Alcohol Co-administration Research Articles

Adolescent alcohol binge drinking and withdrawal: behavioural, brain GFAP-positive astrocytes and acute methamphetamine effects in adult female rats

RationaleAlcopop beverages are generally the first alcoholic beverage that young females drink which contain high levels of sugar and alcohol. The over-consumption of these drinks may encourage alcohol co-administration with methamphetamine (METH) impacting on drinking behaviour and glial function.AimsThe aims of this study were to evaluate the effect of adolescent binge alcohol exposure on consumption level, anxiety-like behaviour, cross-sensitization with METH and on astrocyte expression in reward related brain regions.MethodsAdolescent female Sprague-Dawley rats had daily 1-hour oral alcohol consumption of alcopop (ALCP; with sucrose) or ethanol-only (ETOH; without sucrose), transitioned from 5 to 15% (v/v) ethanol content for 34 days. Water and sucrose groups act as controls. During alcohol withdrawal, rats were tested for anxiety on the elevated plus maze (EPM) and locomotor activity following saline or METH (1 mg/kg i.p) treatment. Brains were then collected to assess astrocyte immunofluorescence for glial fibrillary acidic protein (GFAP) in reward-related brain regions.ResultsRats pretreated with 5% ALCP consumed significantly more volume and ethanol intake when compared to 5% EtOH rats. Both ALCP and EtOH groups had a higher preference ratio for 5% than 15% alcohol solutions and ALCP rats had greater ethanol intake at 15% than EtOH rats. Alcohol withdrawal showed no significant differences between groups on anxiety, METH cross-sensitization effects or GFAP intensity in the regions studied.ConclusionsOverall, the addition of sucrose to alcoholic solutions encouraged female rats to consume larger volumes and greater ethanol intake compared to ethanol-only solutions, yet did not have long lasting effects on behaviour and astrocytes.

Nicotine alleviates alcohol-induced memory and long-term potentiation impairment

Alcohol and nicotine are routinely abused together. There is one plausible explanation that comorbidity can alleviate alcohol-induced cognitive impairment. However, the mechanism involved is not known. The aim of this report was to evaluate the interactive effects of alcohol coadministration with nicotine on hippocampal memory and long-term potentiation (LTP). C57BL/6 mice were distributed into 4 treatment groups: control, alcohol, nicotine, and alcohol plus nicotine. All mice received tap water or alcohol solution and saline or nicotine. In water maze test, the alcohol group showed significant decreases in hippocampus function and acquisition training than control, nicotine, and combined treatment groups. The alcohol group also showed a significantly shorter latency in entering the foot-shock compartment than control, nicotine, and combined treatment groups in a passive avoidance test. Theta burst stimulation was adopted to induce concrete LTP in CA1 field recording using hippocampal slice. Alcohol alone administration failed to maintain LTP. Nicotine alone administration did not alter hippocampal LTP. There were no negative effects of alcohol on hippocampal LTP in mice administrated with nicotine. The current study successfully demonstrated beneficial effects of nicotine on alcohol induced memory impairment accompanied by hippocampal LTP impairment after one week of co-administration and one-day withdrawal.

Effect of alcohol coadministration on the pharmacodynamics, pharmacokinetics, and safety of lemborexant: A randomized, placebo-controlled crossover study.

Background:Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan.Aims:This study was conducted to investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant.Methods:This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory.Results:Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment–emergent adverse event was somnolence.Conclusion:Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant.

Effects of alcohol on metabolism and toxicity of cocaine in rats

As most cocaine users drink alcohol, it is interesting to understand how a non-lethal dose of alcohol affects the metabolism and toxicity of cocaine. In this study, we examined the correlation between dose-dependent toxicity and the metabolism/pharmacokinetic (PK) profile of cocaine with or without alcohol (ethanol, 1 g/kg) co-administration in rats. The cocaine toxicity in rats with or without alcohol co-administration is characterized by not only the commonly used LD50, but also the average times for the appearance of convulsion and death as well as total toxicity level (TTL) in the blood. All these data have consistently demonstrated that co-administration of alcohol increased cocaine toxicity, and that the alcohol-enhanced toxicity of cocaine is mainly attributed to the observed two additional metabolites (cocaethylene and norcocaethylene – products of chemical reactions of cocaine with alcohol catalyzed by metabolic enzymes carboxylesterase-1 and liver microsomal cytochrome P450 3A4) that are more toxic than cocaine itself. So, evaluation of the substance TTL should account for the blood levels of not only cocaine itself, but also its all toxic metabolites. In addition, for rats died of a lethal dose of cocaine (60 or 100 mg/kg) combined with 1 g/kg alcohol, we also determined the TTL at the time of death, demonstrating that death would occur once the TTL reached a threshold (~16 μM).

Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity.

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.

Reducing alcohol and/or cocaine-induced reward and toxicity via an epidermal stem cell-based gene delivery platform

Alcohol use disorder (AUD) is one of the foremost public health problems. Alcohol is also frequently co-abused with cocaine. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse. We recently demonstrated that skin grafts generated from mouse epidermal stem cells that had been engineered by CRISPR-mediated genome editing could be transplanted onto mice as a gene delivery platform. Here, we show that expression of the glucagon-like peptide-1 (GLP1) gene delivered by epidermal stem cells attenuated development and reinstatement of alcohol-induced drug-taking and seeking as well as voluntary oral alcohol consumption. GLP1 derived from the skin grafts decreased alcohol-induced increase in dopamine levels in the nucleus accumbens. In exploring the potential of this platform in reducing concurrent use of drugs, we developed a novel co-grafting procedure for both modified human butyrylcholinesterase (hBChE)- and GLP1-expressing cells. Epidermal stem cell-derived hBChE and GLP1 reduced acquisition of drug-taking and toxicity induced by alcohol and cocaine co-administration. These results imply that cutaneous gene delivery through skin transplants may add a new option to treat drug abuse and co-abuse.

Neurotoxicity of fluoride in ethanol fed rats: Role of oxidative stress, mitochondrial dysfunction and neurotransmitters

Prolonged exposure to fluoride or alcohol affects brain. However, the understanding about their interactions and neurotoxicity following co-exposures is still poor. The present study was designed to assess oxidative stress, mitochondrial dysfunctions, acetylchonlineterase (AChE) activity, neurotransmitter levels and morphological alterations in brain of fluoride or/and ethanol fed rats. Six and eighteen month old animals received sodium fluoride (NaF, 25 mg/kg) and 30% ethanol (EtOH, 1 mL/kg) individually and in combination for 90 days. Brain showed elevation in oxidative stress with age and NaF/EtOH treatment. There was increased lipid peroxidation; decreased glutathione, total and protein thiol content; along with declined activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase under these conditions. Mitochondrial functions were impaired significantly with age and NaF/EtOH treatment. The activities of NADH dehydrogenase, succinate dehydrogenase and cytochrome c oxidase along with mitochondrial respiration rate were decreased whereas the levels of nitric oxide and citrulline were increased in treated animals. Administration of NaF/EtOH showed altered neurotransmitter levels and increased AChE activity in brain. The levels of dopamine and 5-hydroxytryptamine were decreased while 5-hydroxyindoleacetic acid and homovanillic acid were increased significantly. Histological examination showed morphological alterations in treated animals compared to controls. Interestingly, the observed effects were more pronounced in rats co-exposed to NaF and EtOH. It is concluded that neurotoxic effects of fluoride are age dependent and further amplified by alcohol co-administration. These effects are mediated through elevated oxidative stress, mitochondrial dysfunctions and impaired neurotransmitter functions

Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. Clinicaltrials.govNCT02039349.This article is part of the special issue on ‘Neuropeptides’.

Effects of cannabidiol on alcohol-related outcomes: A review of preclinical and human research.

Increased access to medicinal and recreational cannabis will be accompanied by greater exposure to its chemical constituents, including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the primary nonpsychoactive compound. Increasing attention has focused on CBD, in part, due to its potential therapeutic properties. Relatively little is known about how CBD might interact with other commonly used drugs. While a number of studies have explored the influence of cannabis or Δ9-THC on alcohol consumption and treatment outcomes, few have examined the effects of CBD on alcohol-related outcomes. This article reviews preclinical and human studies examining the effects of CBD administration on alcohol responses. Preliminary preclinical results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage. Also reviewed herein are the few existing studies involving CBD and alcohol coadministration in humans. The paucity of such studies precludes any definitive conclusions relating to CBD-alcohol interactions. Effects of CBD on alcohol use and potential therapeutic implications for alcohol use disorder are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A Critical Review of the Effects of Nicotine and Alcohol Coadministration in Human Laboratory Studies.

