Biomedical subjects

R B Stewart

Publications and source records attributed to R B Stewart.

At least 37 records · Page 2Linked to original sources

PubMed1997

Comparison of rats selectively bred for high and low ethanol intake in a forced-swim-test model of depression: effects of desipramine.

This investigation examined if there is a relationship between selective breeding for high or low alcohol intake and immobility in a force-swim-test (i.e., "behavioral despair") model of depression. Time spent immobile in a water-filled cylinder was measured in the alcohol-preferring (P and nonpreferring (NP) lines of rats, and in the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) lines. Each rat was tested for 2 10-min trials administered 24 h apart, and pretreatment with saline or desipramine (10.0 or 20.0 mg desipramine/kg b.wt. i.p.) also was evaluated. Drug was administered immediately after Trial 1 and again 1 h before Trial 2. When tested without pretreatment in Trial 1 or with saline pretreatment in Trial 2, NP rats spent significantly more time immobile than did P rats, but no comparable line differences were found when HAD and LAD rats were tested. Desipramine pretreatment reduced the time spent immobile in rats of the 2 alcohol-nonpreferring lines (i.e., the NP and LAD rats), but had no significant effect in rats of the 2 alcohol-preferring lines (the P and HAD rats). These findings do not support the hypothesis that there is a functional relationship between high alcohol drinking and susceptibility to "behavioral despair" as measured by the forced-swim test. The results with desipramine suggest that selection for high alcohol intake may be associated with insensitivity to desipramine.

Alcohol Drinking↗

PubMed1997

The neurobiology of alcoholism in genetically selected rat models.

Rats selectively bred for their tendency to drink large or small quantities of alcohol are a useful model for investigators examining the possible neurobiological processes underlying alcoholism. Studies with the alcohol-preferring (P) and alcohol-nonpreferring (NP) and the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) pairs of rat lines developed at Indiana University have illustrated differences in several behavioral and neurobiological characteristics associated with alcohol consumption. Specifically, compared with alcohol-avoiding rats, rats with an affinity for alcohol have a greater sensitivity to the stimulatory effects of low to moderate doses and a reduced sensitivity to the negative effects of high doses. Rats that voluntarily drink large quantities of alcohol also acquire tolerance to alcohol's aversive effects. In addition, these rats differ from their alcohol-avoiding counterparts in the levels of several chemical mediators (i.e., neurotransmitters) found in the brain, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and the endogenous opioids.

Alcohol Drinking↗

PubMed1996

Temperature-controlled laser photocoagulation of soft tissue: in vivo evaluation using a tissue welding model.

BACKGROUND AND OBJECTIVES: Laser surgical procedures involving photocoagulation of soft tissue have relied on subjective visual endpoints. The thermal damage to the denatured tissue in these procedures is highly dependent on the tissue temperatures achieved during laser irradiation. Therefore, a system capable of real time temperature monitoring and closed loop feedback was used to provide temperature controlled photocoagulation (TCPC). STUDY DESIGN/MATERIALS AND METHODS: The TCPC system consisted of a 1.32 microns Nd:YAG laser, an infrared thermometer, and a microprocessor for data acquisition and feedback control. A porcine skin model was used. Tissue welds were completed to evaluate the photocoagulation effects at different predetermined temperatures. A quantitative measurement of tissue photocoagulation was obtained by tensile strength measurements of the laser repairs. Histology of the irradiated tissue was used to determine the extent of thermal injury associated with different photocoagulation temperatures. RESULTS: The TCPC system was capable of maintaining a relatively constant temperatures (+/- 4 degrees C) during laser irradiation. The tensile strengths of acute repairs increased with temperature over the range studied (65-95 degrees C). Tensile measurements made after several days of healing showed that higher temperature (95 degrees C) welds had lower strengths than repairs completed at lower (65 degrees C or 75 degrees C) temperatures and were significantly lower at 3 days. Acute histology showed that the amount thermal damage was strongly dependent on the tissue temperature and increased both in tissue depth and lateral to the repair with temperature. The histologic results suggest that the increase in the acute repair tensile strength as the weld temperature increased was due to an increase in the depth of tissue photocoagulation. The increase in the lateral tissue injury measured histologically for higher temperature welds likely resulted in the decreased chronic tensile strengths, as a healing response to excessive thermal damage. CONCLUSION: Tissue temperatures can be controlled during laser photocoagulation of skin. The degree of acute and chronic tissue damage is highly dependent on the temperature during welding. By controlling the tissue temperature during laser procedures, the surgical outcome can be more reliably predicted and reproduced, as compared to the conventional open loop methods. In addition, the use of a TCPC system should significantly reduce the learning curve for photothermal surgical procedures.

