-lasting cellular alterations in selective subpopulations of CeA neurons may lead to unbalanced CeA processing, thus contributing to the progressive aggravation of negative affective states during withdrawal from chronic cocaine exposure.     

Estradiol as a Mechanism for Sex Differences in the Development of an Addicted Phenotype following Extended Access Cocaine Self-Administration

Women progress more rapidly after initial cocaine use to addiction as compared with men. Similarly, female rats appear to require less cocaine exposure before developing an addicted phenotype with evidence implicating estradiol as a potential mechanism. The goals of this study were to determine whether there are sex differences in the magnitude of the addicted phenotype under optimized conditions that induce its development in both males and females and to determine the role of estradiol in this effect. Following acquisition, intact male and intact and ovariectomized (OVX) female rats with and without estradiol replacement were given access to cocaine (1.5 mg/kg per infusion) under either extended access (ExA; discrete trial procedure, 4 trials/h, 24 h/day, 10 days) or short access (ShA) conditions (20 infusions maximum/day, 3 days). Motivation to obtain cocaine (0.5 mg/kg/infusion), as assessed under a progressive-ratio schedule, was then examined following a 2-week abstinence period. Results showed that following ExA self-administration, both males and females developed an addicted phenotype, with 9 of 11 males and 8 of 10 females showing a greater than 15% increase in levels of motivation to obtain cocaine as compared with ShA controls. In contrast, within the OVX groups, responding was enhanced from control levels after ExA self-administration in estradiol-replaced rats only. These results suggest that while females may have an enhanced vulnerability to developing an addicted phenotype, they may be similar to males once addiction has developed. These results also suggest that estradiol is critically involved in the development of an addicted phenotype in females.     

Reduced Forebrain Serotonin Transmission is Causally Involved in the Development of Compulsive Cocaine Seeking in Rats

Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history.     

Different Adaptations in AMPA Receptor Transmission in the Nucleus Accumbens after Short vs Long Access Cocaine Self-Administration Regimens

Ca²⁺-permeable AMPA receptors (CP-AMPARs) accumulate in the nucleusaccumbens (NAc) after ∼1 month of withdrawal from a long-access cocaineself-administration regimen (6 h/d, 10d). This is functionally significantbecause CP-AMPARs mediate the ‘incubated'' cue-induced cocaine craving producedby this regimen. Our present goal was to determine if other commonly employed cocaineself-administration regimens also elicit CP-AMPAR accumulation. We compared four regimens,named according to whether sessions were short-access (ShA, 2 h) or long-access(LgA, 6 h) and the total number of sessions: LgA/10d (already shown to elicitCP-AMPAR accumulation), ShA/11d, ShA/20-24d, and LgA/20-24d. In the latterregimens, rats began with 10 days of ShA and then entered a differential phase(10–14 days) in which ShA sessions either continued or switched to LgA. Controlsself-administered saline. After >40 days of withdrawal, whole-cell patch-clamprecordings were performed in NAc core medium spiny neurons to assess the contribution ofCP-AMPAR transmission, based on the magnitude of synaptic suppression elicited by bathapplication of the selective CP-AMPAR antagonist naspm (100 μM). Naspm produceda non-significant (∼10%) attenuation of electrically evoked local excitatorypostsynaptic current in the saline and ShA groups. By contrast, a significantnaspm-induced synaptic attenuation (25–30%) was observed in both the LgAgroups. Further analyses indicate that this emergence of CP-AMPAR transmission in the LgAgroups is associated with increased baseline responsiveness of MSN to excitatory drive.Together with data on cocaine infusions in each group, our results show that CP-AMPARaccumulation and enhanced glutamate transmission is associated with longer sessions(6 h), rather than the number of sessions or cocaine infusions.     

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

Background:

Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown.

Methods:

This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.

Results:

In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.

Conclusions:

Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.     

Neural Correlates of Reward-Based Spatial Learning in Persons with Cocaine Dependence

Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus-response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory.     

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of >40 days. Although the in vivo duration of CCRQ CocE''s action was <24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE''s actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose–response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine''s reinforcing and interoceptive effects of >30-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food-reinforced responding, these effects were short-lived, lasting <24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.     

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.     

Disruption of Glutamate Receptor-Interacting Protein in Nucleus Accumbens Enhances Vulnerability to Cocaine Relapse

Trafficking and stabilization of AMPA receptors at synapses in response to cocaine exposure is thought to be critical for expression of cocaine addiction and relapse. Glutamate receptor-interacting protein (GRIP) is a neuronal scaffolding protein that stabilizes GluA2 AMPARs at synapses but its role in cocaine addiction has not been examined. The current study demonstrates that conditional deletion of GRIP within the nucleus accumbens potentiates cue-induced reinstatement of cocaine seeking without affecting operant learning, locomotor activity, or reinstatement of natural reward seeking. This is the first study to demonstrate a role for accumbal GRIP in behavior. Electrophysiological recordings revealed increased rectification of AMPAR-mediated currents in the nucleus accumbens and increased AMPAR sensitivity to the GluA2-lacking AMPAR antagonist, 1-naphthylacetyl spermine, indicative of an increased contribution of GluA2-lacking calcium-permeable AMPARs. In addition, accumbal GRIP deletion was associated with blunted long-term depression, similar to what is seen following cocaine self-administration. Taken together, these results indicate that GRIP may modulate addictive phenotypes through its regulation of synaptic AMPARs by controlling their subunit composition and susceptibility to LTD. These effects are associated with changes in vulnerability to cocaine relapse and highlight GRIP as a novel target for the development of cocaine addiction therapeutics.     

The Role of Therapeutic Alliance in Network Therapy: A Family and Peer Support-Based Treatment for Cocaine Abuse

The therapeutic alliance is a well-studied construct factor that is important to outcome in many forms of individual therapy. Therapeutic alliance has been rarely studied in group therapy and results in addiction treatment have been mixed. In this paper, we studied the presence of a therapeutic alliance in Network Therapy: an approach that uses peer and family support in addiction treatment. Twenty-one participants undergoing Network Therapy for cocaine addiction were observed on videotape, and were rated on therapeutic alliance using the Working Alliance Inventory and the Penn Helping Alliance Rating Scale. Results showed a significant positive correlation between therapeutic alliance and outcome as measured by the percentage of cocaine-free urine toxicology screens and by eight consecutive cocaine-free urines.