Subjective Effects Of Cocaine Research Articles

Interactions between estradiol and ERK, but not mTOR, signaling is necessary for enhanced cocaine-induced conditioned place preference in female rats

Women rapidly progress from recreational cocaine use to dependence, consume greater quantities of cocaine, experience more positive subjective effects of cocaine and have higher incidences of relapse during abstinence. These effects have been replicated in animal models of cocaine addiction and indicate an enhanced sensitivity and therefore, vulnerability of females to cocaine addiction. Furthermore, it has been demonstrated that estradiol (E2) is a key mediator of the aforementioned effects of cocaine in women and female animals. However, studies identifying the influence of E2 on cocaine-associated reward and its underlying neurobiological mechanisms are lacking. Here, we further explored the influence of E2 on cocaine conditioned place preference in female rats. We show that E2 mediates cocaine-conditioned reward by potentiating cocaine-context associations. In addition, the E2-mediated increases in cocaine-induced CPP are associated with increased activation of ERK1/2 and mTOR proteins in the nucleus accumbens, dorsal striatum, and ventral tegmental area. To assess the involvement of ERK1/2 and mTOR in E2-mediated enhanced cocaine-CPP, we inhibited ERK1/2 and/or mTOR activity during cocaine-conditioning and before CPP-test. Inhibition of ERK1/2 during conditioning blocked cocaine-CPP in females, inhibition mTOR was without effect, and inhibiting ERK1/2 and mTOR before CPP-test blocked cocaine-CPP. In conclusion, we have established that E2 enhances cocaine-conditioned reward by potentiating cocaine-context associations formed during conditioning. Additionally, activation of ERK1/2 during cocaine-conditioning is necessary for the potentiation of cocaine-conditioned reward by E2. Significance statementStudies characterizing the molecular substrates underlying the effects of E2 during the formation of cocaine-context associations are virtually unknown. In this study, we established the influence of E2 during the formation of cocaine-CPP and characterized the role of ERK1/2 and mTOR activity on this effect within significant nodes of the reward pathway. The elucidation of the role of E2 in cocaine-induced intracellular signaling fills a significant gap in our knowledge regarding the mechanisms by which E2 affects intracellular signaling pathways to indicate the motivational salience of a stimulus. These data are crucial to our understanding of how fluctuating hormone levels can render females increasing sensitive to the rewarding effects of cocaine.

Promoter region variant C-824T in the TH gene modulates the subjective effects of cocaine.

This study examined how a promoter variant of TH (rs10770141) affects subjective effects of cocaine in 65 nontreatment-seeking individuals with cocaine dependence. Participants received cocaine/saline intravenously, and TH genotypes were evaluated. Homozygous individuals for the minor T allele reported greater "good" and "bad" subjective effects to cocaine than those with the major C allele. TH rs10770141 modulates subjective effects of cocaine in participants with cocaine dependence. These results are among the first to indicate that homozygosity of the T allele of rs10770141 modulates greater sensitivity to cocaine.

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine

Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (−15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for ‘depressed’ relative to participants with SLC6A4 hypomethylation (experiment-wise p = 0.002). These findings indicate that SLC6A4 methylation moderates the ‘depressed’ subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.

Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder

BackgroundPreclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). MethodsNon-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). ResultsThirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). ConclusionsWe did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Rivastigmine does not alter cocaine-induced subjective effects or self-administration

BackgroundAcetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. MethodsCocaine-dependent subjects were randomized to daily placebo, riv 3 mg, or riv 6 mg, administered inpatient for 10 days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40 mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20 mg with assessment of subjective effects, and were then able to purchase additional doses at 15 min intervals with study earnings. Results40 subjects were randomized to placebo (n = 16), riv 3 mg (n = 13), or riv 6 mg (n = 12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. ConclusionRivastigmine 3 or 6 mg had no significant effect on the subjective effects of cocaine after 9 days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.

