Behavioral maintenance of high concentrations of blood ethanol and physical dependence in the rat.

Rats maintained on an intermittent food schedule with an available ethanol solution drink to excess (13.1 grams of ethanol per kilogram of body weight, daily). Removal of ethanol produces symptoms of physical dependence including death from tonic-clonic seizures. Overindulgence in oral self-administration of an aqueous ethanol solution, resulting in unequivocal physical dependence, approximates a model of human alcoholism.

The relationship between oxygen delivery and consumption during fluid resuscitation of hypovolemic and septic shock.

The effects of increasing oxygen delivery (DO2) on oxygen consumption (VO2) in eight patients with septic shock and five patients with hypovolemic shock were studied during fluid resuscitation. In the septic shock group, DO2 increased from 315 +/- 29 to 424 +/- 25 ml/min/m2 (p less than 0.01) and VO2 increased from 134 +/- 8 to 151 +/- 7 ml/min/m2 (p less than 0.01). In the hypovolemic shock group, DO2 increased from 239 +/- 26 to 386 +/- 48 ml/min/m2 (p less than 0.01) and VO2 increased from 96 +/- 9 to 135 +/- 6 ml/min/m2 (p less than 0.01). There was no significant difference in either the increase in DO2 or VO2 between the septic shock and hypovolemic shock patients. We conclude that increasing DO2 by fluid resuscitation increases VO2 during both hypovolemic and septic shock.

Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats.

RATIONALE: In previous studies, water-deprived rats offered hypertonic 1.5% NaCl solutions to drink showed increased intakes when treated with agents known to have anxiolytic action in humans. This study explored two non-benzodiazepine (non-BZ) sedative-hypnotic agents, zolpidem and zaleplon, and compared them with three traditional BZs. OBJECTIVES: Although many studies confirm that treatment with BZs possessing sedative-hypnotic and anxiolytic actions also produces acute increases in food and fluid ingestion in animals, zolpidem has yielded conflicting results. To help resolve this question, we compared three BZs with zolpidem and zaleplon with respect to their actions in increasing the ingestion of 1.5% NaCl solution in water-deprived rats. METHODS: Rats were adapted to a water-deprivation schedule permitting drinking for 1 h daily. Once or twice each week, 1.5% NaCl solution was substituted for water during the drinking session and, 15 min pre-session, rats were given a drug or vehicle dose by gavage (p.o.) to delineate the dose-effect relationships for zolpidem, zaleplon, alprazolam, clonazepam, and chlordiazepoxide. Then, the dose-effect relationship for zolpidem was re-determined. A second study with two groups, using both zolpidem and clonazepam, explored whether following the dose-effect determination of a drug by a second determination affected the second relationship, and whether dose-effect determinations of either agent affected the results of the second agent investigated. RESULTS: All agents yielded dose-related increases in 1.5% NaCl solution ingestion, except the first zolpidem determination in the first study. In the second study, all determinations yielded dose-related increases, with no indication that the set of determinations for the first agent affected those for the second agent. CONCLUSIONS: The BZ and non-BZ agents explored yielded significant dose-effect relationships using this procedure, confirming their classification among the anxiolytic agents. The initial negative result for zolpidem in the first study may indicate a less reliable anxiolytic action for this agent, although this could not be resolved as attributable to drug history.

Independent interaction of alprazolam and caffeine under chronic dose regimens on differential reinforcement of low-rate (DRL 45-s) performance.

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics.

RATIONALE: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. OBJECTIVES: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. METHODS: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (Fsrr and Frr). RESULTS: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of Fsrr (13.67%) and Frr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. CONCLUSIONS: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine.

Spontaneous activity as a contingency-controlled behavior within an operant context: alprazolam concentration-effect relations after subcutaneous administration in rats.