Simultaneous use of cigarettes and alcohol is common and may be driven by nicotine increasing alcohol self-administration or vice versa. To better evaluate the causal nature of this relationship, we systematically reviewed human experimental laboratory studies that coadministered nicotine and alcohol with control conditions. Searches of PubMed/MEDLINE and PsycINFO databases and study bibliographies identified 30 studies that met our inclusion criteria. Research methodologies were critically reviewed. Effects of coadministration on drug self-administration and related factors such as craving, subjective response, motivation, and heart rate are reported. Results most strongly supported that alcohol increases nicotine and cigarette self-administration, whereas, depending on the context, nicotine increased, decreased, or had no effect on alcohol self-administration. Craving and subjective drug effects were also impacted by coadministration. Interaction effects of nicotine and alcohol on self-administration and subjective responses were reported infrequently. The effects may be moderated by a number of factors, including dose of administered drug and sex. Recommendations are made for future research, and clinical and policy implications of findings are discussed.

Benefits of Alcohol on Arsenic Toxicity in Rats.

It has been demonstrated earlier that exposure to ethanol and/or arsenic compounds (such as sodium arsenite) produces toxic effects as shown by both in vitro and in vivo experiments. Chronic exposure of humans to arsenic through drinking water, pesticides or consumption of alcoholic beverages has produced major health problem and concern in recent years. Water being one of the main ingredients for alcohol formation (beer fermentation process) can lead to contamination with arsenic. Thus, people consuming such alcohol are getting continuously exposed to arsenic compounds as well along with alcohol. The present study was undertaken to investigate the effect of alcohol co-administration on arsenic induced changes in carbohydrate metabolic status in adult male albino rats. Adult male albino rats of Wistar strain (weighing~100g) were divided into three groups (n=8 rats/group) including Control or vehicle treated (C), Arsenic treated (As) and Arsenic treated alcohol co-exposed (As+Alc). Treatment with Sodium-arsenite included intra-peritoneal injection consecutively for 14 days at a dose of 5.55 mg/kg (equivalent to 35% of LD50) per day. Absolute alcohol (15% v/v) was fed at a dose of 0.5 ml/100 g body weight per day for five consecutive days from start of the treatment schedule. Distilled water (D/W) was used as vehicle. Blood Glucose (BG) level, levels of glycogen, Pyruvic Acid (PA), Free Amino Acid Nitrogen (FAAN), total protein, Glutamate Oxalate transaminase (GOT) and Glutamate Pyruvate Transaminase (GPT) activity, and glucose-6-phosphatase (G6Pase) activity were measured in tissues including liver, kidney and muscle. Treatment with arsenic decreased the levels of BG, liver glycogen and PA, tissue protein and G6Pase activity, GOT activity in liver and muscle, and increased free amino acid content in kidney and muscle, GPT activity in liver and kidney. Alcohol administration to rats co-exposed to arsenic treatment reversed these changes. Thus, it is suggested that combined administration of alcohol with arsenic can result in the suppression of the down-regulating action of arsenic on glucose homeostasis as evidenced by its hypoglycaemic effect and increased gluconeogenesis and transamination in liver.

A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration.

