Project 6A: Muscarinic Influence on Methamphetamine Discrimination (and lntake)

Matthew Ford, Ph.D., Principal Investigator

An emerging base of preclinical literature suggests a prominent role for cholinergic neurotransmission in the mediation of psychostimulant abuse, from initial drug exposure to the transition towards dependence to exacerbation of relapse risk. The overall goal of this pilot project is to explore the pharmacological ramifications of altered muscaranic receptor (mAChR) function on the expression of methamphetamine's discriminative stimulus effects.

The subjective effects of abused drugs are thought to be critically involved in promoting drug seeking by directing this behavior towards drug access, and it is generally believed that the associated brain circuitry and receptor mechanisms underlying drug discrimination also mitigate, at least in part, the reinforcing effects of the drug.

In the past, a pharmacological dissection of the muscarinic basis of psychostimulant discrimination was hampered by the lack of receptor subtype-specific ligands, an issue which is now circumvented by the advent of subtype-preferring drugs and compounds that act through an allosteric binding site on mAChRs.

This project will explore the ability of mAChR agonists, antagonists and positive allosteric modulators (PAMs) to diminish the discriminative stimulus properties of methamphetamine by implementing the pharmacology-based strategies of substitution and pretreatment 'blocking'.

Based on limited work with cocaine and related psychostimulants, it is hypothesized that M1 and M4 subtype-preferring agonists and PAMs will exhibit the greatest potential in reducing the salience of methamphetamine's discriminative cue.

By arriving at a further understanding of how cholinergic neurotransmission alters the perception of methamphetamine’s centrally-mediated effects, more effective therapeutic strategies can be developed to counteract behavioral and cognitive endpoints associated with methamphetamine exposure such as drug seeking, self-administration, locomotor sensitization, and functional brain deficits.