Subjective and cardiovascular effects of cocaethylene in humans

Preclinical studies have shown cocaethylene (the ethyl ester of benzoylecgonine) to produce pharmacologic effects of similar magnitude to those of cocaine. These observations, however, cannot establish whether or not cocaethylene produces cocaine-like subjective effects. We report the results of experiments in which three healthy male, paid volunteers were intravenously injected with the water soluble fumarate salt of cocaethylene in escalating doses. Subjective effects and cardiovascular parameters were the dependent variables. The maximal dose of cocaethylene base administered (0.25 mg/kg) produced subjective effects that were judged as milder and tachycardic effects that were comparable to those produced by the intravenous injection of an equivalent dose (0.25 mg/kg) of cocaine base.     

Cocaine and cocaethylene: Effects on extracellular dopamine in the primate

Cocaine and cocaethylene (a psychoactive metabolite of concurrent cocaine and ethanol consumption) were studied in the anesthetized vervet monkey. The ability of each to elevate extracellular DA in the caudate nucleus was assessed using microdialysis probes acutely lowered through chronic guide cannulae. Blood samples were also collected to determine plasma levels of the two drugs. Doses of 1.5 µmol/kg cocaine (equivalent to 0.5 mg/kg cocaine-HC1) and cocaethylene were administered intravenously. Microdialysis and blood samples were collected at 5-min intervals immediately following drug administration. Both drugs caused a maximal four-fold increase in extracellular DA during the 5- to 10-min period following drug administration. This is the first report of cocaine (and cocaethylene) induced alterations in extracellular DA in primates. The abilities of cocaine and cocaethylene to produce euphoria are being compared in ongoing clinical research studies. The potential use of these results for interpreting the neurochemical basis of any differences in those studies is discussed.     

Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine

Cocaethylene (the ethyl ester of benzoylecgonine) is a product of the interaction between ethanol and cocaine. The results of preclinical studies and of a pilot clinical study have shown cocaethylene to produce pharmacologic effects similar to those of cocaine. However, no information is available concerning the potency and pharmacokinetics of cocaethylene in comparison to those of cocaine in humans. We report the results of a single-blind, crossover study in which six male, healthy, paid volunteers, who were moderate users of cocaine, were intravenously injected with the water soluble fumarate salt of cocaethylene (0.25 mg/kg cocaethylene base) or an equivalent dose of the water soluble hydrochloride salt of cocaine (0.25 mg/kg cocaine base). Each dose was dissolved in normal saline and injected over a 1-min interval. Test sessions were separated by a 1-week interval. The variables measured were: cocaine and cocaethylene plasma concentrations, subjective and cardiovascular effects. The results indicate, that in comparison to cocaine, cocaethylene had a significant smaller elimination rate constant (0.42 versus 0.67 l/h), had a longer elimination half-life (1.68 versus 1.07 h), and induced ratings of high and changes in heart rate that were of lower magnitude (65%, and 43%, respectively). During the period of time that pharmacologic effects were present the plasma concentrations of cocaine and cocaethylene were statistically indistinguishable. This finding supports the conclusion that in humans cocaethylene is less potent than cocaine.     

Comparison of intravenous cocaethylene and cocaine in humans

Rationale: Cocaethylene is a pharmacologically active homolog and metabolite of cocaine, formed by transesterification of cocaine in the presence of ethanol. Here we relate findings from a randomized, placebo-controlled, double-blind study in which we examined the physiological and subjective effects and pharmacokinetics of IV administered cocaethylene in human volunteers using cocaine as a comparator. Methods: Cocaine-dependent participants randomly received one study drug, cocaethylene (0.25 or 0.5 mg/kg), cocaine (0.25 or 0.5 mg/kg), or placebo, during each experimental session which occurred on separate days. Results: Cocaethylene was less potent in elevating heart rate than equivalent doses of cocaine. Similar differences between cocaine and cocaethylene were found for subjective measures (”Cocaine High”, ”Rush”, ”Stimulated” and ”Good Drug Effects”). All active drug conditions produced significant increases in systolic blood pressure relative to placebo, but no significant effect on diastolic blood pressure was observed. Cocaethylene demonstrated a slower clearance, larger volume of distribution and correspondingly longer elimination half-life than cocaine. Conclusion: The findings from this study confirm those of previous studies that show that cocaethylene has pharmacological properties in common with cocaine, but is less potent. Received: 15 July 1999 / Final version: 23 November 1999     