Alcohol and nicotine are often co-abused. Although the N/OFQ-NOP receptor system is considered a potential target for development of drug abuse pharmacotherapies, especially for alcoholism, little is known about the role of this system in nicotine dependence. Furthermore, the effect of prior history of nicotine dependence on subsequent nicotine and alcohol taking is understudied. Using an operant co-administration paradigm, in which rats concurrently self-administer nicotine and alcohol, we found that nicotine dependent rats increased nicotine self-administration over time as compared to non-dependent animals, while patterns of alcohol lever pressing did not change between groups. Pretreatment with the potent NOP receptor agonist AT-202 (0.3–3 mg/kg) increased nicotine lever pressing of both dependent and non-dependent groups, whereas the selective antagonist SB612111 (1–10 mg/kg) elicited a clear reduction of nicotine responses, in both dependent and non-dependent rats. In parallel, AT-202 only produced minor changes on alcohol responses and SB612111 reduced alcohol taking at a dose that also reduced locomotor behavior. Results indicate that a history of nicotine dependence affects subsequent nicotine- but not alcohol-maintained responding, and that NOP receptor antagonism, rather than agonism, blocks nicotine self-administration, which strongly suggests a critical role for the endogenous N/OFQ in the modulation of nicotine reinforcement processes.

Patterns and Effects of Alcohol and Psychostimulant Co-administration: a Brief Review of Pharmacological Considerations and Subjective Responses

Alcohol is commonly used with various illicit and prescription drugs that have psychostimulant properties, but the reasons for this remain incompletely understood. Evidence from community samples of drug users suggest that when alcohol is co-administered with many psychostimulant drugs, its initial use typically precedes the onset of psychostimulant use and that co-administration is often associated with increased alcohol consumption. There is growing experimental evidence that alcohol and psychostimulant co-administration can result in significant pharmacological interactions as well as in the production of positive subjective effects but that the specific nature of the interactions may depend on factors such as the orders, routes, and doses of the substances administered. In this paper, we aim to review similarities and differences in the effects of alcohol co-administration with the psychostimulants cocaine, amphetamine, methylphenidate, and 3,4-methylenedioxymethamphetamine (MDMA) and to link these to their patterns of use by drug users in the natural environment.

Energy drink co‐administration is associated with increased reported alcohol ingestion

While energy drinks (EDs) and alcohol have been reported to be frequently co-administered, little is known about the effect of this co-administration on alcohol drinking patterns. The purpose of the present research was to characterise patterns of ED and alcohol co-administration. Seventy-two ED users were recruited from the Halifax university community. Participants provided information about their lifetime ED and other substance use, in addition to detailing instances of their ED and alcohol use during the previous week using a timeline follow-back interview. Seventy-six per cent of participants reported ever deliberately mixing alcohol with EDs and 19% reported doing so during the previous week. Relative to alcohol drinking sessions in which EDs were not used, participants reported drinking significantly more alcohol when it was co-administered with EDs. Alcohol and ED co-administration is relatively common among ED users and seems to be associated with increased alcohol ingestion. It is recommended that this matter receive more clinical and research attention.

Effects of desloratadine and alcohol coadministration on psychomotor performance

ABSTRACTObjective: This study was set up to evaluate the effects of desloratadine 7.5 mg daily, with and without alcohol, on sedation and psychomotor performance.Research methods: In a double-blind, placebo-controlled, four-way crossover trial, 25 adult patients were randomized to desloratadine 7.5 mg, desloratadine 7.5 mg plus alcohol, placebo, or placebo plus alcohol. Alcohol was weight adjusted to an average blood alcohol concentration of 0.1%. Assessments included the modified Romberg test, Stanford Sleepiness Scale, Digit Symbol Substitution Test, Serial Add Subtract Reaction Time Test, and the Psychomotor Vigilance Test. The primary variable was the mean score of each of the five tests averaged over the treatment period, expressed as the mean percent change from baseline.Results: Across these assessments, differences between desloratadine alone or with alcohol versus placebo alone or without alcohol, were not significant, whereas most differences between desloratadine and placebo alone versus desloratadine and placebo with alcohol were significant ( p < 0.01). Thus, with or without alcohol, desloratadine 7.5 mg does not increase sedation or impair psychomotor performance. Most adverse events (AEs) were mild-to-moderate in severity, with the most frequently reported individual AEs being headache, fatigue, nausea, vomiting, and dry mouth. The study does have potential limitations. The measures used are restricted to a particular profile of the known effects of alcohol only, and the relatively high doses of alcohol used alone demonstrate effects on psychomotor function and attention.Conclusions: A single dose of desloratadine does not potentiate alcohol-mediated CNS impairment. Desloratadine alone or in combination with alcohol was safe and well tolerated.

