Morphine Tolerance as a Function of Ratio Schedule: Response Requirement or Unit Price?

Abstract

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.

Tolerance to Effects of Cocaine on Behavior Under a Response‐initiated Fixed‐interval Schedule

“…That is, tolerance was related to schedule size. Therefore, this study extends findings typically associated with ratio schedules of reinforcement (Hughes & Branch, 1991;Hughes, et al, 2005;Nickel & Poling, 1990;Nickel, et al, 1993;van Haaren & Anderson, 1994) to RIFI schedules of reinforcement.…”

“…One possible interpretation of these findings is that the equal magnitude of tolerance across components was due to the low, but comparable response requirements. Consistent with such a view is that in experiments with ratio schedules, tolerance was evident with small response requirements, but not with larger requirements (e.g., Hughes & Branch, 1991;Hughes, et al, 2005;Nickel, et al, 1993;van Haaren & Anderson, 1994). The results of the current study cast doubt on that view, because the response requirement was held at two for all schedules, and the resulting tolerance was nevertheless modulated by schedule duration.…”

“…Like the study by Hoffman et al (1987), in which a multiple fixed-ratio schedule was used, the PRP under the current RIFI schedules was (1) directly related to the time to the next reinforcement, and (2) inversely related to the overall rate of reinforcement. These are necessary features of all ratio schedules, and are common to arrangements that have consistently yielded parameter-related tolerance (e.g., Hughes & Branch, 1991;Hughes, et al, 2005;Nickel, et al, 1993;Nickel & Polling, 1990;van Haaren & Anderson, 1994). Further, neither of these relationships is present in FI or variable-interval (VI) schedules (except in the relatively rare cases where the pause exceeds the interval value), schedules under which parameter-related tolerance is typically not obtained.…”

“…With daily presession administration of a dose of cocaine that decreased response rates, tolerance to these behavioral effects developed under the FR 5 schedule, but did so less or not at all under the larger value FR schedules. This finding may be referred to as scheduleparameter-related tolerance, and has been obtained in a variety of species (Hughes & Branch, 1991;van Haaren & Anderson, 1994), with different drug types (Hughes et al, 2005;Nickel & Poling, 1990), and with different types and values of ratio schedules (Branch, 1990;Nickel et al, 1993;Yoon & Branch, 2004). These findings have led to subsequent studies attempting to clarify behavioral mechanism(s) involved in producing scheduleparameter-related tolerance.…”

“…Previous research has illustrated that environmental circumstances may play a significant role in the development of tolerance (for reviews see Branch, 1991;Carlton, 1983;Stewart & Badiani, 1993;Wolgin, 1989). For example, contingencies of reinforcement can influence drug tolerance (e.g., Branch, 1990;Hoffman, Branch, & Sizemore, 1987;Hughes & Branch, 1991;Hughes, Sigmon, Pitts, & Dykstra, 2005;Nickel, Alling, Kleiner, & Poling 1993;Pinkston & Branch, 2004;van Haaren & Anderson, 1994;Yoon & Branch, 2004). As an illustration, Hoffman et al (1987) studied the development of tolerance to effects of cocaine on behavior under a multiple fixed-ratio (FR) schedule with FR values of 5, 25, and 125 (FR 50 for one subject).…”