|Factors Contributing to the Development of Tolerance and Sensitization to Drugs of Abuse
|Monday, May 26, 2008
|2:00 PM–3:20 PM
|Area: BPH/EAB; Domain: Basic Research
|Chair: Matt Locey (University of Florida)
|Abstract: The following symposium is comprised of four presentations examining the development of tolerance and sensitization in rats to effects of drugs that are commonly used by humans. All of the presentations revolve around the idea that the expression of either tolerance and/or sensitization depends greatly on the context in which the drug is delivered. The presentations will cover tolerance and sensitization to drug effects on lever pressing, locomotion and stereotypy and will explore drug effects on a variety of schedules of reinforcement. Furthermore, the identification of tolerance and sensitization may depend on whether it is investigated at the individual or group level.
|Is Cocaine Locomotor Sensitization a Within-Subject Effect?
|JULIE A. MARUSICH (University of Florida), Marc N. Branch (University of Florida), Jesse Dallery (University of Florida)
|Abstract: A series of three experiments investigated effects of cocaine on lever pressing and locomotor behavior in rats. In Experiment 1, rats lever pressed on an FR 20 schedule of reinforcement and, after assessments of acute effects, were administered chronic cocaine. Tolerance to lever pressing developed in all subjects. Some subjects developed locomotor tolerance, but none developed locomotor sensitization even when the operant contingency was removed. Experiment 2 examined effects of chronic cocaine administration again, after acute assessments, in rats with no exposure to an operant contingency. Tolerance developed to locomotor effects of cocaine in some subjects, but no subjects developed locomotor sensitization. In Experiment 3, rats were exposed to a shorter drug regimen, and given time off before a sensitization-test session. Only one subject of eight in the cocaine group showed locomotosensitization during the test session. Based on these results and other similar research, locomotor sensitization to cocaine in rats is a common finding only when comparing a cocaine group with a control group, indicating between-group sensitization rather than within-subject sensitization.
|Chronic Nicotine Adminstration Produces Sensitization to Increases in Locomotion and Tolerance to Decreases in Lever Pressing.
|BETHANY R. RAIFF (University of Florida), Jesse Dallery (University of Florida)
|Abstract: Repeated exposure to nicotine increases locomotion in rats, which is often referred to as “sensitization” to the locomotor increasing effects of nicotine. A recent study with cocaine suggests that sensitization to the locomotor increasing effects of cocaine could be masked by the simultaneous availability of an operant task in pigeons (Pinkston & Branch, 2003). No study on the locomotor increasing effects of nicotine included the simultaneous availability of an operant task. The present study exposed 4 male Long-Evans rats to a multiple schedule alternating every 5-min between a variable-interval (VI) 20-sec schedule of food delivery for lever pressing and extinction. Locomotion and lever pressing were recorded simultaneously in an open field activity chamber. Effects of acute exposure to various doses of nicotine were evaluated first, and then one dose (0.56 mg/kg) that initially decreased lever pressing was delivered repeatedly for a minimum of 20 days to evaluate the chronic effects of nicotine. Chronic exposure to nicotine resulted in tolerance to the lever press decreasing effects of nicotine during the VI component. Interestingly, locomotion increased during both the VI and extinction components during chronic nicotine exposure. The results suggest that the simultaneous availability of an operant task does not mask the expression of sensitization to the locomotor increasing effects of nicotine. The current study differed from previous studies in the use of an interval schedule rather than a ratio schedule. It is possible that the nature of the contingency (e.g., ratio versus interval) may play a role in determining whether sensitization develops.
|Modulation of the Topographical Characteristics of Amphetamine-Induced Hyperactivity by an Operant Contingency.
|JONATHAN W. PINKSTON (University of Kansas), Stephen Fowler (University of Kansas)
|Abstract: Amphetamine at 5.0 mg/kg induces a syndrome of stereotypy followed by hyperactivity. Over repeated administrations, the stereotypy phase onsets earlier following drug administration, and the hyperactivity phase persists for longer periods of time. Such changes have been termed “sensitization” to reflect the enhanced effectiveness of amphetamine. Typically, sensitization has been studied in isolated settings, where the animal has very little in the environment to engage its repertoire. The present experiment sought to examine the development of sensitization in an operant context, which provides a comparably more complicated environment than that usually seen in sensitization research. Eight rats were trained to respond on a fixed-ratio (FR) 20 Extinction schedule of water delivery. Once a stable baseline of responding was attained, each rat received 5.0 mg/kg d-amphetamine prior to experimental sessions. Each injection was spaced by 4 days; a total of five administrations were given. Consistent with previous research, repeated d-amphetamine induced profound stereotypy followed by hyperactivity. The hyperactivity, however, was limited to the extinction component of the multiple schedule. During the extinction component, rats circled about the chamber and covered more surface area of the chamber floor. During the FR component, each rat’s locomotion was constrained and they engaged the operant task. Interestingly, operant responding was elevated during the period of hyperactivity. On the surface, it appears that the operant contingency blocked the expression of post-amphetamine hyperactivity. On the other hand, heightened levels of operant responding may indicate that the hyperactivity was not simply blocked during the ratio component, but was manifest in the different topographies engendered by the ratio schedule. Supported by MH043429.
|Supported by MH043429.
Contingencies Affecting the Development of Tolerance and Sensitization: Random-Ratio vs. Random-Interval Schedule.
|ADAM KYNASTON (Utah State University), Wesley P. Thomas (Utah State University), Amy Odum (Utah State University)
|Abstract: Sensitization to the effects of stimulants may be more likely to occur when the effects of the drug do not interfere with earning reinforcers. In this experiment, we are interested in whether random-ratio (RR) and random-interval (RI) schedules can produce differential tolerance and sensitization to the effects of d-amphetamine. In a ratio schedule, responding is directly related to the rate of reinforcement, and therefore, rate-decreasing drug effects are directly incompatible with einforcement. In an interval schedule, the relationship between responding and reinforcement is nonlinear, and a relatively low rate of responding can still earn the maximum available food. In our first experiment, 4 rats responded on a multiple RR RI schedule of food delivery. All four rats showed some degree of sensitization to the rate-decreasing effect of d-amphetamine, however, the use of a multiple schedule did not allow us to determine the contribution of each schedule to the development of sensitization. In our current experiment, eight rats are responding on either a RR or RI schedule of food delivery. Acute doses of d-amphetamine will be administered before and after a 30-day period of chronic injections, and the development of tolerance or sensitization will be assessed.