Animals↗

PubMed1996

Laser assisted vascular welding with real time temperature control.

BACKGROUND AND OBJECTIVE: Previous studies in laser assisted vascular welding have been limited by the lack of a reliable end point for tissue fusion. As a means of improving the reproductibility of laser assisted repairs, a system incorporating real time temperature monitoring and closed loop feedback was used. STUDY DESIGN/MATERIALS AND METHODS: The system consisted of a direct view infrared thermometer for monitoring the laser heated spot, a 1.9 microns diode laser, and a microprocessor for data acquisition and feedback control of the laser power to maintain a constant tissue temperature. Rat aortas were welded under constant surface temperature conditions. RESULTS: In vivo temperature stability of +/- 2 degrees C was achieved over a temperature range of 70-90 degrees C pertinent to welding small vessels. When welds were completed using the feedback system to maintain the tissue temperature at 80 degrees C, the acute success rate was 100% and the burst pressure was 290 +/- 70 mmHg. CONCLUSION: These studies demonstrate that the use of real time monitoring and feedback control results in improved consistency for vascular tissue welding.

Anastomosis, Surgical↗

PubMed1996

Human albumin solder supplemented with TGF-beta 1 accelerates healing following laser welded wound closure.

BACKGROUND AND OBJECTIVE: We examined the possibility that human albumin solder can be used as a vehicle for site specific delivery of growth factors for the purpose of accelerating tissue repair following laser welded wound closure. Certain human recombinant growth factors have been shown to accelerate wound healing in model systems. Pilot in vitro studies have established that several growth factors, including TGF-beta 1, maintain bioactivity following exposure to temperatures achieved during laser tissue welding. Using a temperature controlled laser delivery system (TCL) to precisely maintain welding temperatures, it is now possible to avoid thermal denaturation of exogenous bioactive molecules such as growth factors. STUDY DESIGN/MATERIALS AND METHODS: HB-EGF, bFGF, and TGF-beta 1 were tested in vitro for maintenance of bioactivity after exposure to 80 degrees C. In vivo experiments using porcine skin determined the efficacy of solders augmented with growth factors. Incisions were repaired using human albumin alone or supplemented with HB-EGF (2 micrograms), bFGF (10 micrograms), or TGF-beta 1 (1 microgram). Wounds were excised at 3, 5, and 7 days post-operatively. Tensile strength, total collagen content, and histology were performed. RESULTS: At 3 days, tensile strength (TS) of TGF-beta 1 wounds were 36% (P < 0.05) and 20% (n.s.) stronger than laser alone and suture closures, respectively. By 5 days the TS of the TGF-beta 1 group increased by 50% (P < 0.05) and 59% (P < 0.02) over laser alone and suture groups, respectively. At 7 days the TGF-beta 1 group was 50% (P < 0.05) and 79% (P < 0.01) stronger than laser solder alone or suture, respectively. The HB-EGF and bFGF groups were equivalent to the laser solder group at all time points. Total collagen TGF-beta 1 Accelerates Healing Following Laser Welding content at 7 days increased in the TGF-beta 1 group by 7% (n.s.) over the suture group and 21% (P < 0.05) in the laser group. CONCLUSION: Human albumin solder supplemented with TGF-beta 1 increases the early post-operative strength of laser welded wounds. This novel application of laser tissue soldering augmented with a growth factor has the potential to bring about immediate fluid tight seals while providing site specific delivery of biological modifiers. This may lead to an overall improvement in post-operative convalescence, wound infections, and hospital costs.

Albumins↗

PubMed1996

Orally delivered methadone as a reinforcer in rhesus monkeys.

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625-0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625-0.4 mg/ml) combined with ethanol (0.0325-2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.

Administration, Oral↗

PubMed1996

Genetic differences in tolerance and sensitization to the sedative/hypnotic effects of alcohol.

