Neurochemistry of Abuse Liability Assessment and Primary Behavioral Correlates

This chapter describes the regulatory impetus for potential consideration, with respect to abuse liability assessment, of certain pharmaceutical classes during the drug development process and the associated neuronal systems of potential concern. A high-level overview is provided of the Reward System (i.e., the mesocorticolimbic reward pathway), the conserved homology of the Reward System across species, and the neurotransmitter systems of concern, which are known to impinge upon the Reward System. The transmitter systems/receptors reviewed include dopamine, norepinephrine, serotonin, monoamine transporters, histamine, GABA (gamma-aminobutyric acid), glutamate, cholinergic (ACh), opioid, cannabinoid, and sigma. There is additional consideration of in vitro ligand binding data with some emphasis on receptors of greater concern with respect to abuse liability assessment and a corresponding in vivo behavioral correlate (locomotor activity) that would typically precede the utilization of more specific abuse liability assessments discussed elsewhere in this volume (i.e., self-administration, physical dependence, drug discrimination, Conditioned Place Preference (CPP), and/or Intracranial Self-Stimulation (ISS)).