Differential Development of the Enhanced Metabolic Response during Amphetamine Sensitization

Abstract

Behavioral sensitization elicited by repeated administration of amphetamine does not fully develop until a period after discontinuation of amphetamine, but then persists undiminished for a long time. This experiment investigated the regional metabolic changes in rats pretreated with amphetamine and challenged after different abstinence periods (2, 7 and 28 days), using the 2-[¹⁴C]deoxyglucose method. The results demonstrated that chronic amphetamine administration enhanced rates of local cerebral glucose utilization in specific cerebral regions. The magnitude and distribution of effects varied with the abstinence period. A challenge dose of d-amphetamine 2 days after pretreatment was found to have no more, or only mildly elevated, local cerebral glucose utilization compared with that following a single acute dose. In rats challenged at the 7th and 28th day, a supersensitive metabolic response was found in dopaminergic and non-dopaminergic areas. This finding suggested regional differences in the development of sensitization and underscored the importance of an abstinence period in the study of sensitization and amphetamine psychosis.

Reduced Regional [¹⁴C]2-Deoxyglucose Uptake in Response to Long-Term Clozapine Administration in Rats

“…The decreased 2-DG uptake after haloperidol administration is thought to result from blockade of dopamine neurotransmission in the striatum [5,10]. This is supported by our previous studies of rats treated with long-term amphetamine, a dopaminergic stimulant [11,12]. In these studies, we found that several regions, especially the dopaminergic system, had elevated 2-DG uptake after long-term amphetamine administration.…”

Chronic d-amphetamine depresses an imaging marker of arachidonic acid metabolism in rat brain

“…In another study, 2 d following 2 wk of daily 5 mg/kg d-Amph, rCMR glc was increased in one of 36 regions examined, within expectation by chance (Huang et al, 1997). Thus, the widespread depression of baseline k* for AA following 2.5 mg/kg daily d-Amph in our study (Figure 2) is very distinct from previous studies using rCMR glc measurements.…”

Amphetamine sensitization: Nonassociative and associative components.

“…It has been shown that the stimulated dopamine release was enhanced in the striatal tissue slices of the AMPH-pretreated rats (Castaneda, Becker, & Robinson, 1988;Robinson & Becker, 1982). Thus, apparently a contextual input is not necessary to express the sensitization in the brain tissue in vitro, or even in the whole brain in vivo (see Huang et al, 1995Huang et al, , 1997. These results showed existence of a progressive neuroadaptation to AMPH treatment, but how this effect becomes connected to the CS and to the behavioral sensitization is not clear.…”

“…The development of sensitization and the testing included 3 stages (Huang et al, 1995(Huang et al, , 1997): In the pretreatment stage, rats were injected intraperitoneally with d-AMPH (1 mg/kg, Sigma Chemical, St. Louis, MO) or saline (control) daily for 2 weeks. Following each injection, rats were placed into one of the three contexts for 120 min before being returned to the home cage.…”

“…This "nonassociative" view, however, fails to explain the result showing a complete lack of behavioral sensitization under some conditions. For example, it has been shown, with 2-deoxyglucose imaging technique, that repeated administrations of AMPH (1 mg/kg) for 14 days, followed by 7 days of abstinence, altered metabolism in many brain areas in response to challenge of AMPH (0.5 mg/kg); however, no behavioral sensitization was observed (Huang et al, 1995(Huang et al, , 1997. This puzzling dissociation between presence of brain change and absence of behavioral expression has now become explainable.…”