RATIONALE: Environmental factors affect serum drug concentration-effect relations. For example, after midazolam administration, longer pre-session delays imposed in experimental chambers produced differential concentration-effect relations compared to those of shorter delays. OBJECTIVES: To evaluate the extent to which serum concentrations determine alprazolam's effects on spontaneous activity in the presence and absence of a differential reinforcement of low rate (DRL 45-s) contingency using pharmacokinetic-pharmacodynamic analysis. Serum concentrations reported here were simulated from our published pharmacokinetic parameters for alprazolam. METHODS: One group (n=8) was used to investigate alprazolam's effects on spontaneous activity within the DRL contingency by placing an activity platform beneath each operant chamber to monitor concurrently both spontaneous activity (large and small movements) and DRL performance (shorter-response and reinforcement rates) in 3-h sessions; a parallel group (n=7) was used without the operant context. The concentration-effect relation of the reinforcement rate was compared and contrasted with those of spontaneous activity. RESULTS: Alprazolam decreased large and small movements within the DRL contingency, which corresponded to that of reinforcement rates under the DRL 45-s schedule. In contrast, without the DRL contingency, alprazolam's effects on small movements were short-lived (i.e., 30 min) and no effects on large movements were detected. Hence, the predicted concentration-effect relations for the reinforcement rate function described those of spontaneous activity well within the operant context, but not those without the operant context. Furthermore, the latter showed no correlation between serum alprazolam concentration and large movements; a significant, but low negative correlation for small movements was observed. CONCLUSIONS: The duration of alprazolam's action was dependent on not only dose size but also the behavioral measure examined. By imposing the DRL contingency, spontaneous activity behaves as an ideal pharmacodynamic measure (i.e., continuous, sensitive, and objective).

Contribution of the active metabolite, norcocaine, to cocaine's effects after intravenous and oral administration in rats: pharmacodynamics.

RATIONALE: Oral cocaine is more effective than IV cocaine by pharmacokinetic and pharmacodynamic analysis. One explanation is involvement of the active metabolite, norcocaine, in cocaine's effects. OBJECTIVES: To evaluate norcocaine's contribution to oral cocaine's effects, norcocaine's effects as a parent compound were determined and compared to those of cocaine using a differential reinforcement of low rate (DRL 45-s) schedule and spontaneous activity (large and small movements) after IV and PO routes of administration. METHODS: The effects of cocaine and norcocaine on DRL performance (shorter-response and reinforcement rates) and spontaneous activity were investigated in 3-h sessions. The changes in effects across time (effect-time profiles) and dose-response curves (DRCs) were constructed to evaluate the duration of action and potency (ED50) of both drugs. RESULTS: Under the DRL 45-s schedule, effect-time profiles showed both drugs via the two routes of administration significantly increasing and decreasing shorter-response rates and reinforcement rates, respectively. However, cocaine produced greater effects on shorterresponse rates than norcocaine, while both drugs produced comparable effects on reinforcement rates. For spontaneous activity, although IV cocaine, PO cocaine, and PO norcocaine dose- and time-dependently increased spontaneous activity, cocaine's effects were more profound than those of norcocaine. Effect-time profiles revealed that the duration of drug action was a function of dose, route, and behavioral paradigm used. According to ED50 values, IV cocaine was more effective than PO cocaine; however, PO cocaine was more effective than IV cocaine as judged by ED50 values corrected for absolute oral bioavailability. CONCLUSIONS: Norcocaine's contribution to oral cocaine's effects on DRL performance is evident. Other mechanism(s), such as a greater acute tolerance to IV cocaine's effects than to PO cocaine's effects, can be excluded.

Effects of hetastarch and albumin on coagulation in patients with septic shock.

