Introduction

Determining the underlying therapeutic mechanisms of a drug makes pharmacology a powerful tool for understanding biological phenomena. This chapter reviews the preclinical evidence of the impact of some neurotransmitter systems and related drugs on sleep and wakefulness.

GABA-A and sleep

A series of neurotransmitter systems are responsible for maintaining wakefulness, including norepinephrine (NE), serotonin (5-HT), acetylcholine (ACh), dopamine (DA), excitatory amino acids, hypocretins (i.e. orexins), and histamine (Mendelson 2001; Monti and Jantos 2004; Salin-Pascual et al. 1999; Ursin 2002; Sakurai 2005). Delta sleep, or non-REM sleep, is related to adenosine, GABA, and prostaglandins, among others (Ekimova and Pastukhov 2005; Hayaishi and Matsumura 1995; Johnston 2005; Koyama and Hayaishi 1994). Finally, ACh has a prominent role in rapid eye movement (REM) sleep, together with 5-HT, NE, and hypocretin; these three molecules inhibit cholinergic and cholinoceptive neurons, which are implicated in the initiation of this sleep stage (McCarley 2004; Reinoso-Suarez et al. 2001).

GABA, and molecules that act at GABA-A receptors, have been classically recognized as hypnotics (i.e. benzodiazepines) and anesthetics (i.e. barbiturates). Benzodiazepine (BZD) receptors, a modulatory site on the GABA-A receptor, were discovered in the 1970s. Like other sites on the GABA-A receptor complex, these receptors work allosterically, cooperatively modifying channel permeability to chloride ions.