Mechanisms of drug action

As already pointed out in the Chapters A.1.2.1 and A.1.2.3, psychiatric medications  show very complex receptor profiles. The priority targets used in the treatment of depres‐

sion and schizophrenia are presented in the following. 

The majority of the TCAs act primarily as monoamine reuptake inhibitors by blocking  the norepinephrine transporter (NET) and the serotonin transporter (SERT). Thereby, the  extracellular concentrations of these neurotransmitters are elevated and further neuro‐

transmission  is  enhanced.  The affinity of  TCAs for  the  dopamine transporter  (DAT) is  negligible and dopamine levels are, therefore, not influenced. The more selective SNRIs,  SSRIs and SSNRIs act similarly on the specific transporters. MAO inhibitors block the enzy‐

matical degradation of neurotransmitters by the monoamino oxidase and lead to increased  neurotransmitters concentrations, too. 

The source of the neurotransmitter 5‐HT in brain are mainly neurons of the raphe  nuclei, with a projection into the entire brain (Fig. A.9). Its prevalently inhibitory effects on  the post‐synaptic membrane influence emotion (particularly mood), appetite, sleep, sensoric  perception, including pain, and higher cognitive functions like memory and learning. 5‐HT is  generated  from  tryptophan  (Trp)  via  5‐hydroxytryptophan,  which  is  catalyzed  by  the 

enzymes tryptophan hydroxylase and 5-hydroxytryptophan decarboxylase. It is transported and stored in vesicles which are released by exocytosis. Postsynaptically, HT binds to 5-HT1R coupled to Gi proteins or to 5-HT2 receptors. Binding of 5-HT to presynaptic 5-HT1R inhibits its own release. The action of the neurotransmitter is terminated by reuptake of 5-HT which can be blocked by tricyclic antidepressant drugs. Finally, 5-5-HT is degraded to 5-hydroxyindoleacetic acid by MAO and aldehyde dehydrogenase.

Additionally to their reuptake inhibition, many TCAs act as high-affinity antagonists at the 5-HT2AR, 5-HT2CR, 5-HT6R, 5-HT7R, α1AR and H1R as well as mAChR contributing to their therapeutic efficacy as well as their unwanted side effects.

Fig. A.9. Serotonergic neurotransmission in the CNS and the priority targets used in the treatment of depression.

NE is synthesized largely in the locus coeruleus with projections to almost every other region of the nervous system and also in the lateral tegmental area with projections targeting the hypothalamus (Fig. A.10). It is involved in many general functions like emotion, sleep and wakefulness, neuroendocrine function, temperature regulation. Tyrosine (Tyr) is metabolized to DOPA, dopamine (DA) and finally NE, catalyzed by the enzymes tyrosine hydroxylase, DOPA decarboxylase and finally dopamine-β-hydroxylase. Vesicles transport and store NE, which is released by exocytosis. NE binds postsynaptically to α1AR, which leads to the modulation of Ca²⁺ channels, as well as to mostly presynaptic α2AR, which is linked to

adenylyl cyclase and modulates K⁺ channels. Direct actions of the βγ-subunits of G proteins on K⁺ channels are mediated by NE-activated α₂AR which leads to phosphorylation of ion channels. Binding of the neurotransmitter or MIR and MSN to presynaptic α2AR inhibits further NE and 5-HT release by a negative feedback mechanism. Inhibition of presynaptic reuptake by antidepressants leads to a neurotransmitter surplus in the cleft and the follow-ing down-regulation of βAR and presynaptic α2AR as well as up-regulation of α1AR. Both anti-depressants and antipsychotics display affinities to αAR mediating unwanted side effects like orthostatic hypotension and reflex tachycardia. NE action is terminated by its reuptake, blocked by antidepressant drugs. The degradation of NE is carried out by MAO or catechol O-methyl transferase (COMT).

Fig. A.10. Noradrenergic neurotransmission in the CNS and the priority targets used in the treatment of depression.

Supplementary, the surplus of neurotransmitters through antidepressant therapy is also suggested to increase brain derived neutrophic factor, associated with neurogenesis and improvement of neuronal plasticity (Shirayama et al., 2002; Eisch et al., 2003). The adaptive changes by up- and down-regulation of receptors and neuronal plasticity may explain the delayed onset of two to six weeks of clinical effects of antidepressants.

DA is involved in both intellectual and motoric functions. It is synthesized enzymati-cally from Tyr via DOPA, primarily in the substantia nigra and ventral tegmental area (Fig. A.11). Projections reach to the basal ganglia (forming the nigrostriatal pathway) and the prefrontal cortex and amygdala (forming the mesolimbic pathway). Vesicles transport, store and release DA by exocytosis (inhibited by reserpine). Levels of the second messenger cyclic 3´,5´-adenosine monophosphate (cAMP) increase by the binding of DA to receptors of the D1R family, coupled to the stimulatory G protein (Gs), or decrease by activation of inhibitory G proteins (Gi) by members of the D2R family, prevalent in nigrostriatal and mesolimbic areas. Binding of the neurotransmitter to presynaptic D2R inhibits its own release via an inhibitory feedback. Typical antipsychotic drugs such as butyrophenones inhibit D2 R-trans-mission, whereas agonists such as apomorphine stimulate D2R and can produce schizophrenic-like behavior. DA action is terminated by reuptake into the synapse and inac-tivation by MAO and COMT.

Fig. A.11. Neurotransmission in the CNS and the priority targets used in the treatment of schizophrenia.

The stimulation of the mesolimbic projection in prefrontal cortex and amygdala causes pleasure and, therefore, DA antagonists applied to the nucleus accumbens suppress reward systems. Parkinson's disease is caused by degeneration of nigrostriatal neurons and characterized by tremor, muscle rigidity, poor balance and difficulty in initiating movement

or even loss of the same (akinesia). Therapeutic occupancy at D2R ranges hereby between 60 to 80%. EPS are mainly caused by exceeding this threshold. Atypical antipsychotics show a reduced occupancy here, including a fast dissociation rate of CLO and a higher affinity for serotonin 5-HT2AR over dopamine D2R (Meltzer, 1999) or even partial D2R agonism in the case of aripiprazole (Miyamoto et al., 2005). Furthermore, atypical antipsychotics differ in their ability to modulate dopaminergic D1R, D3R and D4R and serotonergic 5-HT1AR, 5-HT2CR, 5-HT3R, 5-HT6R, 5-HT7R (Lieberman et al., 2008; Miyamoto et al., 2005).