Quarter-life Values Research Articles

Effects of ethanol on cocaine self-administration in monkeys responding under a second-order schedule of reinforcement

BackgroundConcurrent alcohol use among cocaine abusers is common but the behavioral variables that promote co-abuse are not well understood. The present study examined the effects of intragastric (i.g.) ethanol (EtOH) administration in monkeys responding under a schedule of cocaine reinforcement in which extensive drug seeking was maintained by conditioned stimuli. MethodsFour adult male cynomolgus monkeys (Macaca fascicularis) were trained to respond under a second-order fixed-interval (FI) 600s (fixed-ratio (FR) 30:S) schedule of cocaine (0.003–0.56mg/kg/injection) presentation. Sessions ended after 5 injections or 90min had elapsed. Different EtOH doses (0.5–2.0g/kg, i.g.) were administered 30min before the session, typically on Tuesdays and Fridays. Blood ethanol concentrations (BECs) were also assessed. Pattern of FI responding was assessed by determining quarter-life (QL) values. ResultsCocaine self-administration was characterized as an inverted U-shaped function of dose; QL values increased monotonically with dose. EtOH pretreatments dose-dependently decreased self-administration at several cocaine doses in 3 of 4 monkeys. In one animal, EtOH increased low-dose cocaine-maintained responding. For all monkeys, QL values were increased by EtOH when low- and high-cocaine doses were self-administered, suggesting additive effects of EtOH and cocaine. Furthermore, BECs were not altered following cocaine self-administration. ConclusionsThe reductions in cocaine self-administration and the increases in QL values following EtOH, suggest that EtOH was enhancing cocaine-related conditioned reinforcement. A better understanding of the behavioral mechanisms that mediate the co-abuse of alcohol and cocaine will lead to improved treatments for both drugs.

Cocaine self-administration in social dyads using custom-built operant conditioning chambers.

Traditionally, the analysis of intravenous drug self-administration is limited to conditions in which subjects are tested in isolation. This limits the translational appeal of these studies because drug use in humans often occurs in the presence of others. We used custom-built operant conditioning chambers that allowed social dyads visual, olfactory, auditory, and limited tactile contact while concurrently self-administering cocaine. Male rats were trained to respond according to a fixed interval schedule of reinforcement (with a limited hold) in order to determine if patterns of cocaine (0.75mg/kg/infusion) self-administration became more similar over time in social pairs. Cocaine self-administration was tested across five days according to a 10-min fixed interval schedule (with a 5-min limited hold). Quarter-life values (time at which 25% of responses were emitted per interval) were analyzed using intraclass correlations. The total number of reinforcers obtained did not vary across the five days of testing; however, quarter-life values became progressively more similar between individuals within the social dyads. Standard operant conditioning chambers are unable to assess responding in multiple animals due to their small size, the need to prevent subjects from responding on the lever of their partner, and the need to prevent infusion lines from entangling. By using custom-built social operant conditioning chambers, we assessed the effects of social contact on cocaine self-administration. Social operant conditioning chambers can be used as a preclinical method to examine social influences on drug self-administration under conditions that approximate human substance use.

Effects of unsignaled delays of reinforcement on fixed-interval schedule performance

Key pecking of pigeons was maintained by a fixed-interval (FI) 61-s schedule. The effects of resetting and nonresetting unsignaled delays of reinforcement then were examined. The resetting delay was programmed as a differential-reinforcement-of-other-behavior schedule, and the nonresetting delay as a fixed-time schedule. Three delay durations (0.5, 1 and 10s) were examined. Overall response rates were decreased by one and 10-s delays and increased by 0.5-s delays. Response patterns changed from positively accelerated to more linear when resetting or nonresetting 10-s delays were imposed, but remained predominantly positively accelerated when resetting and nonresetting 0.5- and 1-s delays were in effect. In general, temporal control, as measured by quarter-life values, changed less than overall response rates when delays of reinforcement were in effect. The response patterns controlled by FI schedules are more resilient to the nominally disruptive effects of delays of reinforcement than are corresponding overall response rates.

Behavioral effects of nicotine, amphetamine and cocaine under a fixed-interval schedule of food reinforcement in rats chronically exposed to caffeine.

