Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

Abstract

Some people who repeatedly use stimulant drugs, such as amphetamine (AMPH), develop an AMPH-induced psychosis that is similar to paranoid schizophrenia. There has been, therefore, considerable interest in characterizing the effects of chronic stimulant drug treatment on brain and behavior in non-human animals, and in developing an animal model of AMPH psychosis. A review of this literature shows that in non-human animals chronic AMPH treatment can produce at least two different syndromes, and both of these have been proposed as animal models of AMPH psychosis. The first syndrome is called 'AMPH neurotoxicity', and is produced by maintaining elevated brain concentrations of AMPH for prolonged periods of time. AMPH neurotoxicity is characterized by what has been termed 'hallucinatory-like' behavior, which occurs in association with brain damage resulting in the depletion of striatal DA and other brain monoamines. The second syndrome is called 'behavioral sensitization', and is produced by the repeated intermittent administration of lower doses of AMPH. Behavioral sensitization is characterized by a progressive and enduring enhancement in many AMPH-induced behaviors, and is not accompanied by brain damage or monoamine depletion. It is argued that the changes in the brain and behavior associated with the phenomenon of behavioral sensitization provide a better 'model' of AMPH psychosis than those associated with AMPH neurotoxicity. Much of the review involves a critical analysis of hypotheses regarding the biological basis of behavioral sensitization. Research on this question has focused on mesotelencephalic DA systems, and suggestions that behavioral sensitization is accompanied by: an increase in postsynaptic DA receptors; an increase in DA synthesis; an increase in DA utilization and/or release; and a decrease in DA autoreceptors, are evaluated. It is concluded that there is not convincing evidence for an increase in postsynaptic DA receptors or in DA synthesis in animals sensitized to AMPH. In contrast, there is strong evidence to support the notion that behavioral sensitization is due to enhanced mesotelencephalic DA release, especially upon re-exposure to the drug. The evidence that this enhancement in DA release is due to autoreceptor subsensitivity was found to be equivocal, and therefore other hypotheses should be entertained. Lastly, evidence is discussed in support of the idea that behavioral sensitization is not unique to the psychopharmacology of stimulant drugs, but may be produced by many environmental stimuli that directly or indirectly activate brain catecholamine systems.(ABSTRACT TRUNCATED AT 400 WORDS)

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

“…Specific environmental context associated with drug administration is considered to be an important experimental factor for the induction of behavioral sensitization [39,45]. However, in order to prevent these context-dependent influences, the induction of behavioral sensitization was conducted in animal's home cages as described in methods.…”

“…Continued use of psychostimulants is typically associated with the development of tolerance. However, repeated intermittent exposure to these psychostimulants such as AMPH, METH, and cocaine was found to produce behavioral sensitization, which is characterized by progressive and enduring augmentation of the behavioral effects in response to subsequent exposure to the same dose of the drug [38,39]. The potential clinical relevance of behavioral sensitization has been associated with development of craving in addicts and psychosis that arise from repeated exposure to these psychostimulants [13,39].…”

“…However, repeated intermittent exposure to these psychostimulants such as AMPH, METH, and cocaine was found to produce behavioral sensitization, which is characterized by progressive and enduring augmentation of the behavioral effects in response to subsequent exposure to the same dose of the drug [38,39]. The potential clinical relevance of behavioral sensitization has been associated with development of craving in addicts and psychosis that arise from repeated exposure to these psychostimulants [13,39]. The most important characteristic of behavioral sensitization to psychostimulants is long lasting, which persists for months even years after cessation of drug treatment [7,13,38].…”

Human Response to Repeated Low-Dose d-Amphetamine: Evidence for Behavioral Enhancement and Tolerance

“…This phenomenon has been widely studied in animals and has been hypothesized to underlie aspects of human stimulant addiction, as well as several psychiatric syndromes (Robinson and Becker 1986;Robinson and Berridge 1993). Despite the potential importance of behavioral sensitization in human clinical conditions, few controlled human studies of this process have been reported.…”

“…Randomization was stratified by sex, because animal studies suggest sex may influence the development of sensitization (Robinson and Becker 1986). Subjects randomized to the experimental, three d-amphetamine dose (AAA), group received an oral dose of d-amphetamine (0.25 mg/kg) on each of the 3 study days (i.e., protocol days 1, 3, and 5).…”