Intermittent intake of rapid cocaine injections promotes robust psychomotor sensitization, increased incentive motivation for the drug and mGlu2/3 receptor dysregulation.

The choice between smoking, injecting or swallowing a drug influences the risk of addiction, as this determines both how much drug gets into the brain and how fast. Most animal studies on addiction focus on how much drug it takes to produce pathological drug use. How fast drugs get to the brain is generally ignored. A few studies have examined the influence of the speed of drug onset, but speed varied along with cumulative intake. Here we held average cumulative intake constant and determined whether variation in the speed of cocaine onset alone predicts outcome. Two groups of rats self-administered intravenous cocaine (0.25 mg/kg/injection) during daily sessions. Cocaine was available intermittently during each session. This produces the spikes and troughs in brain levels of cocaine thought to model how addicts take the drug. To vary the speed of cocaine onset, each injection was delivered over 5 s to one group, and over 90 s to the other. Average cumulative cocaine intake was the same in the two groups. However, rapid injections promoted robust psychomotor sensitization and potentiated incentive motivation for cocaine (0.063-0.25 mg/kg/injection). This addiction-relevant phenotype was accompanied by enhanced functional activity of metabotropic glutamate group II receptors (mGluR2/3s) in the prelimbic cortex and nucleus accumbens. Pharmacological activation of mGluR2/3s with LY379268 also preferentially decreased the motivation to take cocaine in rats previously exposed to rapid drug injections. Thus, varying the speed of drug onset can be used to parse the neurobiology of addiction from that of mere drug taking.

The Pharmacokinetic Interaction Study between Carvedilol and Bupropion in Rats.

BACKGROUND/AIMS: The effects of multiple-dose bupropion on the pharmacokinetics of single-dose carvedilol were investigated in order to evaluate this possible drug-drug interaction. METHODS: A preclinical study was conducted among white male Wistar rats. Each rat was cannulated on the femoral vein prior to being connected to BASi Culex ABC®. During the reference period, each rat received an intravenous and an oral dose of 3.57 mg/kg body weight (b.w.) carvedilol, at 2 days distance. After 5 days of pretreatment with 21.42 mg/kg b.w. bupropion (by oral route, twice a day - given in order to reach the steady state), during the sixth day, 3.57 mg/kg b.w. carvedilol and 21.42 mg/kg b.w. bupropion were orally co-administrated (test period). After each administration of carvedilol, several samples of 200 µL blood were collected. The pharmacokinetic parameters of carvedilol were analyzed by the noncompartmental method. RESULTS: The 5 days pretreatment with bupropion increased the exposure to carvedilol in rats by 180%, considering the modifications observed in the area under the curve of carvedilol. Carvedilol was shown to have higher plasma concentrations, delay in maximum concentration, and a prolonged half-life, after being pretreated with bupropion. CONCLUSION: The administration of multiple-dose bupropion influences the pharmacokinetics of carvedilol (single oral dose) in rats.

Negative association of pretreatment cigarette use with smoking-induced striatal dopamine release in smokers receiving bupropion treatment.

BACKGROUND AND OBJECTIVES: In an effort to help identify factors that maintain heavy smoking, this study tested the association of pretreatment cigarette use (cigarettes per day) with striatal dopamine release during smoking-cessation treatment. METHODS: Thirteen regular smokers (≥10 cigarettes per day) were evaluated on parameters of smoking behavior, and they entered a smoking cessation treatment protocol, including bupropion administration and individual counseling for 2 months. On week 7 of treatment, 10 of the participants underwent brain scans using [(11) C]raclopride with positron emission tomography to assess smoking-induced dopamine release in the caudate nucleus and putamen, inferred from changes in dopamine D2 -type receptor availability. RESULTS: Receptor availability, measured as binding potential referred to non-displaceable uptake (BPND ) in both striatal regions re-demonstrated a significant decrease after smoking a cigarette; and pre-treatment cigarette use significantly negatively correlated with smoking-induced dopamine release in the caudate. CONCLUSIONS AND SIGNIFICANCE: The negative association of cigarette use with dopamine release suggests tolerance or down-regulation of the dopamine system by chronic smoking, or a pre-existing condition that promotes more frequent smoking. This association should be regarded as preliminary evidence that warrants verification. (Am J Addict 2016;25:486-492).

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4ß2 and α6ß2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4ß2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6ß2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4ß2 and/or α6ß2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

Lack of impairment due to confirmed codeine use prior to a motor vehicle accident: role of pharmacogenomics.

