Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine

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Abstract

Methamphetamine is a strong and long-lasting stimulant that can be easily synthesized and is effective when taken either orally, intravenously, or smoked as `ice'. Due to it's escalating abuse, a clear need exists for laboratory procedures to evaluate motivational components of methamphetamine abuse and their underlying neurobiological mechanisms. In the present experiment, we utilized a `yoked' procedure in which rats were run simultaneously in groups of three, with two rats serving as yoked controls which received an injection of either 0.1 mg/kg methamphetamine or saline which was not contingent on responding each time a response-contingent injection of 0.1 mg/kg methamphetamine was self-administered by the third paired rat. Rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptors levels in the ventral tegmental area (34%) and medial (31%) and dorsal (21%) part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens (15%), as measured by in vitro quantitative autoradiography. Since the decreases in levels of dopamine D1 and D2 receptors which occurred in rats self-administering methamphetamine did not occur in littermates that received either yoked injections of methamphetamine or saline, these changes likely reflect motivational states that were present when methamphetamine injection depended on active drug self-administration behavior.

Introduction

Although the popularity of methamphetamine as a drug of abuse first emerged in the 1940s, it was in the late 1980s that a smokable form of methamphetamine with the street names `ice', `crystal' or `glass' spread eastward from Hawaii and California and became increasingly popular, not only because of its strong and long-lasting stimulant properties but also because of its increasing availability, relatively inexpensive cost and multiple routes of administration (i.e., intravenous injection, `snorting', ingestion and smoking) (Cho, 1990). Methamphetamine abuse has rapidly become a significant health problem since its long-term use may result in serious psychiatric (Sato et al., 1983; Iwanami et al., 1994), neurologic (Weiss et al., 1970; Yu et al., 1983; Rothrock et al., 1988), cardiovascular (Hong et al., 1991; Perez-Reyes et al., 1991) and gastrointestinal changes (Pecha et al., 1996). Also, there is the possibility that human abusers of this drug may be at risk for methamphetamine-induced dopamine neurotoxicity (Woolverton et al., 1989; Wilson et al., 1996; Villemagne et al., 1998).

The reinforcing and psychomotor stimulant effects of amphetamines have been attributed to activation of dopaminergic transmission, particularly in the nucleus accumbens (Hoebel et al., 1983; Carboni et al., 1989; Koob and Le Moal, 1997; Nestler and Aghajanian, 1997; Munzar et al., 1999). A substantial body of literature has established amphetamine-like stimulants as potent indirect agonists at dopaminergic synapses and this agonist activity arises from the combined ability of the drugs to release dopamine not only from presynaptic nerve terminals but also at the level of the cell body (Raiteri et al., 1975; Fischer and Cho, 1979; Cheramy et al., 1981; Butcher et al., 1988; Parker and Cubeddu, 1988), to block dopamine uptake (Harris and Baldessarini, 1973; Parker and Cubeddu, 1988) and, at high doses, to inhibit dopamine degradation by monoamine oxidase (Miller et al., 1980).

Due to it's escalating abuse, a clear need exists for laboratory procedures to evaluate motivational components of methamphetamine abuse and their underlying neurobiological mechanisms. One approach is the use of a `yoked' self-administration procedure in which rats are run simultaneously in groups of three, with two rats serving as yoked controls that receive an injection of either drug or placebo which is not dependent on responding each time a response-dependent injection of drug is self-administered by a third rat. Using such a procedure, Di Ciano et al. (1996)found that dopamine oxidation currents in the nucleus accumbens were significantly greater when rats self-administered d-amphetamine, as compared to rats receiving the identical dose and pattern of yoked infusions. Similarly, Hemby et al. (1997)found that response-dependent administration of cocaine resulted in greater increases in the nucleus accumbens extracellular concentrations of dopamine than observed with response-independent administration, as estimated by in vivo microdialysis.

In the present experiment we used a yoked self-administration procedure to assess behavioral, as distinct from pharmacological, factors in determining neuroadaptations in the dopaminergic system of rats withdrawn for 24 h from chronic methamphetamine self-administration. This was done by first developing a set of conditions under which methamphetamine would be consistently self-administered over time at dose levels low enough to preclude neurotoxic effects. Subsequently, rats were studied in groups of three, with only one rat actively self-administering methamphetamine while the other two received yoked injections of either methamphetamine or saline.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, Wilmington, MA) weighing approximately 300 g at the start of the experiment were individually housed in a temperature- and humidity-controlled environment under a 12-h light/dark cycle (lights on at 7:00 a.m.). In contrast to many previous investigations, rats had no operant history and food and water were available ad libitum in the home cage. Rats were trained and tested between 12:00 and 5:00 p.m. Animals used in this study were maintained in

Acquisition and maintenance of methamphetamine self-administration

For the data from the 0.1 mg/kg/injection dosage group (data not shown), a two-factor ANOVA for repeated measures revealed significant effects between active and inactive hole responding [F(1,461)=448.05, P<0.001] over the 33 sessions [F(32,461)=5.36, P<0.001]. In addition, there was an overall significant interaction between nose-poke responding and sessions [F(32,461)=6.24, P<0.001]. Post-hoc analysis revealed that a significant preference for the active hole occurred on sessions 22–33 (P

Reinforcing effects of methamphetamine

The present data confirm earlier reports that methamphetamine can serve as a positive reinforcer in rats via the intravenous route of administration (Pickens et al., 1967; Yokel and Pickens, 1973; Munzar et al., 1999). With both the 0.1 and 0.3 mg/kg/injection training-dose regimen, self-administration of methamphetamine was acquired, as measured by selective responding in the active vs. the inactive hole, and subsequently maintained by rats. Following the initial acquisition period with

Acknowledgements

We thank Dr. C.W. Schindler for his constructive criticism and Drs. M. Shoaib, M. Asanuma and H. Hirata for help in establishing self-administration and TH-immunohistochemistry protocols employed in the present experiments.

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    Present address: Department of Toxicology, Toxicology Research Institute, Korea Food and Drug Administration, 5 Nokbun-dong, Eunpyung-gu, Seoul, 122-020, South Korea.

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