The emergence of molecular neurobiology has profoundly changed the traditional focus of neuropsychopharmacologic research, shifting it toward events occurring beyond the receptors. One can now entertain the possibility that abnormal behavior patterns—affective, cognitive, and somatosensory—might be the consequence of a disarray in the temporal regulation of gene expression in response to internal (ie, neurohumoral, endocrine) and external (ie, environmental) stimuli that have rendered the individual vulnerable to psychiatric disorder. The demonstration that a nurturing defect in mice is linked to the absence of transcription factor Fos B in the preoptic area of the hypothalamus suggests that this transcription factor controls a complex behavior.
Signal Transduction from Synapse to Nucleus
Most psychotherapeutic drugs (eg, antidepressants, antipsychotic drugs, lithium) require long-term administration to be optimally effective. Apparently, acute interaction at various steps in the agonist-receptor-mediated transduction cascades is not directly responsible for their therapeutic effects. The activation of intracellular messenger pathways and the regulation of neuronal gene expression appear to play a central role in long-term adaptive changes in neuronal function. By altering programs of gene expression, the CNS adapts to conditions that threaten the physical and psychic emotional well-being of the organism. Ultimately changes in programs of gene expression determine the intensities of incoming signals; the sensitivities of neuronal systems to those signals; and the nature, amplitude, and duration of CNS responses (ie, the plasticity of the CNS). In this way, the clinically important actions of psychotropic drugs can be viewed as the restoration of neural plasticity, a plasticity that appears to be impaired in patients with affective or cognitive disorders.
Mechanisms of Regulation of Receptor Function
The regulation of receptor function is associated closely with the plasticity of signal transduction. The homeostasis of signal transduction is a prerequisite for emotional health. Signal transduction appears to be destabilized in patients who have emotional and cognitive disorders. Receptors are regulated at the level of their gene expression (by transcription or translation) and by posttranslational covalent modifications (eg, phosphorylation). In general, the density of receptors is upregulated in response to a decrease of their corresponding neurotransmitters and downregulated in response to an increase of the neurotransmitter. For example, ß-adrenoceptor density increases after depletion of norepinephrine by reserpine and decreases after the blocking of norepinephrine reuptake by antidepressants. The phenomenon of receptor desensitization has been studied extensively in the ß-adrenoceptor–G protein–coupled adenylate cyclase system. The desensitization of the ß-adrenoceptor–G protein–coupled adenylate cyclase system is accomplished by receptor phosphorylation. Two types of protein kinases are involved in receptor phosphorylation: PKA, activated by cAMP; and a second messenger–independent G protein–coupled protein kinase, beta-adrenergic receptor kinase (BARK 1). BARK 1 phosphorylates G protein–coupled receptors (such as the ß-adrenoceptor), predominantly when they are occupied by agonists. BARK 1–mediated phosphorylation has also been implicated in the sequestration of ß-adrenoceptors. Furthermore, the 5-HT2C receptor is phosphorylated by agonist treatment, which results in desensitization of receptor signaling.
Receptor Adaptation & Receptor Cross-Talk
The actions mediated by psychotropic drugs on receptors occur rapidly. These actions do not explain the therapeutic effect that is generally delayed for weeks after initiation of treatment. This discrepancy in the time course, particularly evident with antidepressants, has led to studies on the effect of anti-depressants on more slowly developing receptor-mediated adaptive processes in brain. These studies have revealed that chronic antidepressant treatment (ie, using MAO inhibitors, tricyclic antidepressants, and electroconvulsive therapy) causes a desensitization of the ß-adrenoceptor-coupled adenylate cyclase system in brain, usually associated with downregulation of the density of ß-adrenoceptors. These findings have shifted the focus of research onto the mode of action of antidepressants and the pathophysiology of affective disorders, from acute presynaptic to delayed postsynaptic adaptive processes in the cascade of signal transduction. Besides causing adaptations at the ß-adrenoceptor, chronic administration of antidepressants alters the density of various subtypes of 5-HT receptors (eg, 5-HT2A, 5-HT1A, and 5-HT1B).
All major psychotropic drugs (ie, antidepressants, antipsychotics, anxiolytics) affect directly or indirectly the various receptors that are linked via regulatory G proteins to effector systems, either enzymes or ion channels (Figure 3-7). G proteins are heterotrimers consisting of ß and subunits that are linked to specific intracellular effector systems in a stimulatory (Gs) or inhibitory (Gi) manner. Effector enzymes catalyze the formation of second messengers that activate various protein kinases leading to phosphorylation and activation of pivotal proteins (metabotropic action). Receptors linked to ion channels modify the flux of ions through the membrane (ionotropic action).
Two enzymes are responsible for the catabolism of catecholamines: monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT).
MAO catalyzes the oxidative deamination of amines and is a major enzyme in the metabolism of the biogenic amines (ie, norepinephrine, dopamine, and serotonin). MAO is found throughout the CNS. It is present in both glia and neurons. Studies on the subcellular distribution of the enzyme indicate that it is principally associated with the mitochondrial fraction, although it is also present in a microsomal fraction. In the mitochondrial fraction, the enzyme is present in the outer membrane. The enzyme requires flavin adenine dinucleotide as a cofactor.
Neuropharmacology is the pharmacology of the nervous system. The nervous system coordinates cellular activity, and the neuron is its basic component. The principal mechanism by which neurons communicate with one another is through the release of chemical mediators known as neurotransmitters. A chemical substance must possess several qualities before it can be classified as a neurotransmitter (Table 3-1).
An understanding of neuropsychopharmacology provides a basis for sound therapeutics. Used as tools to probe the central nervous system (CNS), psychotropic drugs have contributed more than anything else to our understanding of the function of the brain. They have helped to establish biological psychiatry as a branch of medicine, and they have contributed to the generation of heuristic hypotheses concerning the biological basis of mental illness.
Neuropsychopharmacology reached prominence as a consequence of seminal contributions made by a number of basic scientists and astute clinical psychiatrists. Many of these contributions are acknowledged in the individual sections of this chapter.