Influence of aripiprazole pretreatment on the reinforcing effects of methamphetamine in humans.

Methamphetamine use disorders remain a significant public health concern. Methamphetamine produces its behavioral effects by facilitating release of monoamines like dopamine (DA) and serotonin (5-HT). Results from animal studies show that acute pretreatment with DA and 5-HT antagonists attenuates the effects of methamphetamine, but this area remains largely unexplored in humans. This study sought to assess whether aripiprazole, a partial agonist at D2/5-HT1A receptors and an antagonist at 5-HT2A receptors, would attenuate the reinforcing and subject-rated effects of oral methamphetamine. Seven subjects with histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 4, 8 or 16 mg) following acute pretreatment with aripiprazole (0 and 15 mg). During each Sampling Session, subjects also completed a battery of subject-rated, cardiovascular, and other performance measures. In subsequent Self-Administration Sessions, subjects were provided the opportunity to earn the previously sampled methamphetamine dose on a progressive-ratio procedure. Methamphetamine functioned as a reinforcer, and produced prototypical stimulant-like subject-rated and cardiovascular effects (e.g., increased ratings of Stimulated; elevated blood pressure). Aripiprazole reduced methamphetamine self-administration and attenuated some of the positive subject-rated effects of methamphetamine (e.g., ratings of Like Drug). These results indicate that acute aripiprazole pretreatment attenuates the abuse-related effects of methamphetamine.

Alternative reinforcer response cost impacts methamphetamine choice in humans.

Methamphetamine use disorders are a persistent public health concern. Behavioral treatments have demonstrated that providing access to non-drug alternative reinforcers reduces methamphetamine use. The purpose of this human laboratory experiment was to determine how changes in response cost for non-drug alternative reinforcers influenced methamphetamine choice. Seven subjects with past year histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 8 or 16 mg) and completed a battery of subject-rated and physiological measures. During subsequent sessions, subjects then made eight discrete choices between 1/8th of the sampled dose and an alternative reinforcer ($0.25). The response cost to earn a methamphetamine dose was always 500 responses (FR500). The response cost for the alternative reinforcer varied across sessions (FR500, FR1000, FR2000, FR3000). Methamphetamine functioned as a positive reinforcer and produced prototypical stimulant-like effects (e.g., elevated blood pressure, increased ratings of Stimulated). Choice for doses over money was sensitive to changes in response cost for alternative reinforcers in that more doses were taken at higher FR values than at lower FR values. Placebo choices changed as a function of alternative reinforcer response cost to a greater degree than active methamphetamine choices. These findings suggest that manipulating the effort necessary to earn alternative reinforcers could impact methamphetamine use.

Effects of methamphetamine on response rate: a microstructural analysis.

Key pecking in pigeons was maintained under a multiple random-interval (RI) 1-min, RI 4-min schedule of food presentation. Several doses (0.3-5.6 mg/kg) of methamphetamine were administered, and effects on overall response rates and on the microstructure of responding were characterized. In three of the four pigeons, methamphetamine dose-dependently decreased overall response rate in both components; in the fourth pigeon, intermediate doses increased response rates. Log-survivor analyses did not produce the clear "broken-stick" pattern previously reported with rats [Shull, R.L., Gaynor, S.T., Grimes, J.A., 2001. Response rate viewed as engagement bouts: effects of relative reinforcement and schedule type. J. Exp. Anal. Behav. 75, 247-274]. A fine-grained analysis of inter-response times (IRTs) revealed clear bands of responding around certain IRT durations. Methamphetamine tended to decrease the frequency of IRTs in the shorter bands and increase the frequency of IRTs across all bins greater than 2s. These results suggest that (a) survivor analyses may not extend to pigeon key pecking, (b) microstructural analyses can reveal order not evident with overall response rate, and (c) a detailed analysis of responding might prove more useful than summary measures in characterizing drug effects on behavior.

Bouts of responding: the relation between bout rate and the rate of variable-interval reinforcement.

By nose poking a lighted key, rats obtained food pellets on either a variable-interval schedule of reinforcement or a schedule that required an average of four additional responses after the end of tile variable-interval component (a tandem variable-interval variable-ratio 4 schedule). With both schedule types, the mean variable interval was varied between blocks of sessions from 16 min to 0.25 min. Total rate of key poking increased similarly as a function of the reinforcer rate for the two schedule types, but response rate was higher with than without the four-response requirement. Analysis of log survivor plots of interresponse times showed that key poking occurred in bouts. The rate of initiating bouts increased as a function of reinforcer rate but was either unaffected or was decreased by adding the four-response requirement. Within-bout response rate was insensitive to reinforcer rate and only inconsistently affected by the four-response requirement. For both kinds of schedule, the ratio of bout time to between-bout pause time was approximately a power function of reinforcer rate, with exponents above and below 1.0.