Sex Differences in the Stages of Cocaine Use Disorder and the Influence of the Mesolimbic Dopamine System

Traditional drug abuse research has primarily focused on male behavior and neurobiology; however, recent work in the field has revealed distinct differences between male and female cocaine responsivity. Specifically, females appear to be more vulnerable to the effects of cocaine, a phenomenon that has been shown to fluctuate with the reproductive cycle in both clinical and preclinical studies. For example, in human studies, women report greater subjective effects of cocaine during the follicular phase of the menstrual cycle, while in rodent studies, mice and rats exhibit greater cocaine taking behavior and preference during the estrus phase of the estrous cycle. Increased sensitivity to cocaine reward has been shown using many behavioral assays including those used to measure initiation of cocaine use, motivation for drug, extinction, and reinstatement. Increased cocaine taking behavior in females has been manipulated further to study the effects of social interaction, natural reward, exercise, and stress on intravenous cocaine self‐administration. Altogether, sex differences, both between males and females and across the stages of estrous, appear to be mediated by differences in the mesolimbic dopamine system according to recent work implicating dopamine projections from the ventral tegmental area to the nucleus accumbens core (NAc).Here, intravenous cocaine self‐administration is used to assess drug taking behavior during the stages of drug addiction including initiation of use (acquisition), escalation, motivation, extinction, and reinstatement. Females in estrus showed faster times to acquisition of cocaine self‐administration and greater motivation to self‐administer cocaine using the behavioral economics protocol Threshold. Female cocaine abuse vulnerability further appears to be mediated by underlying neurobiological differences in cocaine taking between sexes and estrous stage. Females in estrus exhibit less synaptogyrin 3 expression in the NAc compared to their non‐estrus counterparts, a significant finding as decreased synaptogyrin expression in the NAc is associated with higher breakpoints in progressive ratio in males and is associated with dopamine transporter function. Furthermore, using ex vivo fast scan cyclic voltammetry (FSCV) in the NAc, females also exhibit greater dopamine transporter sensitivity to cocaine than males. Overall, these results add to the growing body of literature suggesting that females exhibit greater vulnerability to cocaine use and abuse across the stages of addiction and that these effects are due to an inherent neurobiological difference that this linked to the reproductive cycle and the mesolimbic dopamine system.Support or Funding InformationT32AA007565, P50DA006634This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The serotonin-2C agonist Lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study

BackgroundLorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR) approved for weight-loss therapy. This class can attenuate cue-induced responding and drug taking in preclinical studies, but effects in humans have not been reported. Methods and participantsWe evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low- or high- doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine. ResultsCocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of ‘high’ and ‘stimulated’ after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When active cocaine was self-administered, lorcaserin decreased heart rate after selection of a monetary choice, but increased it following an intravenous choice. ConclusionsCombined treatment with cocaine and lorcaserin was safe in a limited number of subjects, but did not diminish cocaine-motivated behavior or drug-induced ‘high’. Some positive subjective effects of cocaine were enhanced by lorcaserin, and it delayed intravenous choices and decreased craving under some conditions. Effects on heart rate depended on the type of reinforcer being self-administered. Trial registrationclinicaltrials.gov Identifier, NCT02680288.

The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway.

Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine's subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine's behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.

Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation.

Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment.SIGNIFICANCE STATEMENT Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids

Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women

ObjectivesFluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. MethodsPlasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5–7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. ResultsProgesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. ConclusionsAs expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Differential modulation of the discriminative stimulus effects of methamphetamine and cocaine by alprazolam and oxazepam in male and female rats

Drug users often combine benzodiazepines with psychostimulants, such as methamphetamine. However, very little research has been conducted on this type of polydrug use, particularly in female subjects. The present study was therefore designed to examine the effects of two benzodiazepines, alprazolam and oxazepam, on the discriminative stimulus effects of methamphetamine and cocaine in both male and female rats. Rats were trained to discriminate methamphetamine (1.0 mg/kg, ip) or cocaine (10 mg/kg, ip) from saline using a two-lever operant, food-reinforced, drug discrimination design. Pretreatment with oxazepam (5, 10 and 20 mg/kg, ip) significantly attenuated methamphetamine discrimination in both male and female rats. In contrast, however, the high dose of alprazolam (4 mg/kg, ip) actually augmented the subjective effects of lower doses of methamphetamine (0.125 and 0.25 mg/kg, ip). Oxazepam produced similar effects on the subjective effects of cocaine as with methamphetamine, significantly reducing cocaine discrimination in both male and female rats. However, neither the high nor low dose of alprazolam (2 and 4 mg/kg, ip) produced any apparent effect on cocaine discrimination. Finally, while similar results were observed in both male and female rats across these experiments, methamphetamine and cocaine discrimination were more sensitive to oxazepam in female subjects. The results of these experiments suggest that alprazolam and oxazepam can differentially affect the subjective effects of methamphetamine and cocaine. These results also demonstrate that alprazolam can differentially affect the discriminative stimulus effects of methamphetamine and cocaine.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine’s reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Butyrylcholinesterase levels and subjective effects of smoked cocaine in healthy cocaine users