Initial sensitivity to alcohol and the development of alcohol tolerance were examined in rats of the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines. All rats received two alcohol injections (3.0 g/kg b.wt., IP) separated by either 1 or 2 days. P rats were less sensitive to the behaviorally impairing effects of alcohol than were NP rats, as evidenced by a longer latency to lose righting reflex (RR) and a shorter time to recover RR following an initial alcohol injection. When 1 day separated the two alcohol injections, P rats recovered the RR more rapidly following a second injection compared to the first, indicating that the P rats developed tolerance to the sedative/hypnotic effects of alcohol. In contrast, the NP rats recovered the RR more slowly following the second injection compared to the first, indicating that the NP rats developed sensitization to alcohol. Tolerance in the P line and sensitization in the NP line disappeared when 2 days separated the two alcohol injections. Line differences in initial sensitivity and tolerance/sensitization to the behaviorally impairing effects of alcohol may contribute to the differences in alcohol consumption observed in the P and NP lines.

Alcohol Drinking↗

PubMed1996

Place conditioning with alcohol in alcohol-preferring and -nonpreferring rats.

A place-conditioning procedure was used to examine the effect of selective breeding for ethanol preference on sensitivity to the rewarding and/or aversive effects of ethanol. On 4 alternate days, groups of seven to eight alcohol-preferring (P) and alcohol-nonpreferring (NP) rats received IP injections of 0.0 (saline controls), 0.5, 1.0, or 1.5 g ethanol/kg body wt. immediately before 15-min confinement in a novel environment. On the 4 intervening days the same rats received saline injections before 15 min confinement in a different environment. On day 9, a 15-min choice test was given with no injections, in which the rats could move freely between the ethanol and the saline-paired environments. Dose-dependent avoidance of the ethanol-paired environment was observed in both lines of rats (1.0 and 1.5 g/kg), but the magnitude of the avoidance was less in the P relative to the NP rats, indicating that ethanol was less aversive for the P rats. No evidence for a place preference was observed in either line with any of the ethanol doses. An innate reduced sensitivity to the aversive effects of ethanol in rats of the P line and/or an enhanced sensitivity to the aversive effects of ethanol in rats of the NP line may contribute to the different levels of oral ethanol self-administration observed in these selectively bred rat lines.

Animals↗

PubMed1996

Orally delivered methadone as a reinforcer for rhesus monkeys: the relationship between drug concentration and choice.

The relative reinforcing effects of orally delivered methadone were studied in five male rhesus monkeys. Drug deliveries were available under either a fixed-ratio (FR) or a fixed-interval (FI) schedule. Three concentrations of methadone, low (0.05 mg/ml), intermediate (0.2 mg/ml), and high (0.8 mg/ml) were delivered in 0.65 ml volumes. In the first experiment, monkeys were presented with a choice paradigm. Under independent FR schedules responding led to a delivery of either a methadone solution or the water vehicle. For each concentration, deliveries of a methadone solution maintained higher response rates than did deliveries of water. In the second experiment, methadone concentrations were tested in pairs in the following sequence: high vs. low, high vs. intermediate, intermediate vs. low, high vs. intermediate (retest), and high vs. low (retest). The retest of the last two pairs was designed to counterbalance the test sequence, so that order effects, if they existed, could be detected. Regardless of the schedule, the higher concentration of the methadone pair maintained a greater response rate than did the lower concentration. The present results are consistent with the generalization based on other studies that over a broad range of concentrations and across pharmacological classes, reinforcement schedules, and routes of administration, reinforcing effects increase with increases in drug concentration.

Animals↗

PubMed1996

An assessment of sulphide oxidation in abandoned base-metal tailings, Te Aroha, New Zealand.

Tailings from the Tui base-metal mine were characterized using a variety of techniques including scanning electron microscopy (SEM) and flame atomic absorption spectroscopy (FAAS), to assess their potential for use as a plant growth medium. With the notable exception of Pb (10 568 mg kg(-1)), 'total' metal concentrations in the surface tailings (0-200mm) were relatively low (Cu, 113; Fe, 3660; Zn, 486 mg kg(-1)). The theoretical acid generating potential (TAGP) and 'total' concentrations of Cu, Fe and Zn of the tailings, were found to increase greatly with depth, reflecting an increase in the abundance of chalcopyrite (CuFeS(2)), pyrite (FeS(2)) and sphalerite (ZnS), as detected by X-ray diffraction (XRD) analysis. SEM micrographs indicate that the distribution of sulphide minerals in the tailings was originally uniform with depth. The depletion of Cu, Fe and Zn in the surface tailings is considered to be a result of sulphide oxidation, as evidenced by the craggy and highly irregular morphology of the sulphide particles and the high hydrogen ion activity (pH 2.3-4.0) in this zone. The persistence of high concentrations of acid-generating sulphide minerals between 200 and 600 mm has important implications in determining strategies for revegetating the tailings.

