A paradigm to investigate the regulation of cocaine self-administration in human cocaine users: a randomized trial.

RATIONALE: We recently conducted a pilot study supporting the feasibility, safety, and validity of a human laboratory model of ad libitum cocaine administration in which subjects self-selected the timing of infusions. The current study extends this work to include a randomized design with a test-retest component in a larger sample. OBJECTIVES: To investigate the regulation of cocaine intake by humans and its effects on subjective and cardiovascular responses. MATERIALS AND METHODS: Subjects were 14 non-treatment seeking volunteers (10 M, 4 F) with cocaine abuse/dependence. Subjects self-administered cocaine infusions (0, 8, 16, and 32 mg/70 kg) over a 2-h period under a fixed ratio 1, 5-min time-out schedule on 4 consecutive days. A fifth session was conducted at 16-mg dose to assess the paradigm's test-retest reliability. RESULTS: Subjects regulated their cocaine intake in a dose-dependent fashion. Self-reports of cocaine-related subjective effects (e.g., "high" and "stimulated") also varied in a dose-dependent way. Test-retest data and the randomized design support the conclusion that such effects are not due to tolerance or other experimental artifacts. CONCLUSION: The current study replicates prior work demonstrating the feasibility, safety, and validity of our human laboratory paradigm of cocaine administration in a larger sample using a randomized design. The current study also shows the test-retest reliability of these methods, establishing its utility for comparisons of experimental interventions (e.g., pharmacological treatments). Finally, the current study suggests that factors other than drug-induced euphoria (i.e., "high") contribute to the regulation of cocaine-taking behaviors in humans.

Exercise during early, but not late abstinence, attenuates subsequent relapse vulnerability in a rat model.

Exercise has shown promise as a nonpharmacological intervention for addiction, with evidence suggesting a potential utility for relapse prevention. In humans, exercise as an intervention is typically introduced well after the initiation of abstinence, yet neurobiological data from preclinical studies suggest that it may be more effective if initiated during early abstinence. Here, using rat models, we determined whether the beneficial effects of exercise on relapse vulnerability depends on when exercise is first initiated, during early versus late abstinence. Once rats (n=47) acquired cocaine self-administration, they were given 24-h access to cocaine (1.5 mg/kg per infusion) under a discrete trial procedure (four infusions per hour) for 10 days. The rats then began a 14-day abstinence period in which they had access (2 h per day) to a locked wheel throughout abstinence (sedentary) or an unlocked wheel during early (days 1-7), late (days 8-14) or throughout (days 1-14) abstinence (n=10-14 per group). Cocaine seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 15 of abstinence. Exercise beginning during early abstinence robustly attenuated subsequent cocaine seeking, and this effect persisted even when exercise ended on the seventh day of abstinence. In contrast, exercise during late abstinence was not effective and these animals displayed high levels of cocaine seeking similar to those observed in sedentary animals. These results indicate that the timing of exercise availability differentially impacts cocaine seeking with results suggesting that exercise during early, but not late, abstinence may provide long-term protection against cocaine relapse.

Effects of a lacto-ovo vegetarian diet on serum concentrations of cholesterol, triglyceride, HDL-C, HDL2-C, HDL3-C, apoprotein-B, and Lp(a).

The effect of intervention with a lacto-ovo vegetarian diet on serum concentrations of cholesterol, triglyceride, total high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, low-density lipoprotein cholesterol, apoprotein-B, apoprotein-HDL, and Lp(a) was studied in 19 men and 17 women. Most weekday meals were obtained from a single source and dietary records were completed to assess the changes in nutrient intakes. Blood was collected in the 6th wk of each dietary period. Because of strong correlations between many of the changes in nutrient intakes, principal component (factor) analysis was used followed by stepwise multiple regression analysis to identify associations between changes in diet and changes in lipid, lipoprotein or apoprotein levels. Three principal components accounted for 92.0% of the variation in lipid levels: factor 1 represented an increase in saturated fat, total fat, monounsaturated fat, cholesterol, and energy intake: factor 2 represented an increase in fiber and polyunsaturated fat, and decrease in protein intake; factor 3 an increase in total carbohydrate, complex carbohydrate, and energy intake. Where a change in a variable was significantly associated with change in diet, one factor appeared primarily responsible for the change; total cholesterol (factor 2, p = 0.034); triglyceride (factor 3, p = 0.005); apo-HDL (factor 1, p = 0.014); HDL2-C (factor 2, p = 0.023), HDL3-C (factor 3, p = 0.015). A borderline significant association was seen for total HDL-C (factor 2, p = 0.055).