Differences in bioavailability between cocaine and cocaethylene and their implications for drug-reward studies

Cocaethylene, a psychoactive metabolite resulting from combined ethanol/cocaine consumption, is of interest because its psychostimulant properties may partially underlie combined cocaine/ethanol use, and because it has the potential for use as a probe of drug reward mechanisms due to its enhanced selectivity at monoamine uptake sites compared to cocaine. To determine the relative systemic bioavailabilities of cocaine and cocaethylene, sequential plasma samples were obtained from awake rats following drug administration. Following intravenous administration of 3 µmol/kg (molar equivalent of 1 mg/kg cocaine-HCl), both drugs achieved similar time courses and areas under the plasma concentration versus time curve. In contrast, intraperitoneal administration of 44 µmol/kg (molar equivalent of 15 mg/kg cocaine HCl) showed peak plasma levels, and the area under the plasma concentration vs time curve for cocaine to be approximately twice that for cocaethylene. Comparison of dose corrected areas under the curve of the two routes of administration for each drug indicated that relative systemic bioavailability of cocaethylene following intraperitoneal administration is only 58% that of cocaine. In addition, the elimination of both cocaine and cocaethylene was found to be slower following intraperitoneal administration compared to the intravenous route. The implications of these results are discussed with respect to the relative potency of these two compounds, as inferred from behavioral, drug reward, and lethality studies. Also, the differences noted will need to be taken into account when making mechanistic interpretations from comparative drug reward studies.     

Interest for delivery of cocaethylene in a sustained release emulsion vs saline evaluated on behavioral sensitization in naive and cocaine-sensitized mice

Rationale

Repeated administration of psychostimulant elicits behavioral sensitization, characterized by an augmented locomotor response to a subsequent challenge injection. This sensitization is paralleled by neural adaptations. Evidences suggest that the rate at which drugs of abuse are delivered to the brain play a key role in this plasticity. Cocaethylene is a pharmacologically active homolog of cocaine, known to have a pharmacokinetic profile different to that of cocaine.

Objectives

Utilizing locomotor sensitization, we evaluated the consequences of the administration of cocaethylene in a rapid- and slow-onset formulation, in naïve and cocaine-sensitized mice.

Materials and methods

We investigated the development of sensitization after repeated administration of cocaine and cocaethylene and the effects of cocaethylene in animals previously exposed to cocaine. Cocaethylene was dissolved in two vehicles (saline and emulsion).

Results

As observed with cocaine, chronic cocaethylene treatment in saline induced a behavioral sensitization, while in a sustained release emulsion, no behavioral sensitization was observed. Moreover, the expression of the sensitized behavior observed in cocaine-treated mice was reduced or totally abolished after cocaethylene administration in saline and emulsion, respectively. Interestingly, administration of cocaine in mice chronically treated with cocaethylene in saline induced an increase in locomotor activity as compared to control animals. In contrast, no difference was observed after the administration of cocaine in animals chronically treated with cocaethylene in emulsion or control group.

Conclusions

Cocaethylene in a sustained release emulsion blocked locomotor sensitization. These results suggest that cocaethylene, in a specific galenic preparation, such as gum, may be an efficacious harm-reduction alternative to cocaine users.

