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.

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.

Persistent changes in motivation to self-administer cocaine following modulation of cyclic AMP-dependent protein kinase A (PKA) activity in the nucleus accumbens.

Drug-induced neuroadaptations within the nucleus accumbens, including activation of cAMP-dependent protein kinase A (PKA), may contribute to the synaptic plasticity and behavioural changes that underlie drug addiction. As a direct test of this hypothesis, we examined the effects in rats of PKA activation (Sp-cAMPS infusions of 10 and 20 nmol/side) and inhibition (Rp-cAMPS infusions of 10 and 20 nmol/side) in the nucleus accumbens on motivation to obtain cocaine as measured by responding under the progressive-ratio schedule. Bilateral infusions of Sp-cAMPS (20 nmol/side) resulted in an increase in progressive-ratio responding for cocaine and this effect persisted for several days. In contrast, Rp-cAMPS (20 nmol/side) produced persistent decreases in progressive-ratio responding for cocaine beginning on the day of administration and lasting for several days. These data suggest that alternations in PKA activity within the nucleus accumbens as a consequence of repeated cocaine exposure may contribute to addiction by producing persistent increases in motivation to obtain cocaine.

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.

The subjective and objective benefits of a remote-controlled intraurethral device for managing the female acontractile bladder.

OBJECTIVE: To determine the subjective and objective benefits of the Inflow (SRS Medical Systems, N. Billerica, MA, USA) intraurethral device for managing acontractile bladders in women. PATIENTS AND METHODS: Twenty women with acontractile bladders who had been managed unsuccessfully by the usual methods were recruited. All patients were asked to complete a quality-of-life (QoL) questionnaire and were assessed with urine flowmetry and urine culture; to measure the postvoid residual urine (PVR) in the bladder, ultrasonography was used after activating the device. RESULTS: There was a decrease in the QoL score from a mean of 59.6 before insertion to means of 11.2, 8.8, 6.3 and 5.0 at 1, 3, 6 and 12 months afterward. The mean (range) urinary flow rate was 10.7 (9-16) mL/s and the PVR 3 (0-17) mL. Three patients had temporary asymptomatic bacteriuria and two a single infection after the device was inserted that settled readily with antibiotics. CONCLUSION: This study shows that the Inflow device provides an effective method of bladder drainage, with few side-effects and a significant improvement in QoL.

Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement.

In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.

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.

The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study.

BACKGROUND: Prostate carcinoma therapy with combined androgen blockade may result in high bone-turnover with significant bone loss. This study was undertaken to evaluate the antiosteoporotic efficacy of intravenous pamidronate in a double blind, randomized, placebo-controlled, crossover study. METHODS: Twenty-one consecutive men with metastatic prostate carcinoma who were receiving combined androgen blockade with a long-acting gonadotropin-releasing hormone agonist (gosarelin acetate) and an androgen antagonist (flutamide or bicalutamide) were evaluated at baseline and at 6 and 12 months after therapy. They were randomly assigned to receive a single intravenous infusion of 500 mL of normal saline solution diluted with either pamidronate (90 mg) or placebo at baseline and with a crossover at 6 months. Lumbar-spine bone-mineral densities (BMDs) were measured by spinal quantitative computed tomography (QCT), femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA), and markers of bone turnover were measured by noninvasive methods. Data on 10 men with localized prostate carcinoma who were treated with radiotherapy alone, over the same period, was collected for comparison studies. RESULTS: The mean age of the men was 75.1 years +/- 1.6 years. One man withdrew from the study because of deteriorating health, and two died from metastatic disease within the first 6 months. Combined androgen blockade normalized serum prostate-specific antigen activities (from an initial mean value of 86.2 ng/mL +/- 10.1 ng/mL) and maintained serum free testosterone concentrations in the hypogonadal range (< 2.2 pmol/L) in all men throughout the study. Treatment with pamidronate resulted in a 7.8% +/- 1.5% increase in mean lumbar spine QCT from 79.4 mg/cm(3) (95% confidence interval [CI], 64-94 mg/cm(3)) to 85.6 mg/cm(3) (95% CI, 70-101 mg/cm(3)) (P = 0.0005) and a 2% +/- 0.9% increase in mean total femoral neck DXA from 0.98 g/cm(2) (95% CI, 0.90 -1.05 g/cm(2)) to 1.0 mg/cm(2) (95% CI, 0.91-1.08 g/cm(2)) (P = 0.02). Conversely, treatment with placebo, resulted in a 5.7% +/- 1.6% decrease in mean lumbar spine QCT and a 2.3% +/- 0.7% decrease in mean total femoral neck DXA (P = 0.0001 and P = 0.0007 for the comparison of percentage change between the pamidronate and placebo treatments). After pamidronate therapy, serum bone Gla-protein concentrations decreased by 16.8% +/- 5.9%, and urinary deoxypyridinoline excretion rates decreased by 18.5% +/- 12.8% (P < 0.01 respectively for the comparison between pamidronate and placebo treatment). CONCLUSIONS: This study demonstrated that a single intravenous infusion of pamidronate (90 mg) significantly reduced the high bone turnover and bone loss (for at least 6 mos) in men with prostate carcinoma who had been rendered hypogonadal with combined androgen blockade therapy.

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.

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.

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.

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.

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.

Evaluation of interstitial diode laser therapy for treatment of benign prostatic hyperplasia.

In the last decade, a number of new device technologies were developed for benign prostatic hyperplasia (BPH) therapy. These technologies were introduced in an effort to reduce the morbidity of BPH therapy associated with conventional electrocautery transurethral resection of the prostate (TURP). While morbidity is reduced, the aim of new therapy is to achieve near equivalence in efficacy of outcome measures, namely, improved voided flow rate and reduced symptom score. To gain acceptance by urologists, these technologies should be easy to apply and should reduce the economic cost of BPH treatment. The Indigo 830e diode laser system offers simplified laser therapy from a miniaturized solid-state system. This pilot study demonstrates outcome equivalence to TURP in preliminary evaluation and shows an acceptable side effect profile.

The effects of restraint stress on voluntary ethanol consumption in rats.

Sixty Wistar rats (Rattus norvegicus) were assigned to 4 groups of 15 rats each: ethanol stress (ES), ethanol no-stress (EN), isocaloric stress (IS) and isocaloric no-stress (IN). The effect of restraint stress on daily intake of ethanol and a 0.72% solution of glucose was examined in an ABA design (stress-no stress-stress). During the stress phases, 2 groups were subjected to daily 15-min restraint stress, whereas 2 groups were placed in different cages for 15 min as a control. All 4 groups were then given 6-hr access to their assigned liquid alone for 4 days followed by a choice between their assigned liquid and water on the 5th day. The ES group significantly increased their ethanol intake (g/kg) compared to the EN group on choice days but not on forced days. Percentage preference for ethanol was significantly greater and increased at a faster rate over the 75-day testing period compared with the EN group. However, total ethanol consumption (g/kg) and percentage preference did not vary as a function of phase. It is notable that the effects of restraint stress on ethanol self-administration persisted even after the stress schedule was removed.

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.

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.