Effects of cocaine self-administration on food-reinforced responding using a discrete trial procedure in rats.

Cocaine addiction has been characterized by a shift from controlled to uncontrolled and compulsive drug use. Using novel self-administration procedures, we attempted to model this transitional phase and characterize the behavioral changes that underlie it. We chose to use food-reinforced responding across the light/dark cycle as an indicator of the degree to which cocaine was disrupting ongoing behavior as a potential measure of dysregulation. Four groups of rats (n=5-6) were given 24-h access to cocaine (1.5 mg/kg/inj) available in 2, 3, 4, or 5 discrete trials/h. All rats were given continuous access to a second lever that resulted in the delivery of a 45 mg food pellet under a fixed ratio 1 schedule. The results showed that under low access conditions (eg 2 discrete trials/h), both food- and cocaine-reinforced responding were diurnally regulated and occurred coincidentally. As access to cocaine was increased, there was a progressive disruption in the diurnal control over both food- and cocaine-maintained responding. High access conditions also produced transient decreases in the total levels of food-reinforced responding. These findings suggest that high access to cocaine under the discrete trial cocaine self-administration procedure produces a transient disruption in the diurnal control over behavior maintained by food and that the level of control (or loss of) may be a useful marker of dysregulation.

Effects of alcohol consumption on serum lipoprotein-lipid and apolipoprotein concentrations. Results from an intervention study in healthy subjects.

Serum levels of cholesterol, triglyceride, cholesterol in low density lipoprotein (LDL) and in high density lipoprotein (HDL) and its major subfractions, and of apolipoproteins A-I, A-II and B were measured in 48 healthy men at the end of two 6-week periods in which they consumed normal alcohol (5.0%, v/v) or low alcohol (0.9%, v/v) beer, respectively. Other dietary and behavioural variables were kept constant. Mean levels of triglyceride, HDL cholesterol, HDL2- and HDL3 cholesterol, and apolipoproteins A-I and A-II were higher at the end of the normal compared with the low alcohol periods, and levels of LDL cholesterol were lower. Body weight was greater at the end of the normal alcohol period than at the end of the period of low alcohol but multiple regression analysis suggested that the changes in lipoprotein-lipid and apolipoprotein levels were due primarily to the change in alcohol consumption rather than concomitant changes in body weight. This study confirms an effect of alcohol on both major subfractions of HDL and on its major apolipoproteins.

Cocaine-responsive gene expression changes in rat hippocampus.

Chronic cocaine use is known to elicit changes in the pattern of gene expression within the brain. The hippocampus plays a critical role in learning and memory and may also play a role in mediating behaviors associated with cocaine abuse. To profile the gene expression response of the hippocampus to chronic cocaine treatment, cDNA hybridization arrays were used to illuminate cocaine-regulated genes in rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days. Validation of mRNA changes illuminated by hybridization array analysis was accomplished by measuring immunoreactive protein (via specific immunoblots). The induction of protein kinase Calpha, potassium channel 1.1, and metabotropic glutamate receptor 5 seen by hybridization arrays was confirmed at the level of protein. Immunoblot screening of previously described cocaine-responsive genes demonstrated increased levels of protein tyrosine kinase 2, beta-catenin, and protein kinase Cepsilon. While some of these changes exist in previously described cocaine-responsive models, others are novel to any model of cocaine use. The inductions of potassium channel 1.1, protein tyrosine kinase 2 and metabotropic glutamate receptor 5 are novel findings to hippocampal cocaine-responsive gene expression. These proteins have been shown to subserve learning and memory and/or long-term potentiation functions within the hippocampus. Additionally, these genes are known to interact with one another, forming a more complex pattern of gene expression changes. The findings suggest altered expression of genes with a number of different functions in the rat hippocampus after a 'binge' style of non-contingent cocaine administration. These changes in gene expression may play roles in neuronal plasticity and the behavioral phenomena associated with cocaine abuse.

