Pharmacokinetics

Drug Receptors and Signal Transduction

A receptor is a cellular element of an organism with which a drug interacts to produce its effect. Most receptors are proteins, and most drugs bind to a specific binding site (although there are exceptions; for example, alcohol may interact with an ethanol-receptive element, perhaps in a water-containing pocket of receptors; see, Alcohol).

Drugs that bind to receptors and produce an effect are called agonists. Think of an agonist as a key and the receptor as a lock. The key is turned, producing an effect. An antagonist is a drug that binds to receptors and blocks the effect of an agonist. Think of an antagonist as a broken key that goes into a lock, cannot open the lock, and prevents another key from opening the lock. In the body, and particularly the brain, antagonists can produce effects on their own by blocking an endogenous agonist. For example, a dopamine receptor antagonist can block the effects of a dopamine receptor agonist. On its own, however, the antagonist can produce motor initiation deficits by blocking the effects of endogenous dopamine. A drug that binds strongly to the binding site of the receptor with high affinity but is only partially effective (low efficacy) is termed a partial agonist (it partially activates the receptor).

Once a drug binds to a receptor, it must also trigger an effector domain in the receptor that activates various intracellular targets through intermediate components, collectively referred to as a signal transduction cascade. The brain has three major types of receptor binding/effector systems: enzymes, ligand-gated ion channels, and G-protein-coupled receptors. Enzymes and G-protein-coupled receptor systems have intermediate small molecules, called second messengers, which mediate a cascade of biochemical signals that ultimately change the function of cells or neurons in the brain. Ligand-gated ion channels bind some psychoactive agents, such as nicotine, that in turn can directly modulate neuronal excitation by opening or closing ion channels to let in excitatory sodium ions or inhibitory chloride ions. This leads to a fast response (within milliseconds). G-protein-coupled receptors, in contrast, use G proteins to transduce signals to multiple other intracellular proteins in the neuron that ultimately also affect excitability via calcium and potassium channels (Figure 2.6). For example, Gαs proteins activate adenylyl cyclase that in turn activates protein kinase A, which can inhibit potassium channels, facilitate excitatory glutamate neurotransmission, and increase neuronal excitability. Gαi proteins inhibit adenylyl cyclase and in turn inhibit protein kinase A and neuronal excitability. Gαq proteins activate a different enzyme, phospholipase C, causing the release of calcium from intracellular stores and increasing neuronal excitability. These G-protein responses are thought to occur over longer periods of time, from seconds to minutes.

Figure 2.6 Molecular mechanisms of neuroadaptation. Shown are examples of ligand-gated ion channels such as the γ-aminobutyric acid-A (GABAA) receptor and glutamate N-methyl-d-aspartate (NMDA) receptor (NMR) and G-protein-coupled receptors, such as opioid, dopamine, or cannabinoid CB1 receptors, among others. These receptors modulate the levels of second messengers like cAMP and Ca2+, which in turn regulate the activity of protein kinase transducers. Cocaine and amphetamines, as indirect sympathomimetics, stimulate the release of dopamine which acts at G-protein-coupled receptors, specifically D1, D2, D3, D4, and D5. These G-protein receptors modulate via the α subunit the levels of second messengers like cyclic adenosine monophosphate (cAMP) and Ca2+, which in turn regulate the activity of protein kinase transducers. Such protein kinases affect the functions of proteins located in the cytoplasm, plasma membrane, and nucleus. Among the membrane proteins affected are ligand-gated and voltage-gated ion channels (VGCC). Gi and Go proteins also can regulate K+ and Ca2+ channels directly through their βγ subunits. Protein kinase transduction pathways also affect the activities of transcription factors. Some of these factors, like cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), are regulated post-translationally by phosphorylation; others, like Fos, are regulated transcriptionally; still others, like Jun, are regulated both post-translationally and/or transcriptionally. While membrane and cytoplasmic changes may be only local (e.g., dendritic domains or synaptic boutons), changes in the activity of transcription factors may result in long-term functional changes. These may include changes in the gene expression of proteins involved in signal transduction and/or neurotransmission, resulting in altered neuronal responses. For example, chronic exposure to psychostimulants has been reported to increase the levels of protein kinase A (PKA) and adenylyl cyclase in the nucleus accumbens and decrease the levels of Gαi. Chronic exposure to psychostimulants also alters the expression of transcription factors themselves. CREB expression, for instance, is depressed in the nucleus accumbens by chronic cocaine treatment. Chronic cocaine induces a transition from Fos induction to the induction of the much longer-lasting Fos-related antigens such as ΔFosB. Opioids, by acting on neurotransmitter systems, affect the phenotypic and functional properties of neurons through the general mechanisms outlined in the diagram. Chronic exposure to opioids has been reported to increase the levels of PKA and adenylyl cyclase in the nucleus accumbens and decrease the levels of Gαi. Chronic exposure to opioids also alters the expression of transcription factors themselves. CREB expression, for instance, is depressed in the nucleus accumbens and increased in the locus coeruleus by chronic morphine treatment, whereas chronic opioid exposure activates Fos-related antigens such as ΔFosB. Alcohol, by acting on neurotransmitter systems, affects the phenotypic and functional properties of neurons through the general mechanisms outlined in the diagram. Alcohol, for instance, has been proposed to affect the GABAA response via protein kinase C (PKC) phosphorylation. Gi and Go proteins also can regulate K+ and Ca2+ channels directly through their βγ subunits. Chronic exposure to alcohol has been reported to increase the levels of PKA and adenylyl cyclase in the nucleus accumbens and decrease the levels of Giα. Moreover, chronic ethanol induces differential changes in subunit composition in the GABAA and glutamate inotropic receptors and increases the expression of VGCCs. Chronic exposure to alcohol also alters the expression of transcription factors themselves. CREB expression, for instance, is increased in the nucleus accumbens and decreased in the amygdala by chronic alcohol treatment. Chronic alcohol induces a transition from Fos induction to the induction of the longer-lasting Fos-related antigens. Nicotine acts directly on ligand-gated ion channels. These receptors modulate the levels of Ca2+, which in turn regulate the activity of protein kinase transducers. Chronic exposure to nicotine has been reported to increase the levels of PKA in the nucleus accumbens. Chronic exposure to nicotine also alters the expression of transcription factors themselves. CREB expression, for instance, is depressed in the amygdala and prefrontal cortex and increased in the nucleus accumbens and ventral tegmental area. Δ9-Tetrahydrocannabinol (THC), by acting on neurotransmitter systems, affects the phenotypic and functional properties of neurons through the general mechanisms outlined in the diagram. Cannabinoids act on the cannabinoid CB1 G-protein-coupled receptor. The CB1 receptor also is activated by endogenous cannabinoids such as anandamide. This receptor modulates (inhibits) the levels of second messengers like cAMP and Ca2+, which in turn regulate the activity of protein kinase transducers. Chronic exposure to THC also alters the expression of transcription factors themselves. CaMK, Ca2+/calmodulin-dependent protein kinase; ELK-1, E-26-like protein 1; PLCβ, phosphlipase C β; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; R, receptor. [Modified with permission from Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron, 1998, (21), 467-476.]

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