Psychotropic Drugs
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).
Figure 3–7. Receptors for neurotransmitters. Neurotransmitters can operate through two classes of receptors: metabotropic and ionotropic (channel) receptors. Metabotropic receptors are coupled with second messenger systems through G proteins activating phospholipase C (PLC) and activating (AC+) or inhibiting (AC–) adenylate cyclase. Stimulation of
Antidepressants
Antidepressants (eg, MAO inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, bupropion, venlafaxine) acutely increase the synaptic availability of norepinephrine or 5-HT or both, via different mechanisms. MAO inhibitors inhibit the metabolism of the neurotransmitters, whereas other antidepressants inhibit the reuptake of neurotransmitters into the presynaptic neuron. These neurotransmitters activate various receptor cascades (Figure 3-8). Norepinephrine stimulates the formation of cyclic adenosine monophosphate (cAMP) via ß-adrenoceptors, whereas -2-adrenoceptor activation by norepinephrine inhibits cAMP formation. cAMP activates protein kinase A (PKA). 5-HT receptors are linked, depending on their subtype, to adenylate cyclase (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F), phospholipase C (5-HT2A, 5-HT2B, 5-HT2C), or to ion channels (5-HT3). Phospholipase C converts inositol 4,5-biphosphate to two second messengers: diacylglycerol (DAG) and inositol 1,4,5-tris-phosphate (IP3). DAG activates protein kinase C (PKC) and IP3 via mobilization of intracellular calcium activates calcium/calmodulin-dependent protein kinase. Thus protein phosphorylation is probably the final common pathway for signal transduction. Evidence indicates that the activation of protein kinases is an obligatory step in the sequence of events by which extracellular signals produce physiologic responses in neurons. It remains to be elucidated whether G proteins have a role in the action of antidepressants.
Figure 3–8. Neurotransmitter signal transduction cascades as a target for antidepressant drugs. Antidepressant drugs can influence the information flow at various levels of the signal transduction cascade: (1) change in the synaptic availability of the primary signals norepinephrine (NE) and serotonin (5-HT) (MAO inhibitors, blockade of reuptake, autoreceptor subsensitivity); (2) change in receptor number or sensitivity; (3) change in the function of G proteins; (4) change in the formation of second messengers; (5) change in the activity of protein kinases (amplifier function); (6) modification of nuclear events (eg, gene transcription). (Reproduced, with permission, from Rossby SP, Sulser F: [Historical perspective and new neurobiological aspects of the modes of action of antidepressant drugs.] ZNS J 1993;1:10 [German].)
Studies on the mechanism of action of lithium have shown that this widely used psychotropic agent influences the synaptic availability of 5-HT and norepinephrine and has profound effects on signal transduction pathways. These findings, together with the observation that reserpine—which depletes brain 5-HT and norepinephrine—can precipitate depression, have led to the simple but heuristic hypothesis that depression results from an amine deficiency that is corrected by antidepressant drugs (eg, the catecholamine and indoleamine hypotheses of affective disorders, respectively). The well-known therapeutic delay associated with antidepressant drugs has led to modifications of these early hypotheses, involving more slowly developing adaptive processes at the level of receptors and at sites beyond the receptors.
Antipsychotics
Antipsychotic drugs, or neuroleptics, are thought to exert their therapeutic action by blocking different subtypes of dopamine receptors. Neuroleptics (eg, phenothiazines, butyrophenones) display a high affinity for dopamine D2 receptors linked in an inhibitory way via G proteins to adenylate cyclase. The rank order of antipsychotic drug affinity to the D2 receptor parallels the rank order of clinical potency. Compared to typical antipsychotic drugs, the atypical antipsychotic clozapine exhibits about a 10-fold higher affinity for the D4 receptor, which, like the D2 receptor, is coupled via Gi to adenylate cyclase. Because clozapine also binds to numerous dopamine and other receptors (eg, 5-HT2A), the question of whether D4 receptor blockade is singly responsible for the unique therapeutic profile of clozapine (antipsychotic activity with little or no extrapyramidal side effects) remains unanswered. With the development of specific D4 receptor antagonists, these hypotheses can be tested.
Anxiolytics
Benzodiazepines, the most widely used antianxiety agents, appear to produce all of their therapeutic effects by binding to the benzodiazepine receptor. The benzodiazepine receptor is an integral binding site on the GABAA receptor channel. By allosteric modulation, benzodiazepines augment the affinity of GABA to the GABA binding site. It remains to be seen whether buspirone (a non-benzodiazepine partial 5-HT1A agonist) will be as effective as the benzodiazepines in the treatment of anxiety disorders.