Somatic findings in patients with psychogenic polydipsia.

An epidemiologic investigation found a 17.5% prevalence of psychogenic polydipsia in 241 hospitalized psychiatric patients. A randomly selected sample of 10 polydipsic patients revealed such associated disorders as sporadic convulsive seizures, comatose states, hydronephrosis, enuresis/urinary incontinence, projectile type vomiting, malnutrition and, in one case, cardiomegaly and edema. Psychogenic polydipsia is a frequently overlooked disorder, and the somatic consequences of the excessive fluid intake are usually ascribed to other causes.

Reinstatement of cocaine self-administration in rats: sex differences.

RATIONALE: Results obtained with both humans and animals suggest that rates of relapse, or levels of reinstatement responding, may differ between males and females. However, the results obtained with humans are equivocal, and few studies have compared male and female animals on reinstatement responding. OBJECTIVES: The present experiment was designed to compare male (n=8) and female (n=8) rats on reinstatement of extinguished cocaine-reinforced responding. METHODS: Reinstatement of responding was examined using a priming model in which lever pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions (2 h) with saline infusions (5 h). After responding extinguished during hour 3, reinstatement of responding was tested by administering one of several priming injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline. RESULTS: Although males and females did not differ in the number of saline infusions self-administered after either saline or 0.32 mg/kg cocaine-priming injections, female rats self-administered significantly more saline infusions than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections. Additionally, the effects of 0.32 mg/kg cocaine-priming injections were significantly different from those of saline-priming injections for female, but not male, rats. There was no significant difference between males and females in total cocaine self-administered during hours 1 and 2. CONCLUSIONS: These findings indicate that female rats are more sensitive than males during the reinstatement phase of drug abuse.

Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats.

RATIONALE: Despite numerous reports that male and female animals differ in behavioral responses to drugs, few studies have investigated sex differences in drug-reinforced behavior. OBJECTIVES: Acquisition of IV cocaine and heroin self-administration was compared in 20 female and 22 male Wistar rats. METHODS: An autoshaping procedure was used to train rats to press a lever that resulted in either a 0.2 mg/kg infusion of cocaine or a 0.015 mg/kg infusion of heroin under a fixed-ratio 1 (FR 1) schedule. Daily sessions consisted of six 1-h autoshaping components followed by a 6-h self-administration component. During each autoshaping component, a retractable lever briefly (15 s) extended into the test chamber on a random interval schedule with a mean of either 90 s (cocaine groups) or 480 s (heroin groups) and either ten (cocaine groups) or five (heroin groups) computer-automated infusions were delivered each hour. During each 6-h self-administration component, the lever remained extended and each response on the lever resulted in an infusion of either cocaine (0.2 mg/kg) or heroin (0.015 mg/kg). The criterion for acquisition of cocaine self-administration was a mean of at least 100 infusions and the criterion for heroin self-administration was a mean of at least 20 infusions during the self-administration component over five consecutive sessions. RESULTS: Female rats acquired both cocaine and heroin self-administration more rapidly than males. Acquisition of cocaine self-administration occurred in a greater percentage of female rats compared to males. Female rats self-administered more cocaine than males after acquisition criteria had been met. CONCLUSIONS: These findings indicate that female rats were more vulnerable than males to the acquisition of cocaine and heroin self-administration under the conditions of the present experiment.

Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats.

RATIONALE: Previous research with both humans and animals suggests that there are sex differences in cocaine self-administration; in rodents, ovarian hormones may underlie these differences. OBJECTIVES: A two-lever drug self-administration procedure was used to compare regulation of intravenously self-administered cocaine in male and female rats and among females in different phases of the estrous cycle. METHODS: Eleven female and seven male age-matched Wistar rats were trained to self-administer nine doses of cocaine (0.0-2.4 mg/kg) during daily 5-h sessions. Experimental test chambers were equipped with two levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in cocaine dose increased the infusion duration by 3 s, and a response on the other lever decreased the infusion duration by 3 s. RESULTS: After responding for cocaine stabilized, regulation was disrupted more in females than in males (r2=78.9, r2=92.6, respectively) with the greatest disruption observed in females during the estrus phase (r2=48.5). Mean dose size varied considerably for males and for females in the metestrus/diestrus and proestrus phases; however, estrus females responded almost exclusively on the lever associated with an increase in cocaine dose. CONCLUSIONS: These findings indicate sex differences in the regulation of cocaine self-administration, and they suggest that ovarian hormones may be responsible for the observed sex differences.