     

Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. Objective: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. Methods: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed. Received: 22 January 1999 / Final version: 16 April 1999     

The pharmacology of cocaethylene in humans following cocaine and ethanol administration

BACKGROUND: Concurrent use of cocaine and alcohol results in formation of a cocaine homolog and metabolite-cocaethylene. METHODS: To characterize cocaethylene pharmacology, ten paid volunteer subjects were given deuterium-labeled (d(5)) cocaine (0.3, 0.6, and 1.2 mg/kg and cocaine placebo) by a 15-min constant rate intravenous injection 1 h after a single oral dose of ethanol (1 g/kg) or ethanol and cocaine placebo using a double-blind, crossover design. Six of the same volunteers subsequently received a 1.2 mg/kg dose of cocaine alone. A small (7.5 mg) nonpharmacologically active dose of deuterium-labeled cocaethylene-d(3) was concurrently administered with the cocaine to enable calculation of absolute cocaethylene formation and clearance. Plasma and urine cocaine, cocaethylene, and benzoylecgonine concentrations, physiologic and subjective effects were measured. RESULTS: When co-administered with ethanol, 17+/-6% (mean+/-S.D.) of the cocaine was converted to cocaethylene. Cocaethylene peak plasma concentrations and AUC increased proportionally to the cocaine dose. Ethanol ingestion prior to cocaine administration decreased urine benzoylecgonine levels by 48% and increased urinary cocaethylene and ecgonine ethyl ester levels. Subjects liked and experienced more total intoxication after the combination of cocaine and ethanol than after either drug alone. CONCLUSIONS: In the presence of ethanol, the altered biotransformation of cocaine resulted in 17% of an intravenous cocaine dose being converted to cocaethylene and relatively lower urinary concentrations of benzoylecgonine.     

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys

 A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine’s reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine’s, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine’s reinforcing potency, but there appear to be individual differences with respect to ethanol’s ability to stimulate rates of drug-maintained responding. Received: 24 April 1996 / Final version: 7 November 1996     

Isoprostanes as a biomarker of lipid peroxidation in humans: physiology,pharmacology and clinical implications

Isoprostanes are a complex family of compounds produced from arachidonic acid via a free-radical-catalyzed mechanism. They can be quantified as reliable markers of lipid peroxidation. Among the isoprostanes, 15-F(2t)-IsoP and 15-E(2t)-IsoP are biologically active and mediate vasoconstriction and bronchoconstriction and augment nociception. These effects are thought to be mediated via the activation of prostanoid TP receptors, with isoprostanes acting as full or partial agonists. A strong link between lipid peroxidation and diseases associated with ischaemia-reperfusion, atherosclerosis and inflammation has been suggested by elevated levels of F(2)-isoprostanes observed in such diseases. Thus, quantification of F(2)-isoprostanes as a pathophysiological marker provides a unique opportunity to investigate lipid peroxidation in human diseases and provides an interesting biomarker for rational dose selection of antioxidants in diseases where oxidative stress might be involved.     

Influences of ethanol ingestion on olfactory function in humans

Rationale Although ethanol is known to influence, in humans, psychophysical measures of visual, auditory, and vestibular function, the influence of this drug on the ability to smell is not clear.Objectives To evaluate, in eight men and eight women, the influences of ethanol ingestion on four well-validated measures of olfactory function: an ethanol odor detection threshold test, a phenyl ethyl alcohol odor detection threshold test, a 40-item smell identification test, and an odor discrimination/short-term odor memory test.Methods In this double-blind experiment, grape juice alone was administered prior to the olfactory tests on one test occasion, and a grape juice–vodka mixture, designed to produce blood levels of ethanol near the legal level of intoxication, on another. The order of the two drug conditions was counterbalanced, as was the order of the presentation of the olfactory tests.Results Ethanol ingestion markedly influenced the detection threshold for ethanol (all 16 subjects exhibited higher thresholds under the ethanol than under the non-ethanol condition) and had a significant, albeit small, influence on odor discrimination performance, as measured by the total number of correct responses independent of delay interval. Women performed significantly better than men on the latter measure. No influences of ethanol on odor identification, the phenyl ethyl alcohol detection threshold, or the delay interval (memory) component of the odor discrimination/memory test were observed.Conclusions Alcohol ingestion markedly and selectively alters olfactory sensitivity to ethanol, perhaps via habituation processes, and may subtly influence some measures of odor discrimination.     