Epidemiological surveys demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in drug abuse. To characterize the behavioral nature of caffeine interactions with other psychomotor stimulants, we examined the effects of chronic caffeine exposure on the behavioral responses to nicotine, amphetamine, cocaine, the selective D1 agonist SKF-82958 and the selective D2 receptor agonist NPA, in rats responding under a fixed interval (FI) schedule of food reinforcement. Following stabilization of rates and temporal patterns of responding (mathematically expressed as quarter-life values, QL), twenty-one Sprague-Dawley rats responding under a 5-min FI schedule of food reinforcement were divided into two groups; one (twelve rats) maintained on tap water (control) and the other (nine rats) on caffeine (3 mg/ml added to the drinking water). Following the substitution of caffeine solution for tap water, behavior was temporarily disrupted as evidenced by decreases in responding and QL values which reached a maximum after 72 h (rate 60% and QL 30% below baseline levels). Rats developed complete tolerance to these effects of caffeine over 5 days of caffeine exposure. After response rate and QL values stabilized, effects of drugs were evaluated. Nicotine (0.01-1.0 mg/kg; SC), amphetamine (0.1-5.6; IP), and cocaine (1.0-17; IP) each produced biphasic dose-dependent changes in response rate with maximum increases in response rate following intermediate doses and decreases in response rates following higher doses. The increase in rates of responding produced by amphetamine or cocaine (but not nicotine) were greater (P<0.05) in caffeine-drinking than in water-drinking rats. Both SKF-82958 (0.001-0.3 mg/kg; IP) and NPA (0.0001-0.1; IP) produced only dose-dependent decreases in rates of responding. Caffeine-drinking rats were less sensitive to the rate-depressant effects of SKF-82958 (P<0.05) than water-drinking rats. However, similar changes (P>0.05) were produced by NPA in both groups. Except for amphetamine, the remaining drugs produced similar (P>0.05) dose-dependent decreases in QL values in water- and caffeine-drinking rats. Amphetamine produced smaller decreases in QL values in caffeine-drinking rats than in water-drinking rats (P<0.05). Chronic exposure to caffeine produced complete insurmountable tolerance to the response-rate increasing (stimulant) effects of acute caffeine (3.0-17 mg/kg; IP) in caffeine-drinking rats. In conclusion, our study revealed that chronic caffeine exposure potentiates the behavioral response to amphetamine and cocaine but not to that of nicotine in rats responding under a FI schedule of food reinforcement. Thus, it is likely that these effects are mediated through different pharmacological mechanisms.

Sustained Stress and Fixed Interval Performance

Kant, G. J., R. A. Bauman, J. J. Widholm, S. Ghosh and N. Sharma. Sustained stress and fixed interval performance. Physiol Behav 61(2) 279–284, 1997.—The effects of sustained stress on response rate and temporal patterning (quarter-life) of rats performing either a previously learned fixed-interval schedule (FI 60) or learning an FI 60 simultaneously with stress onset were determined. Rats lived 24 h/day in operant cages, where they earned all of their food via lever-pressing. During the stress portion of each experiment, one group of rats was able to avoid or escape signalled intermittent footshock (Avoidance/Escape Group), a second group (Yoked) did not have control over shock termination, a third group never received shock (Control). Shock trials were presented around the clock at approximately 5-min intervals and the stress portion of each study lasted 1–2 weeks. We have previously reported that rats tolerate this paradigm well and avoid/escape 99% of the shock trials. In rats previously trained on the FI task, both rate of responding and quarter-life values were significantly decreased on the first day of stress for both the Avoidance/Escape and Yoked Groups. Food intakes and quarter-life values were not significantly different from the controls by stress Days 3 and 2, respectively. In the acquisition study, controls learned the FI task by Day 4 as judged by quarter-life of responding. FI task acquisition was significantly impaired in stressed rats compared to controls, not reaching asymptotic performance until Day 9 of stress. There were no major differences between the 2 stress groups in either study. These data demonstrate that stress may impair both the rate and patterning of behavior, and suggest that this rodent paradigm may usefully model some aspects of the effects of stress in humans.

Molecular and molar analyses of fixed-interval performance.

Fixed-interval performances of rats were described either in terms of the individual intervals of the session or in terms of a single average interval constructed for the entire session. Responding in the individual intervals usually followed break-and-run and single response patterns rather than the scalloped pattern that emerged when the results were averaged. There was, however, a reasonable correspondence between the quarter-life values calculated from individual intervals and those calculated from the averages. According to the pattern exhibited by the average interval, the probability of a response increased as the interval elapsed. The same conclusion was indicated by more molecular analyses of the conditional probabilities of pause terminations. The results showed that descriptions of fixed-interval data in terms of overall averages reveal aspects of performance that are not immediately apparent within individual intervals.

