Date of Award

2012-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Manuel Miranda

Abstract

Methamphetamine (METH) abuse is a persistent problem in the U.S. and abroad. Escalation of METH use among independent users occurs for a variety of physiological and psychological reasons. Methamphetamine dependence may be attributed to the rewarding effect of this drug via the dopaminergic systems of the central nervous system (CNS). The presence of METH in the CNS increases synaptic release of dopamine. This increase in dopaminergic neurotransmission is thought to be directly attributed to the rewarding effects of METH. Following METH use, compensatory changes have been found to occur in the dopaminergic system during various periods of abstinence. It is proposed that these molecular compensatory responses during periods of abstinence following stimulant usage may in part be responsible for facilitating addiction behavior and drug relapse.

Previous studies have shown that rats given extended access to methamphetamine self-administration display an escalation of drug intake as compared to animals given limited access to this drug. Many other studies using both self-administration operant conditioning and non-contingent delivery of METH in rodents have found various changes in key dopaminergic proteins following access to high-dose METH under limited durations. However, dopaminergic protein changes which may occur shortly following an extended access (20 days or more) METH paradigm are not well-characterized. The goal of this study was to compare changes in dopaminergic systems in rats allowed extended versus limited access to methamphetamine self-administration following an extended access paradigm.

Adult Wistar rats (n=10 extended, n=7 limited, n=8 naí¯ve) were given either extended (6 hr/day) or limited (1 hr/day) access to intravenous self-administration (IVSA) of METH (0.025 mg/infusion) for 28 days. Control rats received surgical implantation of intravenous catheters, but were not given access to METH IVSA. The rats were sacrificed 72 hours after the final self-administration session. All groups were compared with respect to striatal dopaminergic protein expression (Tyrosine hydroxylase, TH, dopamine transporter, DAT, and dopamine receptor 2, D2R) using western-blot and immunocytochemistry procedures.

The results revealed that rats given extended access to METH displayed an escalation of METH intake during the first hour of each session, and this behavior was not observed in animals given limited access. Seventy-two hours after termination of extended access paradigm the largest changes in striatal dopaminergic markers were observed between drug naí¯ve controls versus rats that self-administered METH for the extended access (6hrs) duration. Western-blot analyses of striatal tissue revealed no significant difference in immunoreactivity for TH between treatment groups and naí¯ve animals. By contrast, a significant increase in total striatal DAT was found in extended access self-administration rats as compared to naive controls. Preliminary immunocytochemistry analysis was consistent with the latter results, suggesting an increase in the levels of DAT throughout the corpus striatum. On the other hand, no significant changes were found between METH IVSA and naí¯ve controls for D2R striatal immunoreactivity.

Taken together, our results revealed that rats allotted 6 hours access to METH IVSA showed an escalation of intake compared to rats allotted 1 hour of access. In addition, it was found that expression of dopaminergic markers in the striatum were altered after extended methamphetamine self-administration access. These findings cast new insight into the molecular mechanism of long-term METH use and subsequent escalation, which may evoke cravings for sustained use and relapse during initial periods of withdrawal.

Language

en

Provenance

Received from ProQuest

File Size

62 pages

File Format

application/pdf

Rights Holder

Joe Luevano

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