BACKGROUND: We examined forensic serum toxicology and pharmacogenomics data from a woman on codeine shortly before she caused a motor vehicle accident. METHODS: A woman driving erratically collided with a parked car of a highway seriously injuring 2 men working to repair the parked vehicle. The woman tested positive for codeine, acetaminophen and barbital. She had been taking these medications for 20 years due to migraine headache. Serum toxicology and genotype analysis for cytochrome P450, UDP glucuronosyltransferase, and other metabolizing enzymes were measured. RESULTS: The woman was tried and convicted of driving under the influence resulting in bodily harm and was sentenced to 6 years. Toxicology results on peripheral blood showed a total and free codeine of 840 and 348 µg/L, respectively, and total morphine of 20 µg/L (17, 3, and 0 µg/L for morphine-3-glucuronide, morphine-6-glucuronide, and free morphine, respectively). She was heterozygous for CYP 2D6 *2/*4 (extensive/poor metabolism) and heterozygous for UGT 2B7 *1/*2 (extensive/ultra-rapid metabolism). The woman was also taking fluoxetine and bupropion which are strong inhibitors of CYP 2D6. CONCLUSIONS: Based on her genotype and phenotype and reports by the arresting officer, we suggest that the subject in question was not intoxicated by opiates at the time of her motor vehicle accident and may have been falsely incarcerated.

Transplantation of human retinal pigment epithelium cells in the treatment for Parkinson disease.

BACKGROUND AND PURPOSE: To assess the clinical effect of transplantation of human retinal pigment epithelial (hRPE) cells into the unilateral postcommissural putamen for treatment for Parkinson disease (PD). METHODS AND RESULTS: Cells from postmortem human eye tissue (10-20 weeks of gestation) were cultured in vitro. Cells from -generation passage were implanted in PD postcommissural putamen with stereotactic operation in 12 patients with PD. All patients tolerated surgery well, and no major adverse events occurred. Eleven patients showed improvement in the primary outcome measure at 3 months post-treatment, particularly the Unified Parkinson's Disease Rating Scale-M score in the off state. Response reached a peak at 12 months and declined during the next 24 months. At the 36-month endpoint, there were eight patients who felt better than at baseline. Positron emission tomography (PET) showed a trend with increased dopamine (DA) release during the first 6 months. CONCLUSION: Human retinal pigment epithelial cells have the characteristics of neural progenitor cells and can be induced to differentiate into DA neurons. The results of this clinical trial suggest that the treatment of transplanted hRPE cells could improve symptoms of PD. These cells might serve as a useful source of DA neurons for neural graft in the treatment for PD.

Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects.

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with (3)H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>10(5)) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

Smoking cessation-recent advances.

BACKGROUND: Smoking continues to be a major contributor to the burden of disease across the world although there has been a decrease in some developed countries such as USA and Australia. In countries of South-East Asia with a high prevalence of smoking, the incidence of tobacco-related diseases will continue to increase. METHODS: We reviewed the literature in relation to the pharmacology of nicotine, the measures used to determine the efficacy of anti-smoking therapies, and the randomised controlled trials and systematic reviews of pharmacotherapies published between 2004 and 2010. We focused primarily on the three first line therapies that are currently available: nicotine replacement therapy (NRT), bupropion and varenicline. RESULTS: Randomised controlled trials and meta-analyses have demonstrated that single therapy with either NRT, bupropion or varenicline are all more effective than placebo for smoking cessation. Abstinence rates for monotherapies varies from 13.3% to 19% for NRT compared to 7.5% to 14% for placebo, 19% to 19.7% for bupropion versus 10.9% to 11% for placebo and 25.5% to 25.6% for varenicline versus 11.2% to 14.8% for placebo. Of current therapies varenicline appears to be more effective at achieving abstinence. Some combination therapies with one or two formulations of NRT or NRT plus bupropion have demonstrated superior results to monotherapy. To date there are no randomised controlled trials of varenicline in combination with NRT or bupropion. CONCLUSION: Further studies are required to address the uncertainty that exists on the most appropriate duration of therapy as well as the effectiveness and safety of combination pharmacotherapy. Post-marketing surveillance continues to play an important role in monitoring the adverse effects events associated with these therapies.

Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice.

Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.

Prospective association of dopamine-related polymorphisms with smoking cessation in general care.

