An Escalating Dose/Multiple High-Dose Binge Pattern of Amphetamine Administration Results in Differential Changes in the Extracellular Dopamine Response Profiles in Caudate-Putamen and Nucleus Accumbens

Abstract

Amphetamine (AMPH)-induced psychosis is most frequently associated with a chronic high-dose "binge" or "run" pattern of stimulant abuse, generally preceded by a period of gradually escalating doses of the drug. We showed previously that animals subjected to such a regimen of AMPH administration developed, over multiple daily binges, a unique pattern of behavioral response that included a decrease in stereotypy and a pronounced increase in locomotion. Because of the involvement of mesolimbic and mesostriatal dopamine (DA) pathways in locomotion and stereotypy, respectively, we hypothesized that a persistent shift in the relative magnitude of caudateputamen (CP) and nucleus accumbens (NAC) DA transmission may contribute to this altered behavioral profile. To test this hypothesis, we examined CP and NAC extracellular DA in response to multiple high-dose AMPH binges. Our results revealed that with multiple binges the CP DA response but not the NAC response developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. These differential regional response alterations seem to correspond to the shift in the relative expression of stereotypy and locomotion. We hypothesize that changes in DA synthesis, perhaps mediated by regionally specific adaptations in DA autoreceptor function, contribute to the differential extracellular transmitter response profiles, and suggest that these neurochemical changes may have important implications for the mechanisms underlying the addictive and psychotogenic properties of AMPH.

Escalating Dose Methamphetamine Pretreatment Alters the Behavioral and Neurochemical Profiles Associated with Exposure to a High-Dose Methamphetamine Binge

“…This observation is consistent with our previous finding of no decrease in brain levels of METH and AMPH as a function of ED pretreatment (Segal and Kuczenski, 1997c). Furthermore, although ED pretreatment does lead to a decrease in the caudate-putamen extracellular DA response and a corresponding attenuated stereotypy response to a subsequent binge (see below for further discussion), the decreased DA response is selective to caudate-putamen DA; that is, neither the nucleus accumbens DA response, nor the hippocampus NE response was attenuated (Segal and Kuczenski, 1997a;Kuczenski and Segal, 1997). Therefore, it appears that drug dispositional changes may occur only when METH pretreatment and/or binge doses are relatively high.…”

“…Therefore, to more closely approximate highdose METH abuse patterns, including the progressive increase in drug dose that typically precedes high-dose use, we have employed an ED-daily multiple administrations paradigm. Our previous results revealed that this stimulant protocol produced the progressive emergence of a unique behavioral profile and concomitant regionally specific DA response patterns in the striatum (Segal and Kuczenski, 1997a, b, c;Kuczenski and Segal, 1997). These effects appear to be both qualitatively as well as quantitatively different from the responses we have observed with any acute dose or single daily injection pattern of stimulant treatment.…”

“…Since the pattern of drug administration, as well as dose, can significantly influence both the quantitative and qualitative effects of the drug (Gawin and Khalsa, 1996;Unterwald et al, 2001;Riddle et al, 2002a), we suggested that animal model paradigms designed to study the effects of high-dose stimulant abuse should attempt to simulate this pattern of ED exposure (Segal and Kuczenski, 1997a, b, c;Kuczenski and Segal, 1997). In the present study, we demonstrated that ED pretreatment profoundly altered the response to a single binge with high-dose METH, both with respect to striatal DA markers most often assessed in human METH abusers, as well as a behavioral response profile, that is, stereotypy, known to be significantly mediated by METH actions on striatal DA systems.…”

Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

“…Norepinephrine can also facilitate excitatory transmission by depressing the level of basal activity (Woodward et al, 1979). Thus, by virtue of their DA and NE amplifying capacity (Kuczenski and Segal, 1997;Solanto, 1998), stimulants may enhance task-specific signaling in target neurons within specific circuits.…”

A threshold neurotoxic amphetamine exposure inhibits parietal cortex expression of synaptic plasticity-related genes

“…The decreased AMPH-induced upregulation of Arc, NGFI-A, and NGFI-B expression might be considered to be a tolerance effect (Kuczenski and Segal, 1997;Shilling et al, 2000). While this is possible, rats challenged with 7.5mg/kg AMPH after twice daily injections of 7.5mg/kg AMPH do not exhibit locomotor behavioral tolerance (Persico et al, 1993).…”