The effect of 6% hydroxyethyl starch (hetastarch) and 5% human serum albumin (albumin) infusion on coagulation in 12 patients with septic shock was evaluated. Patients were randomly assigned to receive either albumin (N = 6) or hetastarch (N = 6) infusion over a 24-hour study interval. The prothrombin time (PT), partial thromboplastin time (PTT), and quantitative platelet count (PC) were obtained prior to and following 24 hours of fluid infusion. Hetastarch patients received 4934 +/- 1354 mL and albumin patients received 3067 +/- 256 mL over the study interval. After hetastarch infusion, the PT increased 2.2 +/- 0.7 seconds, PTT increased 20.0 +/- 4.1 seconds (P less than .01), and PC decreased 158 +/- 36 X 10(3)/mm3 (P less than .02). After albumin administration, the PT decreased 1.2 +/- 1.7 seconds, PTT increased 20.5 +/- 10.6 seconds and PC decreased 100 +/- 34 X 10(3)/mm3. There were no significant differences in the changes in PT, PTT, or PC between the groups. The authors conclude that hetastarch infusion does not result in increased bleeding in patients with septic shock compared with albumin infusion, despite moderate effects on the hemostatic coagulation profile.

Pharmacokinetic determinants of cocaine's differential effects on locomotor and operant behavior.

Dose-response, effect-time and concentration-effect relations of intravenous cocaine (1-4 mg/kg) were investigated on contingency-controlled [fixed-ratio (FR) 70 performance] and unconditioned (locomotor activity) behaviors. Cocaine dose-response curves exhibited decreasing rates of response under the FR 70 schedule but increasing locomotor activity in a dose-related fashion. Effect-time profiles confirmed that these changes were time-dependent and provided additional clarity by mirroring the biexponential decay of cocaine concentrations with time. The duration of action of cocaine was comparatively shorter on locomotor activity than on FR performance. We integrated effect-time profiles of the two behaviors with concentration-time profiles simulated from our previously published pharmacokinetic parameters to derive cocaine's pharmacodynamic parameters. Classical inhibitory Emax and sigmoidal Emax models were used to describe cocaine's effects on FR performance and locomotor activity, respectively. Simultaneous pharmacokinetic-pharmacodynamic modeling reveals evidence of acute tolerance to cocaine in locomotor activity, as indicated by decreasing potency with dose, but not in contingency-controlled behavior.

Midazolam oral self-administration.

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).

Establishing preference for oral cocaine without an associative history with a reinforcer.

Using schedule-induced polydipsia (SIP), a stable, oral, preference for cocaine solution to water presented concurrently can be established by first presenting cocaine in a preferred vehicle, and subsequently fading the vehicle to water. The present study showed that rats exposed to a history of choosing 0.48 mg/ml cocaine in preference to concentrated lidocaine (2 mg/ml) under SIP conditions subsequently maintained this preference when the lidocaine concentration was progressively decreased to zero (water). Preference for lidocaine was tested by fixing it at 0.38 mg/ml (equimolar with 0.48 mg/ml cocaine) while subsequently increasing cocaine from 0.48 mg/ml to 2.5 mg/ml. Lidocaine preference did not occur, rather, preference for concentrated cocaine persisted. The results suggest that the avoidance of lidocaine solution may force the discrimination of the relation between high oral cocaine intake and its reinforcing effects, thereby instituting a stable preference for cocaine.

Schedule-induced oral self-administration of cocaine and ethanol solutions: lack of effect of chronic desipramine.

Groups of rats drinking either solutions of cocaine HCl (0.16 mg/ml), ethanol (2.5% v/v), or water, drank excessive, equivalent volumes in daily, 3-h sessions of food-pellet delivery under a fixed-time 1-min (FT 1-min) schedule. During single-session exposures to pellet-delivery schedules using longer inter-pellet values (FT 3- or 5-min probe sessions), the cocaine and ethanol groups, but not the water group, drank greater ml/pellet amounts, confirming previous research. Inasmuch as enhanced ml/pellet intake during the greater FT probes correlated with the abuse potential of the drinking solution in previous research, the effect of chronic desipramine HCl (2 mg/kg, i.p. daily) on this enhanced intake response was determined. For all groups, chronic desipramine treatment (2 mg/kg was judged to be the maximum dose free of non-specific, suppressive effects) affected neither FT 1-min schedule-induced polydipsia nor did it affect the enhanced ingestional response to the greater FT probes for the cocaine and ethanol groups. Chronic administration of desipramine may have therapeutic efficacy in treating cocaine abuse only in subjects attempting to refrain from cocaine who are aided in their passage through a withdrawal phase by desipramine.