AIMS: Genetic contributions to nicotine dependence have been demonstrated repeatedly, but the relevance of individual polymorphisms for smoking cessation remains controversial. MATERIALS & METHODS: We examined genotypes at two dopamine-related loci, DRD2/ANKK1 (rs1800497) and DBH (rs77905), in 577 heavy smokers participating in a prospective study of smoking cessation in general care in Germany. RESULTS: Smoking status after 1 year was significantly associated with DRD2/ANKK1, odds of abstinence being 4.4-fold (95% CI: 1.5-12.9) increased in TT- versus CC-homozygous subjects (p = 0.008). No effect was observed for the DBH genotype. The smoking cessation drug bupropion appeared to be particularly effective in CC-homozygotes (among CC subjects there was a 28% higher cessation probability among those taking buproprion; among T carrier subjects there was an increase only by 12%). CONCLUSION: The large effects observed for DRD2/ANKK1 might be related to our study design, in which individual therapy was decided by the physician. Further studies are needed to clarify the genetic effects of DRD2/ANKK1 especially in 'real-life' settings outside clinical trials.

Transplacental transfer and metabolism of bupropion.

OBJECTIVE: In order to evaluate the potential use of bupropion as smoking cessation therapy during pregnancy, the aim of this investigation was to determine transplacental transfer and metabolism of bupropion and its distribution among placental tissue and maternal and fetal circuits of the dually perfused placental lobule. METHODS: Placentas obtained from healthy term pregnancies were perfused with bupropion at two concentrations 150 ng/ml and 450 ng/ml, along with the marker compound antipyrine 20 microg/ml. Radioactive isotopes of the two drugs were co-transfused to enhance their detection limits. Concentrations of bupropion and its metabolite were determined by liquid chromatography and liquid scintillation spectrometry. RESULTS: The fetal/maternal concentration ratio of bupropion was 1.07 +/- 0.22. Following 4 h of its perfusion, 48 +/- 6% of bupropion was retained by placental tissue, 32 +/- 5% remained in the maternal circuit, and 20 +/- 6% was transferred to the fetal circuit. A metabolite of bupropion, threohydrobupropion, was identified. CONCLUSIONS: Bupropion was transferred from the maternal to fetal circuit and was biotransformed by placental tissue enzymes to its metabolite threohydrobupropion. Bupropion and its metabolite did not affect placental tissue viability or functional parameters. These data suggest that bupropion has the potential of being used for smoking cessation during pregnancy and should be further investigated for its safety and efficacy.

Progesterone attenuates cocaine-induced responses.

In this review, we summarize literature focused on how progesterone alters cocaine-induced psychomotor, reinforcement, and physiological responses. Clinical studies suggest that progesterone attenuates the subjective effects of cocaine. Similarly, preclinical studies have demonstrated that cocaine-induced reward and psychomotor responses are attenuated after progesterone administration. In rats progesterone also reduces the reinforcement effects of cocaine attenuates acquisition, escalation, reinstatement of cocaine self-administration, and cocaine-seeking behaviors. Progesterone also counteracts the facilitatory effects of estrogen on cocaine self-administration and psychomotor activation. These findings suggest that progesterone has a potential in clinical applications as a treatment for cocaine addiction. Constantly changing progesterone serum levels in female humans and rats affect the female's reinforcement responses to cocaine and may in part contribute to the known sex differences in cocaine responses.

Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

Stimulant abuse continues to be a growing problem among women. Over the last 10-15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics.

Transdermal delivery of bupropion and its active metabolite, hydroxybupropion: a prodrug strategy as an alternative approach.

This investigation includes an evaluation of the percutaneous absorption of bupropion (BUP) and hydroxybupropion (BUPOH) in vitro and in vivo. In addition, a carbamate prodrug of BUPOH (But-BUPOH) was evaluated in vitro. In vitro diffusion studies were conducted in a flow-through diffusion cell system. The in vitro mean steady-state flux of BUP was significantly higher (p < 0.001) compared to BUPOH (320 +/- 16 nmol cm(-2) h(-1) vs. 27 +/- 4 nmol cm(-2) h(-1)). Additionally, a good correlation existed between in vitro and in vivo results. Mean steady-state plasma concentrations of 442 +/- 32 ng/mL and125 +/- 18 ng/mL were maintained over 48 h after topical application of BUP and BUPOH in hairless guinea pigs in vivo, respectively. Although BUP traversed human skin at rates sufficient to achieve required plasma levels, it is chemically unstable and hygroscopic, and unsuitable for transdermal formulation. On the other hand, BUPOH is stable but its transport across skin is much slower. Alternatively, the prodrug But-BUPOH was found to be stable, and also provided a 2.7-fold increase in the transdermal flux of BUPOH across human skin in vitro. Thus, But-BUPOH provides a viable option for the transdermal delivery of BUPOH.