Journal Article↗

PubMed1995

Relative reinforcing effects of different doses of orally delivered cocaine.

The relative reinforcing effects of different doses of oral cocaine were investigated in two adult male rhesus monkeys. In the first experiment, a range of cocaine doses (0.1-0.8 mg/ml) was studied with drug and water concurrently available for 3 h each day under identical and independent fixed-ratio schedules. The side positions of the drug and vehicle were alternated from session to session. Drug deliveries always exceeded vehicle deliveries, i.e., orally delivered cocaine functioned as a reinforcer. The highest rates of responding occurred at either the lowest or next to lowest dose (0.1 or 0.2 mg/ml). In the second experiment, pairs of different cocaine doses were systematically presented under identical and independent fixed-ratio schedules. The higher of two concurrently available doses usually maintained the higher response rate. These findings suggest that the relative reinforcing effects of orally delivered cocaine increase with dose. Absolute response rates obtained with single cocaine doses and water concurrently available do not always reflect the magnitude of the reinforcing effects indicated when pairs of cocaine doses are studied together. The results of this study are in agreement with earlier investigations in which the relative reinforcing effects of pairs of intravenous cocaine doses or oral pentobarbital doses were studied. Taken together these findings indicate that, over a range of doses and across pharmacological classes and routes of administration, relative reinforcing effects of a drug increase directly as a function of increases in dose.

Administration, Oral↗

PubMed1995

Cross-sectional design and fatigue durability of cantilevered sections of fixed implant-supported prostheses.

PURPOSE: Characterizing the fatigue behavior of cantilevered implant-supported prostheses requires an understanding of both the material and its intended application. The relationships between applied load, component geometry, and the fatigue characteristics of a specific material often can be difficult to establish. Four different cross-sectional designs of cantilevered frameworks used clinically were tested for fatigue durability, and the results were compared with theoretical tip deflections and stresses. MATERIALS AND METHODS: Fatigue tests were conducted on specimens with I-, U-, and L-shaped and elliptical cross-sections after static stress analysis. Specimens with uniform cantilevered length were sprued, invested and cast from the same high-palladium alloy. Statistical results, SEM evaluation of fracture surfaces, and theoretical predictions provided further insight into the framework design. RESULTS: Based on intraoral space restrictions, corrections for dimensional changes inherent in casting, the mean number of cycles to failure for each cross-sectional geometry, and the performance of design groups as predicted by static analysis can be ranked in order from best to worst as I, L, U, and then elliptical. SEM evaluation showed varying degrees of porosity and shrinkage cavities specific to the specimen cross-sections. CONCLUSIONS: Four designs for the cantilevered sections of implant-supported frameworks were evaluated for fatigue durability and were compared with the results of the theoretical analysis. As tested, fatigue durability was predictable when compared with theoretical calculations of tip deflection and normal stress. Although all four shapes have considerable merit for rigidity, in limited intermaxillary conditions, the I- and L-shaped cross-sections may optimize performance and use of space.

Chi-Square Distribution↗

PubMed1995

The future of pharmacy: Armageddon or Pollyanna?

OBJECTIVE: To review important events and predictions about pharmacy that have occurred in the practice since my career began and describe changes in opportunities that have developed over the past 35 years. DATA SOURCES: I used personal recollections and information from the State of Florida Pharmacy Association journal over a 35-year period. Other supporting data were used to describe current practice opportunities. DATA SYNTHESIS: Over the past 35 years many people have predicted the demise of the pharmacy profession. The reasons stated for this demise have varied over the years and include government interference, the expansion of chain and mail-order pharmacies, managed care, loss of the compounding function, Medicaid reimbursement, national health insurance, and pharmacy technicians. Despite these gloomy predictions, community and hospital pharmacies have flourished over the past 35 years and new roles for pharmacists have emerged in managed care, consultant pharmacy, academic pharmacy, and the pharmaceutical industry. With the enactment of the Omnibus Budget Reconciliation Act of 1990 requirements, it appears that the public has even greater expectations from community pharmacists as medication advisors. The pharmacy profession is changing more rapidly than ever and pharmacists must prepare for these rapid changes. Colleges of pharmacy should inculcate in their students the importance of lifelong learning to keep abreast with change. CONCLUSIONS: Society will always need experts on drugs. Pharmacists must rise to the challenge and accept new and changing roles in drug therapy management. If that occurs the future of pharmacy will be ensured.