Conditions sufficient for the production of oral cocaine or lidocaine self-administration in preference to water.

Groups of rats were given a chronic history of drinking cocaine solutions of different concentrations in daily, 3-h schedule induced polydipsia sessions. Animals failed to develop a preference for cocaine solution to concurrently presented water. Schedule-induction conditions were maintained, and the animals were divided into separate groups, drinking either cocaine or lidocaine placed in a highly acceptable vehicle (glucose-saccharin solution). Animals preferred their respective drug solutions to concurrently presented water, and these preferences remained stable after the glucose-saccharin vehicle was gradually faded to water, leaving only cocaine or lidocaine, respectively, in the solution. Thus a stable preference for drug solution to water could be instituted in rats for either cocaine or lidocaine solution (putative reinforcing and nonreinforcing agents, respectively) given an appropriate associative history, with high intakes maintained by schedule-induction. Conditions sufficient for the initiation of an oral preference and high intake for a putatively reinforcing drug cannot be assumed to occur owing to the drug's reinforcing property in the absence of demonstrating the ineffectiveness of an appropriate negative control substance.

Oral cocaine as a reinforcer: acquisition conditions and importance of stimulus control.

Schedule-induced polydipsia in rats was established in daily, 3h sessions with a fixed-interval 1min food schedule, and continued with two fluids available on concurrent fixed-ratio 6 schedules. A 2% ethanol solution was preferred to water, and succeeding drug solutions (0.16mg/ml cocaine, 0.1mg/ml caffeine, 0.01mg/ml nicotine, 0.11mg/ml lidocaine) also were preferred. Except for lidocaine, these drugs are known to function as reinforcers. Drug solution position was alternated daily, with location indicated by a discriminative stimulus (S(D)) light. Subsequent S(D) manipulations indicated that lidocaine and cocaine preferences were attributable to the prior association of the S(D) with ethanol rather than to the pharmacological effects of the currently accessible drug. Furthermore, when concurrent water choices were instituted, animals continued to choose the water source indicated by the S(D). The effectiveness and durability of the S(D) in determining polydipsic choice attests to the importance of the associative history of environmental S(D)s in triggering and maintaining drug seeking and drug taking. A model is outlined which suggests that drug abuse is a special case of a more general set of excessive behaviors induced by current environmental conditions, with choice of behavior remaining under S(D) control determined, in part, by the associative history of the S(D).

Schedule-induced polydipsic choice between cocaine and lidocaine solutions: critical importance of associative history.

Two groups of rats given daily, 3-h, intermittent food-pellet sessions, which induced polydipsia, drank either cocaine (COC) or lidocaine (LIDO) solutions. Then water was made available concurrently, but neither group preferred drug solution. When drug was presented in a glucose-saccharin vehicle, which was subsequently faded out, both the COC and LIDO groups acquired a strong preference for drug solution rather than water. Half of each group was continued, and half was directly faded to a preference for the other drug solution rather than water. Then COC and LIDO solutions were available concurrently and animals overwhelmingly preferred the drug solution that historically had been associated with the glucose-saccharin vehicle. Finally, the COC-preferring and LIDO-preferring groups had the concentrations of their preferred drug increased step-wise several times and preferences were maintained. Thus, acquired drug preferences remained stable as preferred drug concentration was increased, making it more bitter than the nonpreferred drug. The abuse potential of COC affords it little advantage over LIDO in the institution and maintenance of oral drug preference, suggesting that the post-ingestive pharmacological action of a drug is less important for acquiring drug-taking than is a history of associating the drug with another reinforcing event.