Neuroimmunology of the gut: physiology, pathology, and pharmacology

It has been increasingly appreciated that an intimate interaction between cells of the nervous and immune systems takes place in the gut, and may have a role in diverse inflammatory disorders. Thus, for instance, activation of the enteric nervous system may reduce intestinal epithelial permeability, via several mediators including S-nitrosoglutathione and vasoactive intestinal peptide (VIP). Moreover, ablation of glial cells instigated enterocolitis in murine models. These neuronal effects are particularly intriguing given our current understanding of the immunopathogenesis of Crohn's disease, in which intestinal barrier defect is suspected to at least partly drive the immune hyper-reactivity and ensuing inflammation. Parasympathetic nicotinic signaling, primarily via nicotinic acetylcholine receptor alpha7 (alpha7 nACHr), also exerts immunomodulatory effects, possibly underlaying the detrimental effects of smoking on Crohn's disease, and its beneficial impact on ulcerative colitis. These, and others, neuro-immune interactions may pave the way to the design of novel therapeutic agents for the treatment of chronic inflammatory bowel disorders.     

Impairment of avoidance behavior following short-term ingestion of ethanol,tertiary-butanol,or pentobarbital in mice

Acquisition of a shock avoidance task was impaired in mice after cessation of chronic consumption of ethanol, tertiary-butanol (t-butanol), or pentobarbital. The drugs were administered in liquid diets for 7 days and avoidance behavior was impaired in a test 1 day after withdrawal of the drugs. The avoidance deficit was also observed 8 days after withdrawal from chronic pentobarbital. There was no apparent relationship between the avoidance deficit and physical dependence, as measured by a decrease in body temperature or convulsions on handling, since at 6 h after withdrawal only moderate withdrawal signs were seen in the mice consuming ethanol or t-butanol, and no withdrawal signs were seen in any of the mice at the time of avoidance testing. These results suggest that impairment of avoidance behavior after chronic exposure is a general effect of central nervous system depressants and, in the case of ethanol, is not due to the production of acetaldehyde.     

A comparison of motivations for use among users of crack cocaine and cocaine powder in a sample of simultaneous cocaine and alcohol users

This study examined the motivations for using cocaine and alcohol comparing those who primarily smoked crack and those who primarily used cocaine powder when using simultaneously with alcohol. Motivations examined included: 1) to cope with a negative affect, 2) enhancement, 3) to be social and 4) to conform. The research design was a cross-sectional study in which clients in treatment for cocaine and alcohol problems completed a self-administered questionnaire about their substance use. Among those who primarily smoked crack or snorted cocaine when also using alcohol (n = 153), there were 93 participants who reported primarily snorting cocaine and 60 participants who primarily reported smoking crack. Bivariate analyses found that those who primarily smoked crack reported lower social motivations to use alcohol and cocaine. When adjusting for other covariates in a multivariate analysis, social motivation was still significantly different between groups. Additionally, those who primarily smoked crack were more likely to be older, report higher cocaine dependence severity, be unemployed and were less likely to have completed some post-secondary education, than those who primarily snorted cocaine. No differences were found in enhancement, coping or conformity motivations between the two groups. These results suggest that simultaneous cocaine and alcohol use may have social importance to those who primarily snort cocaine, but that this importance is less evident to those who smoke crack. Consequently, future studies examining motivations for simultaneous cocaine and alcohol use should distinguish between different routes of cocaine administration.     

Pepsinogens: physiology, pharmacology pathophysiology and exercise.

