Elsevier

Biological Psychiatry

Volume 44, Issue 11, 1 December 1998, Pages 1171-1177
Biological Psychiatry

Original Articles
Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans

https://doi.org/10.1016/S0006-3223(97)00454-XGet rights and content

Abstract

Background: Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressive behavioral response. Although animal models of sensitization are well established, the phenomenon has been relatively little studied in humans. In a previous study, we reported enhanced responses following a second as compared to a first amphetamine dose in eye-blink rate and ratings of increased motor activity/energy, increased speech, and elevated mood in normal human volunteers. This current study extends those findings in a new sample of normal volunteers.

Methods: Eleven normal human volunteers were administered three single oral doses of d-amphetamine (0.25 mg/kg) at 48-hour intervals, alternating with matched placebo in a randomized, double-blind trial. Hourly behavioral ratings included eye-blink rate, symptoms (elevated mood, increased speech, increased motor activity/energy), and subjective drug effects.

Results: Eye-blink rate and increased motor activity/energy ratings progressively increased following each challenge with the third amphetamine dose response significantly greater than all other conditions 4 hours postadministration. Similar, although less pronounced, responses were observed for elevated mood and subjective drug effect.

Conclusions: These results provide further evidence for sensitization of some amphetamine-induced behaviors in human subjects.

Introduction

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively greater or more rapid behavioral response. Sensitization has been widely studied in a variety of animal models and is a robust, replicable measure of neural plasticity Segal et al 1980, Segal et al 1981, Robinson and Becker 1986. It has been demonstrated in essentially every mammalian species in which it has been examined (Robinson and Becker 1986), but has been little studied in humans.

Despite this lack of studies in humans, processes homologous to behavioral sensitization have been hypothesized to contribute to the development of schizophrenia (Segal et al 1981), recurrent affective syndromes (Post 1992), posttraumatic stress disorder (Yehuda and Antelman 1993), and stimulant-induced psychoses Bell 1973, Sato et al 1983. Sensitization may also play a role in the development of stimulant abuse syndromes, although the specific mechanisms for this are unclear. Robinson and Berridge (1993) have proposed that sensitization may underlie the development of drug craving, thereby contributing to substance dependence and relapse. Additionally, behavioral sensitization produces progressive psychomotor stimulating effects in many mammalian species, and the neurobiological mechanisms underlying psychomotor stimulation have also been hypothesized to underlie the positive reinforcing properties of stimulants (Wise and Bozarth 1987). Understanding behavioral sensitization in humans may therefore lead to improved understanding of the pathophysiology of a range of psychiatric and substance use disorders.

Recently, we examined behavioral sensitization in normal human volunteers using a placebo-controlled, randomized, double-blind study of repeated low-dose d-amphetamine challenges (Strakowski et al 1996). In these subjects, we observed an enhanced response in measures of eye-blink rate, motor activity/energy, rate of speech, and elevated mood following a second amphetamine challenge as compared to the first. This study was the first placebo-controlled demonstration of sensitizationlike activity in humans, supporting previous clinical and uncontrolled observations Bell 1973, Sato et al 1983, Brady et al 1991, Satel et al 1991, Szechtman et al 1988, although Rothman et al (1994) reported a lack of cocaine-induced sensitization in a sample of subjects with cocaine dependence.

In this current study, we replicated and extended our previous work in a new sample of normal volunteers by administering a third d-amphetamine challenge to determine whether behavioral responses would continue to progressively increase. In animal studies, progressive behavioral enhancement following several repeated stimulant challenges is a more rigorous demonstration of sensitization than are two-dose paradigms. Additionally, in this current study we added subjective measures of stimulant effects that are commonly employed in substance abuse research to clarify the role behavioral sensitization may play in the development of stimulant abuse and dependence. We hypothesized that the measures previously demonstrated to be enhanced, following a second amphetamine challenge would continue to progressively increase following a third challenge.

Section snippets

Methods and materials

The methodology employed in this study is essentially identical to that of our previous report (Strakowski et al 1996), except that an additional 2 days were added to the study protocol to permit the third amphetamine and placebo challenges, and subjective measures of stimulant effects were administered in addition to the ratings used previously. This sample of normal volunteers is entirely different from that used in our previous study (Strakowski et al 1996). Details are as follows.

Results

Eleven consecutively recruited normal volunteers completed the protocol. Five of these subjects were men, and 6 were women, with an average age of 24 years (SD = 2 years) and average education of 16 years (SD = 2 years). Six subjects (55%) were randomized to receive amphetamine on the first day, and 5 (45%) received placebo. No adverse events from amphetamine administration were encountered during this study. Moreover, minimal changes were observed in vital sign measures, and blood pressure and

Discussion

This study replicates and extends our previous work by demonstrating a progressive behavioral response following three low-dose d-amphetamine challenges in normal human volunteers. Measures of eye-blink rate and increased motor activity/energy, which showed the most robust behavioral enhancement in our original study (Strakowski et al 1996), also demonstrated a steady progression following each of the three amphetamine challenges in this current study. Both the increased magnitude and duration

Acknowledgements

Supported in part by a NIDA/VA Substance Abuse Medications Development Research Unit Award Y01 DA50038.

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