Background: Butyrylcholinesterase (BChE) is beginning to attract attention as a possible target for cocaine abuse treatment because of its role in metabolizing cocaine. Objective: The purpose of this analysis was to assess whether endogenous BChE levels are associated with the subjective effects of cocaine. Methods: Data from 28 participants in five inpatient cocaine self-administration studies were included in the present analysis. Four minutes after each smoked cocaine dose, participants rated their drug-related effects from 0–100 using a computerized self-report Visual Analogue Scale (VAS). The main outcome measures were nine change-in-VAS ratings between a baseline placebo dose and a 25-mg smoked cocaine dose. Results: After controlling for age, sex, total years of cocaine use, total milligrams of cocaine administered before the 25-mg dose being analyzed, and baseline diastolic blood pressure, endogenous BChE was not significantly associated with any of the nine change-in-VAS ratings. Conclusion: Though BChE appears to be a possible target for cocaine abuse treatment, these data suggest that endogenous levels of BChE may not play a role in modifying the subjective effects of cocaine. Future larger studies of BChE in respect to the subjective effects produced by cocaine are needed to confirm or refute these findings.

Genders and the concurrent use of cocaine and alcohol: Pharmacological aspects

AimsGender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. MethodsThe MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. ResultsBesides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. ConclusionsThe observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.

Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine

Subjective effects of cocaine are mediated primarily by dopamine (DA) transporter (DAT) blockade. The present study assessed the hypothesis that different DAT conformational equilibria regulate differences in cocaine-like subjective effects and extracellular DA induced by diverse DA-uptake inhibitors (DUIs). The relationship between cocaine-like subjective effects and stimulation of mesolimbic DA levels by standard DUIs (cocaine, methylphenidate, WIN35,428) and atypical DUIs (benztropine analogs: AHN1-055, AHN2-005, JHW007) was investigated using cocaine discrimination and DA microdialysis procedures in rats. All drugs stimulated DA levels with different maxima and time courses. Standard DUIs, which preferentially bind outward-facing DAT conformations, fully substituted for cocaine, consistently producing cocaine-like subjective effects at DA levels of 100-125% over basal values, regardless of dose or pretreatment time. The atypical DUIs, with DAT binding minimally affected by DAT conformation, produced inconsistent cocaine-like subjective effects. Full effects were obtained, if at all, only at a few doses and pretreatment times and at DA levels 600-700% greater than basal values. Importantly, the linear, time-independent, relationship between cocaine-like subjective effects and DA stimulation obtained with standard DUIs was not obtained with the atypical DUIs. These results suggest a time-related desensitization process underlying the reduced cocaine subjective effects of atypical DUIs that may be differentially induced by the binding modalities identified using molecular approaches. Since the DAT is the target of several drugs for treating neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder, these results help to identify safe and effective medications with minimal cocaine-like subjective effects that contribute to abuse liability.

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective 'high' (P = 0.00006), 'any drug effect' (P = 0.0003) and 'like' (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater 'high' and 'like', and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

Estrous cycle and sex affect cocaine-induced behavioural changes in CD1 mice

Several findings on sex differences in cocaine response suggest a role for hormonal milieu in modulating the subjective effects of cocaine. Nitric oxide (NO) has been involved in the neurochemical, hormonal, and behavioral changes related to stress and anxiety. Within the brain, the anteroventral subdivision of the medial amygdala (MeAV) is an important area involved in processing emotional responses such as anxiety and a high density of NO-producing neurons is observed in this area. In this study, we hypothesize the possibility of sex/hormonal differences in response to cocaine and that these differences may reflect a change in the MeAV nitrergic system. We have examined cocaine's acute effects on nicotinamide adenine dinucleotide phosphate diaphorase (nadph-d) expression, as well as its effect on motor activity and anxiety in male and estrus and diestrus females. Our results show that acute cocaine administration produces an increase in both anxiety behaviors and nadph-d expression in the MeAV. Male and diestrus female mice were more susceptible to these effects of cocaine than estrus female mice in which no differences were detected. In addition, we examined individual differences in male and female mice responding to intravenous cocaine reinforcement in a self-administration paradigm. Female mice acquired cocaine self-administration at a faster rate than males and showed a higher motivation to self-administer cocaine under a progressive ratio schedule of reinforcement. Our data suggest a complex interaction between hormonal milieu and the behavioral and reinforcing effects of cocaine.