Monoamines and Anhedonia : old targets, new concepts

Abstract

Anhedonia is one of the core symptoms of depression and is characterized by the inability to experience pleasure. Anhedonia is difficult to treat with the current available antidepressants. A novel class of antidepressants, the triple reuptake inhibitors (TRIs), are believed to act as broad-spectrum drugs with an early-onset antidepressant effect. TRIs might be particularly useful for the treatment of anhedonia. TRIs block the transporters of all three monoamines simultaneously: serotonin (5-HT), norepinephrine (NE) and dopamine (DA). In particular the effects on the DA transporter are thought to be important for the treatment of anhedonia. In this thesis in rats the role of 5-HT, NE and especially DA in brain mechanisms involved in anhedonia and in brain stimulation reward was investigated. In vivo microdialysis studies were performed in which the effects of monoaminergic drugs were measured on extracellular monoamine concentrations in several brain areas that are involved in depression. On the other hand effects of psychotropic drugs on brain reward sensitivity in an intracranial self-stimulation paradigm were investigated. In chapter 2, the use of TRIs in the treatment of different subtypes of depression was reviewed. First, a distinction was made between different subtypes of depression; melancholic and atypical depression, which both have their own symptom profile. Specific symptoms were linked to distinct disturbances in monoaminergic brain mechanisms, which resulted in a revisited monoamine hypothesis of depression, stating that monoaminergic neurotransmission is out of balance, rather than deficient in the subtypes of depression. In chapter 3 and 4 it was shown that the triple reuptake inhibitor DOV 216,303 increased 5-HT, NE and DA in the prefrontal cortex and dorsal hippocampus, brain areas that are important in depression. Furthermore, chronic treatment with DOV 216,303 lead to a faster metabolism of the drug compared to an acute challenge, which might be a limitation for this drug in clinical use. In chapter 5 it was shown that DOV 216,303 induced long-lasting enhancement of brain reward activity without showing withdrawal-associated reward deficits, suggesting that an enhancement of DA does not necessarily mean that a drug has abuse potential. In chapter 6, enhancement of DA neurotransmission did not enhance brain reward systems, as the 5-HT1A/1B receptor agonist eltoprazine increased DA concentrations and decreased 5-HT concentrations in the brain, but resulted in increased ICSS thresholds. It was concluded that besides DA, also 5-HT might be important in mediating reward. In chapter 7, the acute and chronic effects of escitalopram, reboxetine and methylphenidate were investigated on monoamine release in the prefrontal cortex and nucleus accumbens in combination with the effects of these drugs on brain stimulation reward. Only methylphenidate, which increased DA levels in the nucleus accumbens, enhanced brain stimulation reward. In chapter 8, the main results of the thesis are discussed with implications for further research. In summary, it is concluded that TRIs might serve as good first-line antidepressants, especially in the treatment of anhedonia