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THC and its major metabolites, most likely because it decreased the rate of clearance of THC from the body.15

In mice, THC inhibits the release of luteinizing hormone, the pituitary hormone that triggers the release of testosterone from the testes; this effect is increased when THC is given with cannabinol or CBD.113

Cannabinol also lowers body temperature and increases sleep duration in mice.175 It is considerably less active than THC in the brain, but studies of immune cells have shown that it can modulate immune function (see ''Cannabinoids and the Immune System'' later in this chapter).

The Pharmacological Toolbox

A researcher needs certain key tools in order to understand how a drug acts on the brain. To appreciate the importance of these tools, one must first understand some basic principles of drug action. All recent studies have indicated that the behavioral effects of THC are receptor mediated.27 Neurons in the brain are activated when a compound binds to its receptor, which is a protein typically located on the cell surface. Thus, THC will exert its effects only after binding to its receptor. In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds.

Compounds that activate receptors are called agonists. Binding to a receptor triggers an event or a series of events in the cell that results in a change in the cell's activity, its gene regulation, or the signals that it sends to neighboring cells (Figure 2.1). This agonist-induced process is called signal transduction.

Another set of tools for drug research, which became available only recently for cannabinoid research, are the receptor antagonists, so-called because they selectively bind to a receptor that would have otherwise been available for binding to some other compound or drug. Antagonists block the effects of agonists and are tools to identify the functions of a receptor by showing what happens when its normal functions are blocked. Agonists and antagonists are both ligands; that is, they bind to receptors. Hormones, neurotransmitters, and drugs can all act as ligands. Morphine and naloxone provide a good example of how agonists and antagonists interact. A large dose of morphine acts as an agonist at opioid receptors in the brain and interferes with, or even arrests, breathing. Naloxone, a powerful opioid antagonist, blocks morphine's effects on opiate receptors, thereby allowing an overdose victim to resume breathing normally. Naloxone itself has no effect on breathing.

Another key tool involves identifying the receptor protein and determining how it works. That makes it possible to locate where a drug activates its receptor in the brain—both the general region of the brain and



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