Smoking cessation therapy considerations for patients with chronic kidney disease.

Cigarette smoking is a readily modifiable cardiovascular and chronic kidney disease (CKD) risk factor. Smoking cessation aids include nicotine replacement therapy (NRT), bupropion, and varenicline. Several reports suggest that patients with CKD who use tobacco products be encouraged to stop; however, very little is offered to the healthcare provider as to how to successfully prescribe and monitor smoking cessation therapy for this patient population. This article reviews NRT, bupropion, and varenicline pharmacokinetics and dosing literature for patients with CKD. Evidence for the benefit of smoking cessation in patients with CKD is also reviewed.

The binding sites for cocaine and dopamine in the dopamine transporter overlap.

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.

Rhabdomyolysis associated with bupropion use as a smoking cessation adjunct: review of the literature.

A case of rhabdomyolysis associated with a therapeutic dose of bupropion sustained release is presented. Other features of the use of bupropion are also discussed.

Genetics and smoking cessation improving outcomes in smokers at risk.

This article reviews evidence supporting the potential utility of a pharmacogenetic approach to the treatment of nicotine dependence. There is substantial evidence that nicotine dependence and smoking persistence are heritable, and are determined by a complex interplay of polygenic and environmental influences. The most robust evidence for specific genetic influences on nicotine dependence is found in studies of genetic variation in nicotine-metabolizing enzymes. Data also support the role of genes in the dopamine and opioid pathways as predictors of dependence and smoking relapse; however, the evidence for genetic associations is not always consistent. Emerging data from pharmacogenetic trials of nicotine-dependence treatment are promising, suggesting that genetic profiles of smokers someday may be used by providers to choose the type, dose, and duration of treatment for individual smokers. However, additional trials including larger and more diverse populations are needed before such data can be translated to practice to reduce smoking prevalence and tobacco-related disease.

Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity.

AIM: The aim of this study was to investigate the activity of the drug-metabolizing enzyme cytochrome P450 (CYP) 2B6 before and after in vivo induction by rifampin (INN, rifampicin) in white subjects and Chinese subjects by use of the probe drug bupropion (INN, amfebutamone). METHODS: Healthy male white subjects (n = 9) and Chinese subjects (n = 9) (age range, 19-34 years) of known CYP2B6 genotype received orally administered bupropion (Zyban SR, 150 mg) alone and during daily treatment with rifampin (600 mg). Blood samples were taken for up to 72 hours after each bupropion dose, and plasma concentrations of bupropion and its active metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, were measured by HPLC. The subjects' CYP2B6 genotype was determined by use of a matrix-assisted laser desorption /ionization-time of flight (MALDI-TOF) mass spectrometry assay. RESULTS: Rifampin treatment increased the apparent clearance of bupropion in Chinese subjects and white subjects combined (n = 16) from 2.6 L x h(-1) x kg(-1) (95% confidence interval [CI], 2.3-3.0 L x h(-1) x kg(-1)) after bupropion alone to 7.9 L x h(-1) x kg(-1) (95% CI, 6.8-10.1 L x h(-1) x kg(-1)) during rifampin treatment. Rifampin treatment decreased the half-life of bupropion from 15.9 hours (95% CI, 13.5-20.4 hours) to 8.2 hours (95% CI, 6.7-12.4 hours). Rifampin treatment increased the hydroxybupropion maximum concentration from 395 ng/mL (95% CI, 341-497 ng/mL) to 548 ng/mL (95% CI, 490-638 ng/mL), decreased the area under the concentration-time curve extrapolated to infinity of hydroxybupropion from 14.7 microg x h/mL (95% CI, 12.7-18.4 microg x h/mL) to 8.4 microg x h/mL (95% CI, 7.4-10.2 microg x h/mL), and reduced the elimination half-life of hydroxybupropion from 21.9 hours (95% CI, 20.3-24.0 hours) to 10.7 hours (95% CI, 8.6-14.5 hours). There was no significant difference in the pharmacokinetics of bupropion or hydroxybupropion between white subjects and Chinese subjects before and after treatment with rifampin, once corrected for body weight. CONCLUSIONS: Rifampin significantly induces CYP2B6 activity in vivo, and the clinical consequences of potential interactions between rifampin and CYP2B6 substrates deserve further investigation. Rifampin appears to induce the elimination of hydroxybupropion. Differences in bupropion pharmacokinetics that were observed between white subjects and Chinese subjects can be attributed to differences in body weight, suggesting that, for a given subject weight, CYP2B6 activity is similar in white subjects and Chinese subjects.