The effect of nicotinic acid and alcohol co-administration in Wistar rats

The effects of co-administration of nicotinic acid (NA) and alcohol (Alc) on liver function in male Wistar rats were evaluated. The rats were randomized into five groups: (i) Olive oil (Oil), (ii) Alc+Oil, (iii) NA+Oil, (iv) NA+Alc+Oil, and (v) Controls (fed only normal rat chow). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), total cholesterol and triglycerides (TG) were measured. Liver histopathology was also assessed. The Alc+Oil group had higher TG levels compared with the NA+Alc+Oil group and all other groups, as well. NA+Oil group had higher levels of AP compared with Alc+Oil and Oil groups. The NA+Oil group had higher ALT levels compared with the Oil group. The Oil group had lower ALT levels compared with the control group. The Alc+Oil group had higher AST levels compared with the NA+Alc+Oil group, as well as with all other groups. Liver histopathology was within the normal range. A moderate amount of Alc daily together with NA is safe in rats. The NA and Alc co-administration reduces the TG and AST levels in rats, compared with the administration of Alc alone.

M.561 The effect of alcohol and Gemfibrozil co-administration in Wistar rats

M.561 The effect of alcohol and Gemfibrozil co-administration in Wistar rats

M.561 The effect of alcohol and Gemfibrozil co-administration in Wistar rats

M.561 The effect of alcohol and Gemfibrozil co-administration in Wistar rats

Interactive effects of nicotine and alcohol co-administration on expression of inducible transcription factors in mouse brain.

Nicotine and alcohol are abused substances that are often used concurrently. Despite their combined usage, little is known about how they interact to produce changes in behavior and neural activity. Two experiments were conducted to identify interactions on both behavior and neural targets resulting from the co-administration of nicotine and alcohol. In Experiment 1, male C57BL/6J mice were administered saline, alcohol (2.4 g/kg, i.p.), nicotine (0.5 mg/kg, i.p.) or an alcohol/nicotine mixture and returned to their home cage. In Experiment 2, a higher dose of nicotine (1.0 mg/kg, i.p.) was included and animals were exposed to a novel environment. Several behavioral measures were analysed during novelty exposure. Immunohistochemical detection of inducible transcription factors (c-Fos and Egr1) was used in both experiments to identify changes in neural activation. Behavioral results suggested that the drugs were interacting in the production of behaviors. In particular, alcohol produced locomotor stimulation while it suppressed counts of rearing and leaning. When co-administered, nicotine appeared to counteract the alcohol-enhanced locomotor activity. Several brain regions were observed to have altered transcription factor expression in response to the different drug treatments, including amygdalar, hippocampal and cortical subregions. In a subset of these brain areas, nicotine and alcohol counteracted one another in the expression of transcription factors. These results identify several interactive target sites within the hippocampus, extended amygdala and cortical regions. The interactions appear to be a result of antagonizing actions of nicotine and alcohol. Finally, the results suggest that the combined use of nicotine and alcohol may offset the effects of the drug administered independently.

Cocaine and alcohol interactions in the rat: Effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics

This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatments for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and alcohol+cocaine (10% v/v in drinking water+15 mg/kg/day ip). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC–UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-Emax model was used to describe the brain cocaine concentration–neurochemical effect (dopamine) relationship, and an indirect phar-macodynamic response model was used to describe the plasma cocaine concentration–cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUCp, αt1/2, and βt1/2. Cocaine pretreatment significantly increased cocaine bioavail-ability, absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUCp and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the Emax for dopamine, with no effect on the EC50. Acute alcohol coadministration with cocaine significantly increased the Emax for dopamine and reduced the EC50. Cocaine pretreatment significantly decreased the Imax for blood pressure, IC50, and Rmax. For the heart rate response, both alcohol and cocaine pretreatments significantly increased the IC50, with no effect on Imax. These results indicate that both cocaine and alcohol pretreatments as well as acute alcohol coadministration lead to significant alterations in cocaine pharmacodynamics that are due, at least in part, to the changes in cocaine pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol abusers may respond differently to cocaine administration compared to naïve users and may be at higher risks of cocaine central nervous system toxicity.