Effects of terminating chronic phencyclidine on schedule-controlled behavior in rats

Six rats were trained to respond under a multiple fixed-ratio 30, fixed-interval 3-min schedule for food presentation. Acute administration of phencyclidine (0.1–3.2 mg/kg, IP) produced decreases in fixed-ratio response rates at doses above 0.3 mg/kg, but fixed-interval response rates were only decreased at the highest dose. However, the pattern of fixed-interval responding (as evidenced by quarter-life values) was affected at doses above 0.3 mg/kg. Osmotic minipumps were implanted, SC, which infused saline (2 rats) or phencyclidine (4 rats, 10.0 mg/kg/day) for 10 days, and then removed. Daily behavioral sessions were conducted during infusions and for 10 days afterwards. The effects of phencyclidine infusions on fixed-ratio responding were variable. Fixed-interval response rate and quarter-life values were only modestly affected during drug infusion. All three parameters were markedly affected upon cessation of chronic phencyclidine dosing, but there did not appear to be differential effects between the schedule components. No effects on responding were observed during or after saline infusions.

Behavioral effects of CGS 8216 alone, and in combination with diazepam and pentobarbital in dogs

Beagle dogs (N=3) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 schedule of food presentation. The pyrazoloquinoline derivative CGS 8216, given either intravenously (0.01–3.0 mg/kg) or orally (0.1–30.0 mg/kg) had little effect on either the rate or temporal pattern of responding during either component. Both diazepam (0.3 to 17.5 mg/kg, PO) and pentobarbital (0.1–17.5 mg/kg, PO) produced qualitatively similar effects on behavior. Rates of responding during the FI components first increased, then decreased with increasing doses; both drugs produced only dose-related decreases in the rate of responding during the FR components. CGS 8216 antagonized some of the behavioral effects of diazepam; FI and FR response rates returned to baseline, however the effects of diazepam on quarter-life values were not appreciably altered by CGS 8216. The effects of pentobarbital on schedule-controlled responding were not antagonized by CGS 8216. These results indicate CGS 8216 is a selective benzodiazepine antagonist that does not produce benzodiazepine-like behavioral effects.

Pyrazoloquinoline benzodiazepine receptor ligands: Effects on schedule-controlled behavior in dogs

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896 and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.

Effects of norepinephrine and serotonin uptake inhibitors on the schedule-controlled behavior of the pigeon

The effects of nortriptyline, amitriptyline, desipramine, chlorimipramine, protriptyline, doxepin, nisoxetine, fluoxetine and iprindole were determined on responding by pigeons under a multiple fixed-ratio 30-response, fixed-interval 10-minute schedule of grain presentation. Those drugs which have been shown to block uptake of norepinephrine decreased fixed-interval quarter-life values. Those which are considered most selective as norepinephrine uptake inhibitors also increased overall fixed-interval responding. These increases in fixed-interval responding, both on local and overall rates, in pigeons appear to be due to the actions of these drugs to inhibit uptake of norepinephrine rather than to other actions.

Effects of caffeine on schedule-controlled responding in the rat

Six male Harlan/Wistar rats were trained to barpress under a F1300 sec schedule of food presentation until responding was stable. Caffeine (6.0 and 12.0 mg/kg, IP) increased overall response output significantly during the first half-hour after administration; 24.0 mg/kg decreased output significantly during the third and fourth half-hour. The drug also decreased quarter-life values. Rate-dependency analyses indicated that the effect was partially rate-dependent, but intermediate control rates were enhanced relatively more by caffeine than the lowest control rates.

The effect of deprivation upon fixed-interval responding: A two-state analysis

Responding under fixed-interval schedules was studied in three pigeons as a function of three deprivation procedures. Postreinforcement pauses and response rate were measured separately, and quarter-life values were determined. The terminal performance for each bird was characterized by break-and-run patterns of response. Chronic changes in body weight of 5% to 10% of the bird’s free-feeding weight systematically influenced response rates, but postreinforcement pauses and quarter-life values did not change. Neither prefeeding nor acute periods of deprivation up to 72 h resulted in consistent changes in any of the dependent measures. Deprivation primarily influences postreinforcement pausing under fixed-ratio schedules, while response rate is unaffected. Thus deprivation appears to influence behavior differentially under the two schedules.