Methamphetamine and amphetamine differentially affect associative learning: behavioral and neurobiological correlates

Hall, Darien A.

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Description

Title

Methamphetamine and amphetamine differentially affect associative learning: behavioral and neurobiological correlates

Author(s)

Hall, Darien A.

Issue Date

2010-05-14T20:49:44Z

Director of Research (if dissertation) or Advisor (if thesis)

Gulley, Joshua M.

Doctoral Committee Chair(s)

Gulley, Joshua M.

Committee Member(s)

• Juraska, Janice M.
• Korol, Donna L.
• Schantz, Susan L.

Department of Study

School of Molecular & Cell Bio

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• methamphetamine
• amphetamine
• associative learning
• rats

Abstract

One factor hypothesized to contribute significantly to addiction processes is maladaptive associative learning wherein substance-related cues become closely associated with the drug response. These strong associations are thought to contribute significantly to drug craving and promote the cycle of abuse by increasing susceptibility to relapse. One goal of the studies presented here was to model aspects of the addiction process by examining psychostimulant-induced alterations of associative learning, and how specific neurobiological mechanisms, namely glucocorticoid or dopamine receptor activation, contribute to these alterations. A second goal was to investigate potential differences in the effects of two psychostimulants; methamphetamine (METH) and amphetamine (AMPH). These drugs were chosen because, while structurally very similar, they have differing abuse liabilities. Some of the disparities in rates of use and abuse can be accounted for by availability, with METH being more affordable and easier to obtain than AMPH. However, increasing diversion of prescription AMPH for non-medical use is thought to contribute to the rise in prescription drug abuse indicating that it is unlikely to be just a question of greater availability of METH. There are many methods by which the effects of psychostimulants on associative learning can be assessed, however two particular techniques, Pavlovian-to-instrumental transfer and sensitization, were chosen for use in the studies presented here. In Experiment 1, a sensitization paradigm was utilized to determine whether repeated administration of low to moderate doses of AMPH or METH result in differing levels of locomotor sensitization, conditioned locomotor behavior, or cross-sensitization. The results of this study suggest that both drugs elicit approximately equal levels of sensitization and conditioned behavior. However, rats that were pre-treated with METH exhibited cross-sensitization to AMPH, but rats pre-treated with AMPH did not exhibit sensitization to METH. Another important finding from Experiment 1 was that when drugs were given in the presence of salient stimuli, METH was able to modulate associative learning to a greater degree than AMPH. In Experiment 2 a PIT paradigm was utilized to determine whether AMPH and METH capable of differentially impacting the ability a conditioned stimulus to energize responding for an unconditioned stimulus. The results of this experiment suggest that both METH and AMPH interfered with PIT, but METH still exhibited a greater impact on associative learning than AMPH. Differing, but sometimes overlapping, cellular and molecular events define the two phases of sensitization- expression and induction. Given that stress and subsequent glucocorticoid release can influence the sensitized response to psychostimulants it is important to understand the mechanisms that govern these changes. In Experiment 3, I examined whether glucocorticoid receptors contribute to induction or expression of psychostimulant-induced sensitization, as well as whether METH- compared AMPH-induced activity is differentially altered by inactivation of GRs. The results of this experiment suggest that GR activation plays relatively distinct roles in AMPH- and METH-induced sensitization. Locomotor sensitization has been shown to be dependant upon DA transmission in the mPFC; it has not been shown whether D1 receptor activation is critical to the locomotor response to psychostimulants. In Experiment 4, I examined whether a D1 receptor blockade within the mPFC differentially alters METH- compared to AMPH-induced locomotor activity. This was accomplished by infusing the D1 receptor antagonist SCH 23390 directly into the mPFC prior to psychostimulant administration. The results of this experiment suggest that activation of mPFC D1 receptors play a critical role in psychostimulant induced locomotor activity, but are most likely not the mediating factor underlying differences between METH and AMPH. In the experiments presented here both METH and AMPH were found capable of altering associative learning, but METH appears to have a greater impact on these processes than AMPH. It is possible that these differential effects are mediated by activation of GRs. The initial locomotor response to both of these drugs is heavily dependant upon D1 receptor activation in the mPFC, but this is most likely not the mediating factor in the differences between the two drugs. These findings indicate that the differing abuse liabilities between METH and AMPH may be partially predicated by their influence on associative learning processes. Furthermore, overlapping, but somewhat distinct neurobiological mechanisms likely govern these drug-induced differences in associative learning.

Graduation Semester

2010-5

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Copyright 2010 Darien A. Hall

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