The occurrence of abnormal serum proteins in patients with epithelial neoplasms.

In a series of 99 patients with paraproteinaemia, nine had carcinoma without myeloma. A review of the literature suggests that this may be a significant association, and its theoretical and clinical significance is discussed.

Personality factors and results of lumbar disc surgery.

Patients undergoing surgery for herniated lumbar discs were evaluated prospectively with a battery of psychological tests. Personality factors in patients having a good outcome were compared to those in patients having a bad outcome. Both groups had similar surgical findings. Patients with a good outcome were more stable, cautious, efficiently defensive, self-confident, realistically concerned with their illness, mildly depressed, generally optimistic regarding outcome, and able to withstand setbacks without resorting to emergency reactions. Patients with a bad outcome were less stable, were unpredictable, had inefficient defenses, were more obviously depressed, and were less able to withstand stress and breakdown. However, even the degree of psychological testing used in this study does not definitely predict outcome.

Apolipoprotein A-I and A-II levels in an Australian population.

Values for apolipoproteins A-I and A-II (apo A-I and apo A-II) are reported for 389 women and 390 men in the town of Busselton, Western Australia. Apo A-I levels were found to be relatively constant with age in men but to rise with age in women. Apo A-II levels remained constant with age in men until older age, when they declined, but rose with age in women, showing a fall in the oldest age group. Apo A-I levels were greater in women than in men, but apo A-II levels were lower in younger women than in younger men, and higher in older women than in older men. On stepwise multiple regression analysis, neither apo A-I nor apo A-II levels showed an independent relationship with age in women; the same was true for apo A-I in men. Alcohol consumption was directly associated with apo A-I and A-II levels in both sexes; adiposity was inversely associated with apo A-I levels in both sexes but with apo A-II only in women. Triglyceride levels showed an inverse association with apo A-II in women. Frequency of exercise was independently and directly associated with apo A-I and A-II levels in women only.

Effect of smoking cessation on serum apolipoprotein A-I and A-II concentrations.

This study investigated the effects of 6 weeks' smoking cessation on serum levels of total-cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C) and apolipoproteins A-I and A-II (apo A-I and apo A-II) in 64 subjects of both sexes. Smoking cessation was associated with an increase in levels of apo A-II. Concurrent changes in weight and alcohol consumption during attempted smoking cessation, together with change in thiocyanate level, were entered as predictor variables into a multiple regression analysis. The change in apo A-II was found to be best accounted for by change in plasma thiocyanate level, and, in women, change in HDL-C and apo A-I by change in weight. The changes induced by smoking cessation may be due, at least in part, to associated changes in alcohol consumption and/or dietary intake, but in the case of apo A-II there is evidence of a more direct effect.

Levels of cholesterol, triglyceride, high-density lipoprotein-cholesterol and apoprotein-HDL in an Australian rural population.

Serum levels of total cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C) and apoprotein-HDL (apo-HDL) have been measured in adults of Busselton, Western Australia (males, n = 1600; females, n = 1968) and the distribution of values by age and sex are reported. The data confirm previously reported trends with age for cholesterol and reveal strikingly different ranges and trends with age for triglyceride between males and females, mean values in males increasing more rapidly with age and showing greater variation and more marked positive skew. Mean HDL-C values show little change with age in males, and a slight rise with age in females, up to the 7th decade, and then a fall. Apo-HDL levels show very similar distributions to HDL-C in each sex.

Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats.