Forecasting↗

PubMed1995

A longitudinal evaluation of dipyridamole drug use in an ambulatory elderly population.

STUDY OBJECTIVE: To determine the pattern of dipyridamole use over the past 14 years. DESIGN: A longitudinal health screening program of ambulatory elderly participants was used to study changes in dipyridamole drug use. Participants included all subjects screened in the Florida Geriatric Research Program since 1978. The main outcome measure in this study was self-reported dipyridamole use at every visit to the program since August 1, 1978. RESULTS: A total of 3.6% of men (mean age, 82.6 years) and 3.4% of women (mean age, 80.8 years) reported the use of dipyridamole in the 1991-1992 period. The prevalence of dipyridamole use ranged from a low of 1.6% in 1978-1979 to a high of 7.3% in 1986-1987. There was a significant increase in the use of this drug from 1978-1979 to 1991-1992 (p < 0.038). Over the 14-year period of study, the percent of subjects using dipyridamole concurrently with coumarin anticoagulants ranged from a low of 5.8% to a high of 17.9%. CONCLUSIONS: The level of dipyridamole use in this elderly population has increased since 1978-1979. The only FDA indication for this drug is in combination with coumarin anticoagulants to prevent postoperative thromboembolic complications of cardiac valve replacement. Less than 20% of patients in this study used the drug in combination with coumarin anticoagulants. Educational programs are needed to improve the prescribing of dipyridamole.

Aged↗

PubMed1994

Consumption of sweet, salty, sour, and bitter solutions by selectively bred alcohol-preferring and alcohol-nonpreferring lines of rats.

To determine whether selective breeding for high or low oral ethanol consumption is associated with different preferences for nonpharmacological solutions with various flavors, the oral intake of a range of concentrations of sucrose (0.5-64.0 g/100 ml), NaCl (0.025-3.2 g/100 ml), citric acid (0.008-2.048 g/liter), and sucrose octaacetate (0.002-0.512 g/liter) was studied in alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. Separate groups of 7-8 rats from each line were tested for consumption of each of the four flavors. The flavored solutions were presented continuously with water and food always available, and the concentrations were doubled every 48 hr. Although rats from both lines showed a strong preference for the sucrose solutions, P rats consumed greater amounts than NP rats [F(7,98) = 5.57, p < 0.001]. Rats of the P line drank less of the NaCl solutions than NP rats [F(7,98) = 3.88, p < 0.001], but the effect was not as robust as the line differences seen with sucrose. The P and NP rats did not differ in citric acid or sucrose octaacetate intake at any of the concentrations tested. Selective breeding for high oral ethanol preference appears to be positively associated with consumption of sweet solutions and negatively associated with intake of salty solutions.

Alcohol Drinking↗

PubMed1994

Theoretical assessment of cross sections for cantilevered implant-supported prostheses.