Human gastric mucosa contains aspartic proteinases that can be separated electrophoretically on the basis of their physical properties into two major groups: Pepsinogen I (PGA, PGI); and Pepsinogen II (PGC, PGII). Pepsinogens consist of a single polypeptide chain with molecular weight of approximately 42,000 Da. Pepsinogens are mainly synthesized and secreted by the gastric chief cells of the human stomach before being converted into the proteolytic enzyme pepsin, which is crucial for the digestive processes in the stomach. Pepsinogen synthesis and secretion are regulated by positive and negative feed-back mechanisms. In the resting state pepsinogens are stored in granules, which inhibit further synthesis. After appropriate physiological or external chemical stimuli, pepsinogens are secreted in the stomach lumen where hydrochloric acid, secreted by the parietal cells, converts them into the corresponding active enzyme pepsins. The stimulus-secreting coupling mechanisms of pepsinogens appear to include at least two major pathways: one involving cAMP as a mediator, the other involving modification of intracellular Ca(2+)concentration. Physiological or external chemical stimuli acting through the intracellular metabolic adenyl cyclase are more effective in inducing ' de novo ' pepsinogen synthesis than those acting through intracellular Ca(2+). The activation of protein kinase C (PK-C) would appear to be involved in regulatory processes. The measurement of pepsinogens A and C in the serum is considered to be one of the non-invasive biochemical markers for monitoring peptic secretion and obtaining information on the gastric mucosa status of healthy subjects. Recently, pepsinogen measurements have been used as an effective biochemical method for evaluating and monitoring patients with gastrointestinal diseases and for checking the effects of drug treatment. The level of PGA in the serum is always high in normal gastritis, while in atrophic gastritis it is always low. In both cases the PGC level in the serum is high. In most gastrointestinal pathologies the ratio between the PGA/PGC decreases. Various reports concerning hormone and/or enzyme modification as well as gastrointestinal distress in the case of long distance exercise have been reported. It has been suggested that the origin of the gastrointestinal distress experienced by long distance runners is a transient ischaemia of the gastric mucosa; it is also suggested that a hypobaric-hypoxic environment could contribute to induce gastric mucosa necrosis. Interrelation between gastrointestinal distress, hypobaric-hypoxic environment and modifications of PGA and PGC, gastrin and cortisol was evaluated in 13 athletes after a marathon performed at 4300 m. Gastrointestinal symptoms occurred in approximately 40% of the athletes. After the race the athletes showed a significant increase of gastrin and cortisol, while the ratio between PGA/PGC decreased. No relationship was observed between gastrointestinal symptoms and hormonal changes after the race. A control group of five subjects, who had been exposed to the same environmental conditions, showed no gastrointestinal or hormonal alteration. Conversely, control subjects presented a significant decrease of cortisol related to the circadian rhythm. The same incidence of gastrointestinal symptoms at high altitude and at sea level and the absence of pathological alteration of PGA and PGC in the serum of the athletes indicates that running a marathon and living for 6 days at 4300 m does not induce gastric mucosa necrosis. Cortisol and gastrin alteration observed in the athletes at this altitude would seem to be related to an activation of the mesopontine and forebrain structures involved in the behavioural and metabolic integration of the autonomic control and arousal and psychophysical-exercise stress. 2000 Academic Press@p$hr Copyright 2000 Academic Press.     