Previous work from this laboratory has revealed that female rats acquired cocaine self-administration at a faster rate than male rats and that a greater percentage of females acquired self-administration [Psychopharmacology 144 (1999) 77.]. It has been suggested that sex differences in stimulant self-administration may be related to ovarian hormones, particularly estrogen. To investigate this possibility, we compared four groups (n = 10) of female rats: ovariectomized (OVX) treated with either estradiol benzoate (EB) or vehicle (VEH), and sham-operated intact (SH) females treated with either the antiestrogen tamoxifen (TAM) or VEH. An autoshaping procedure was used to train rats to lever press for intravenous infusions of cocaine (0.2 mg/kg). The criterion for cocaine acquisition was a mean of 100 self-administered infusions over five consecutive 6-h sessions. Results revealed that 70% of the OVX + EB group and 80% of the SH + VEH group acquired self-administration, while only 30% of the OVX + VEH group and 50% of the SH + TAM group met the acquisition criterion. Rats that had estrogen chemically or surgically blocked exhibited significantly less responding for cocaine over the acquisition testing period, and fewer of these rats met the acquisition criterion compared to intact rats and to OVX rats with estrogen (EB) replacement. The percentages for females with estrogen (70% and 80%) vs. those without (OVX, 30%) were similar to those reported for intact females (70%) and males (30%) in the previous study [Psychopharmacology (2000)]. Taken together, these results suggest that estrogen is a key factor influencing drug-seeking behavior in female rats, and it may underlie sex differences in drug-reinforced responding.

Transurethral microwave thermotherapy: symptom relief v urodynamic changes.

Transurethral microwave thermotherapy (TUMT), whether in its low- or high-energy form, seems to reduce the symptoms of benign prostatic hyperplasia, with low-energy treatment resulting in less improvement than high-energy treatment. Low-energy TUMT has a minimal effect on bladder outlet obstruction, as judged by urodynamic findings, and may not be suitable to treat those patients with significant obstruction. High-energy TUMT does seem to relieve obstruction significantly, although it is not as effective as TURP. Urodynamic studies may provide the answer as to which therapy to offer the patient.

Regulation of drug intake.

Regulation of drug intake refers to the maintenance of relatively constant levels of drug over a specified time period. An understanding of regulation of drug intake may be critical in determining how drugs function as reinforcers and how their reinforcing effects may be modified. However, little is known about regulation of drug intake, and the mechanisms underlying it are poorly understood. Three mechanisms that have proposed to account for findings of regulation of drug intake were discussed to determine their relevance for drug-reinforced responding. These mechanisms include aversive effects, direct effects, and satiation. Although a greater role for satiation was supported in this review, drugs may vary on the degree to which they can produce satiation and whether satiation acts in concert with either the aversive effects or the direct effects of drugs is unclear.

Regulation of intravenously self-administered nicotine in rats.

Ten male Wistar rats had access to 9 doses of nicotine (0.01-0.10 mg/kg i.v.) during daily 5-hr sessions. Once responding for nicotine stabilized, nicotine infusions were replaced with either cocaine infusions (0.0-2.4 mg/kg) or saline infusions. Saline substitution results indicate that nicotine functioned as a reinforcer. Regulation of nicotine intake was compared with that of cocaine by obtaining the correlation between mean interdose interval and preceding dose size. Results reveal that although this correlation was significant for both nicotine and cocaine self-administration, nicotine self-administration was less precisely regulated than cocaine self-administration. This procedure suggests that there are differences in regulation among self-administered drugs and that it may serve as a useful baseline for studying differences in vulnerability to drug abuse and potential treatment strategies.

Effects of amphetamine, butorphanol, and morphine pretreatment on the maintenance and reinstatement of cocaine-reinforced responding.

Three groups of rats (N = 23) self-administered intravenous cocaine (0.4 mg/kg/infusion) during the initial 2 hr of daily 7-hr sessions. During the remaining 5 hr of these sessions, responding produced saline infusions. On test days, each rat was pretreated with an assigned dose of either butorphanol, morphine, amphetamine, or saline before the self-administration session followed by a priming injection of cocaine (3.2 mg/kg i.v.) or saline at the beginning of the 4th hr. Results showed that both amphetamine (0.5, 1.0, and 2.0 mg/kg) and morphine (0.3, 1.0, and 2.0 mg/kg) pretreatment dose-dependently reduced cocaine self-administration whereas only amphetamine affected (increased) reinstatement responding. Butorphanol pretreatment (8 mg/kg) suppressed cocaine self-administration and blocked the effect of the cocaine priming injections on pretreatment testing days. These findings indicate that (a) pretreatment drugs with similar stimulus properties potentiate reinstatement of responding and (b) pretreatment drugs can differentially affect maintenance and reinstatement of responding.