PURPOSE: Occlusal forces concentrate at the cantilevered section(s) of fixed implant-supported prostheses. Investigators in early clinical applications of these prostheses described fractures of the metal alloy framework at the cantilevered-distal abutment junction. Improved performance was noticed when the framework's cross-sectional area was increased and the metal alloys used had an increased tensile strength and elastic modulus. Long-term service of a cantilevered implant-supported prosthesis is directly dependent on the fatigue life of the metal alloy framework. Two fatigue durability factors that are alterable by the technician/clinician are the framework material and the cross-sectional design of the structure. These factors can increase rigidity and alter the stress distribution through the framework. The importance of cross-sectional design on the rigidity may become more critical in situations with decreased intermaxillary space, especially if lengthened cantilevers are required or patients show discernible parafunctional habits. The theoretical aspects of beam deflection and the cross-sectional design of cantilevered structures under stress were investigated in this study. A subsequent report will provide results from experimental evaluations of designs similar to those assessed in this study. MATERIALS AND METHODS: The cross-sectional designs considered are an L, I, U and a nearly elliptical-shaped configuration. The size of the framework was determined by approximating the total cross-sectional space available for the restoration, minus the space required for artificial teeth in severe restrictions. All theoretical and actual specimens were modeled within these confines. Some allowance for the contours of the inferior surface of the artificial teeth was made to optimize the dimensions of each framework. Calculations enabled comparison of relative deflection and stress characteristics of each design group and predictions of fatigue durability. RESULTS: The displacements of each cantilever were found to be dependent upon the heights of each framework. As evaluated, the L and elliptical designs experienced larger maximum end deflections than the I- and U-shaped designs. The maximum normal stresses were observed to be less in the I and elliptical sections than in the U and L sections. CONCLUSIONS: The space restrictions for limited intermaxillary conditions reveal that the I cross-sectional design may provide the least displacement and smallest maximum normal stress under conditions in which each framework is subjected to an identical load. Each of the framework cross sections considered, however, is a viable candidate for use. The effectiveness of any particular shape in an intraoral environment cannot be easily assessed from the simple statistical analysis. Limitations of the predictability with statistical analysis as opposed to actual mechanical testing or in vivo use was noted. Less severe space restrictions would probably improve the estimated performance of the other designs.

Dental Implants↗

PubMed1994

Polypharmacy in the aged. Practical solutions.

Elderly patients use more medications than younger patients and the trend of increasing drug use continues through 80 years of age. Studies conducted in a variety of settings have shown that patients over 65 years of age use an average of 2 to 6 prescribed medications and 1 to 3.4 non-prescribed medications. Success of pharmaceutical and medical research has resulted in an abundance of effective drugs to treat acute and chronic conditions. Most research resulting in the development and marketing of these medications has been directed at proving the efficacy and safety of single drug products. Little research has been directed to determine the safety and efficacy of combining multiple medications to treat concurrent conditions in a single patient. It is known that the use of multiple medications increases the risks of adverse drug reactions, drug-drug interactions, and makes compliance with medication regimens more difficult. Numerous studies have been conducted to better understand factors that are associated with increased drug use in elderly people. Studies also have been conducted to identify interventions that can improve drug treatment for the elderly, and reduce polypharmacy. Multiple drug use is common in older people, and may give rise to drug related problems. Methods to reduce the risks of polypharmacy include patient education, physician education, such as education and feedback systems, and regulatory intervention. Continual drug and disease monitoring is essential.

Aged↗

PubMed1994

Establishing benzodiazepines as oral reinforcers: midazolam and diazepam self-administration in rhesus monkeys.

Oral benzodiazepine self-administration was examined in four adult male rhesus monkeys with histories of ethanol- and pentobarbital-reinforced behavior. Drug solutions and vehicle were concurrently available for 3-hr each day under fixed-ratio (FR) reinforcement schedules. Initially, the monkeys rejected a midazolam solution (0.1 mg/ml) after direct substitution of the drug for an 8% ethanol solution. However, midazolam self-administration was subsequently established by using a fading procedure in which increasing amounts of drug (0.0125-0.2 mg/ml) were gradually added to an 8% ethanol solution, followed by gradual reduction of the ethanol concentration to zero. Midazolam was an effective reinforcer for three of four monkeys tested, i.e., responding that was maintained by the drug solution exceeded that maintained by the drug vehicle. The fourth monkey also self-administered midazolam but drug-maintained responding was not consistently greater than vehicle-maintained responding. The responding maintained by the drug was an inverted-U-shaped or bitonic function of midazolam concentration. The midazolam intake (in milligrams per kilogram) increased as a function of increases in the drug concentration. At the higher concentrations, marked sedative intoxication was observed. There was an inverse relationship between FR size (varied from FR 8 to FR 32) and the amount of drug self-administered. The three monkeys in which midazolam functioned as a reinforcer were then tested with diazepam (0.2 mg/ml), which maintained drug self-administration behavior on direct substitution for 0.2-mg/ml midazolam. Diazepam-maintained responding usually exceeded water responding as the diazepam concentration was increased to 0.8 mg/ml. These data demonstrate robust reinforcing effects of both "short-" and "long-acting" benzodiazepines delivered by the oral route.

Administration, Oral↗