The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats

Lever-pressing responses of a group of five rats (Group E) were rewarded with i.v. injections of cocaine (0.1 mg/kg) under conditions of continuous access for eleven 24-h sessions. When the rats were partially food-deprived every third day, cocaine infusions more than doubled during that session. When saline was substituted for cocaine, responding diminished over a 10-day period (Extinction Phase), but when the rats were subsequently food-deprived every third day (Testing Phase), for a total of six cycles (20 sessions), high rates of responding for saline were reinstated only during food deprivation sessions. Seven control groups were included to investigate several questions regarding this effect. Group C-1 received cocaine but no food deprivation experience during the Training Phase, and Group C-2 received food deprivation experience without cocaine access. The results showed that simultaneous presentation of both the food deprivation condition and cocaine was necessary to reinstate food deprivation-induced increases in responding during the Testing Phase. To test for the importance of the contingency between responding and cocaine infusions during food deprivation (and satiation) in the Training phase, Group C-3 was yoked to Group E; they received the same number and pattern of infusions during the Training Phase, but infusions were not contingent upon lever-press responses. This group showed only small increases in saline-maintained responding due to food deprivation during the Testing Phase. Groups C-4 and C-5 were treated as Groups C-3 and E, respectively, except they were partially food-deprived during the 10-day Extinction Phase. Three of five rats in Group C-4 and all rats in Group C-5 showed no increases due to food deprivation during the Testing Phase. Group C-6 was pre-exposed to food deprivation before the experiment began, and Group C-7 was exposed to food deprivation only once during the Training Phase. Both procedures weakened the ability of food deprivation to produce high rates of saline-maintained responding. It was concluded that novel interoceptive stimuli related to food deprivation had become associated with the relatively novel reinforcing effects of cocaine and these interoceptive stimuli functioned as conditioned reinforcers to increase the maintenance and reinstatement of drug-seeking behavior.     

Concurrent administration of diethyldithiocarbamate and 4-methylpyrazole enhances ethanol-induced locomotor activity: the role of brain ALDH

RATIONALE: It has been proposed that brain aldehyde dehydrogenase (ALDH) plays a role in the modulation of some psychopharmacological effects of ethanol. Diethyldithiocarbamate (DDTC), an ALDH inhibitor, elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by DDTC. OBJECTIVE: To investigate the effects of concurrent DDTC and 4-MP administration on ethanol-induced locomotor activity in mice. METHODS: Mice were pretreated IP with saline (S+S) or 4-MP (10 mg/kg) (S+4-MP), then received IP injections of ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg) prior to testing in the open field. RESULTS: Pretreatment with 4-MP does not modify the spontaneous or ethanol-induced locomotor activity. In the second experiment, the DDTC (114, 228 and 456 mg/kg) and 4-MP (DDTC+4-MP) were administered 8 h prior to testing locomotor activity in the open field. Animals were then treated with ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg), and placed in open field chambers. The locomotor activity of animals pretreated with DDTC and 4-MP was significantly enhanced here compared to groups S+S and S+4-MP. These effects cannot be attributed to elevated blood acetaldehyde levels, as pretreatment with 4-MP prevented peripheral accumulation of acetaldehyde. CONCLUSIONS: These data suggest that brain ALDH may contribute to the effects of ethanol on locomotor activity. This role of the enzyme ALDH in some of the psychopharmacological effects of ethanol may be a result of its ability to regulate levels of acetaldehyde in brain.     

Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior

RATIONALE: It is known that social defeat can modulate cocaine self-administration. However, it is unclear whether this psychosocial stressor affects drug-taking behavior to the same extent across all individual animals, particularly those with differing propensities to self-administer psychostimulants. OBJECTIVE: This study examined the effect of social defeat on cocaine self-administration in animals that differ in novelty-seeking behavior that predicts differences in drug self-administration. METHODS: Male Sprague-Dawley rats were first classified into high-responder (HR) and low-responder (LR) groups. HR and LR rats were categorized based on their locomotor activity in a novel environment, with HR rats exhibiting higher locomotor activity than LR rats. Then, male rats were exposed on four occasions to an aggressive Long Evans male rat over the course of 4 days. Control rats were not exposed to the social defeat. All rats were subsequently implanted with jugular catheters and 3 days later placed into the self-administration box to study the acquisition of cocaine self-administration (0.25 mg per infusion). RESULTS: HR non-defeated animals self-administered more cocaine than the LR non-defeated animals. Following social defeat, the acquisition of cocaine self-administration is significantly delayed in HR rats and enhanced in LR rats. CONCLUSION The unique patterns of responsiveness in the HR and LR animals suggest that social defeat plays a role of equalizer of individual differences in drug-taking behavior.