A schedule induction probe technique for evaluating abuse potential: comparison of ethanol, nicotine and caffeine, and caffeine-midazolam interaction.

Previous research has shown that under daily 3h sessions of food schedule-induced drug solution polydipsia (on a fixed-time 1min (FT 1min) schedule, session probes at greater FT values induced comparatively more ml/pellet drinking of solutions of drugs possessing abuse potential (ethanol, cocaine, midazolam) than of vehicle or other drug solutions. The present study extended these findings to nicotine and caffeine, drugs that usually do not function as reinforcers in i.v. self-administration studies with animals, but are known to have reinforcing effects for humans. The positive effects for nicotine and caffeine did not depend upon prior overindulgence in ethanol. Results on the effects of chronic, presession s.c. doses of midazolam could not be interpreted as contributing to the abuse potential of caffeine, but had independent dipsogenic effects. The FT probe technique, as well as schedule-induced i.v. self-administration, are useful methods for discerning the abuse potential of agents which are usually not distinguished by i.v. self-administration methods.

Schedule-induced polydipsic consumption of hypertonic NaCl solutions: effects of chlordiazepoxide.

Rats were exposed to daily, 3-h sessions of schedule-induced polydipsia (SIP) in which either water, hypertonic NaCl solution (1.5% or 2.2%), or concurrent water and 1.5% NaCl were available. Each condition was in effect for several, consecutive weeks. Presession subcutaneous injections of chlordiazepoxide (CDZP) produced dose-related increases in the polydipsic ingestion of both NaCl solutions but had smaller and less certain effects on water consumption. Under the concurrent-fluid presentation condition, CDZP primarily increased NaCl solution consumption. Conditions generating SIP may function to attenuate what might be viewed as the punishing effects of ingesting highly hypertonic NaCl solutions, thereby permitting the chronic self-administration of large, daily amounts. Like many benzodiazepines, CDZP can attenuate the effects of punishment and thereby also increase NaCl solution ingestion. The two sources of punishment attenuation may be additive, with both differentially effecting greater increases in hypertonic NaCl ingestion, compared to water, when both fluids are presented concurrently.

Prior exposure to a running wheel and scheduled food attenuates polydipsia acquisition.

Groups of rats were given different histories before exposure to daily, 2-h fixed-interval (FI) 1-min food-schedule sessions with water available. In a previous study, a group with a history of chronic exposure to FI 1-min sessions without water subsequently had a reduced rate of acquisition and final level of schedule-induced polydipsia compared to a control group lacking this history. In the present study, groups with histories of chronic exposure to FI 1-min sessions and a concurrent running wheel were even more attenuated in their subsequent acquisition of polydipsia. Substitution of 5% ethanol for session water in the final phase produced a convergence in group intakes, except for a group which continued to have access to the running wheel. The ethanol intake of this group was relatively suppressed.

Prior schedule exposure reduces the acquisition of schedule-induced polydipsia.

Two groups of rats were given different initial histories before exposing them to daily, 2-hr fixed-interval 1-min (FI 1-min) food-pellet sessions with water freely available. For the initial-history phase (approximately 17 weeks), a Schedule-History Group had no water available during FI 1-min sessions, while a Home-Cage-History Group was maintained at the same body weight (80% of free feeding) in home cages. When water then became available for both groups during FI 1-min sessions, the Schedule-History Group was retarded in their rate of acquisition and final level of schedule-induced polydipsia relative to the Home-Cage-History Group. Substitution of 5% ethanol solution for session water in the final phase produced a like intake level for both groups typical for these inducing conditions. It was concluded that the probability of drinking water in a session situation is reduced by a lengthy history of water unavailability, thereby attenuating the acquisition rate and final level of schedule-induced water overdrinking.