Medical Pharmacology: Drugs Used to Manage Depression

Antidepressant Medication Overview, continued¹⁰⁷

Long-term antidepressant drug effects may involve changes in regulatory mechanisms that promote therapeutic efficacy.
- Many factors may be involved in this transition, including:
  - Increased receptor-G protein coupling and cyclic nucleotide signaling
  - Regulation of neurotrophic factors
  - Changes in adrenergic or serotonergic receptor sensitivity or density and
  - Neuronal hippocampal proliferation.¹⁰⁷

**Corpus Callosum & Hippocampus¹²²**

Attribution: Droual R Brain Stem Model: Corpus Callosum & Hippocampus https://www.youtube.com/watch?v=YJLHDPTrUYk drbobrd YouTube Channel: https://www.youtube.com/channel/UC15YK7pMCRkJOrjOq0Qu5qA

Hippocampus Localization: Animation¹²³
An argument stressing the importance of the hippocampus in major depressive disorder has been proposed. In support of this view has been the observation that the hippocampus shares both afferent and efferent connections with limbic structures including those that regulate mood and cognition, e.g. prefrontal cortex and amygdala.¹²¹
- Abnormal cognitive function and mood noted in major depressive disorders may be caused by pathologies in neuronal networks relating the hippocampus with other limbic nuclei.
- Pathological changes in amygdala and prefrontal cortex may be associated with major depressive disorder.
- Changes in cognitive deficits and mood alterations in major depressive disorder are associated both with cognitive behavioral therapy and chemical antidepressant agents.¹²¹
  - These findings suggest that hippocampal dysregulation and dysregulation of related structures influence prominent symptoms of major depressive disorder, especially those related to alteration in mood and cognitive ability.
  - The molecular and cellular basis for hippocampal dysregulation in this setting emphasize both neurogenic and neurotrophic aspects of neuronal plasticity.
  - Major depressive disorder is associated with a decrease in hippocampal volume, as assessed by brain imaging studies. In depressed patients, temporal lobe atrophy may be induced by decreased neurotrophic factor expression and neurogenesis.
    - Antidepressant intervention increases both adult hippocampal neurogenesis and expression of hippocampal neurotrophic factors.¹²¹

Chronic treatment with antidepressants that appear to target a particular neurotransmitter system may induce long-term changes in the neurotransmitter-transporter.^{107,
124}

**Structure of SERT and NET¹²⁵**

Serotonin transporter (SERT), left and norepinephrine transporter (NET), right.

**Representation of the 12-transmembrane loop structure of the norepinephrine transporter¹²⁶**

NET (norepinephrine transporter), a transmembrane protein consists of 12 transmembrane domains.

For example, repeated desipramine administration decreases norepinephrine transporter (NET) expression and appears associated with antidepressant-like behavior.¹²⁴

Desipramine

Utilizing a binding technique specific for the transporter (³H-nisoxetine was the probe) changes in NET expression could be determined.

Nisoxetine

**Reduction in ³H-nisoxetine binding to the norepinephrine transporter associated with chronic desipramine treatment.¹²⁴**

"Dose–response functions were determined for the ability of chronic desipramine treatment to reduce norepinephrine transporter (NET) expression in the cerebral cortex and hippocampus, determined by³H-nisoxetine binding."¹²⁴

The reduction in NET expression assessed by this technique in both cerebral cortex and hippocampus was associated also with reduced immobility in a forced-swim test, using a rat model.¹²⁴
- This antidepressant-like effect on forced-swim behavior was verified 48 hours following discontinuation of desipramine administration and at a time when both plasma and brain levels of desipramine as well as the demethylated metabolite were no longer detectable.
Decreased NET expression was associated with decreased norepinephrine uptake measured in vitro as well as increased noradrenergic transmission measured in vivo using microdialysis.¹²⁴
The dose response and time-of-recovery relationship for changes in NET expression coincided with those associated with antidepressant-like behavioral effects.¹²⁴
- Enhanced noradrenergic neurotransmission associated with the persistent antidepressant-like behavioral effect was also demonstrated through blockade of this effect by inhibition of catecholamine synthesis, using α-methyl-p-tyrosine.
  - These results suggest that the long-term desipramine behavioral effects may involve, at least in part, changes in norepinephrine transporter regulation.
Time course of events associated with desipramine administration underscores the challenge of association between short-term, acute drug affects and longer-term drug and behavioral actions.¹²⁴
- For example, initially desipramine enhances noradrenergic neurotransmission as a result of reuptake inhibition (NET inhibition).
- Later, a compensatory, adaptive down-regulation of β-adrenergic receptors is observed along with desensitization of α₂ presynaptic adrenergic receptors.
- Down-regulation of β-adrenergic receptors is an adaptation, in opposition to initial acute drug effects.
- On the other hand, the clinical antidepressant actions are typically progressive and unidirectional.
  - Presynaptic α₂ adrenergic autoreceptors, which remain functional after chronic desipramine administration, are not likely to explain chronic, clinical desipramine. effects
  - By contrast, antidepressant-induced changes in the norepinephrine transporter appears consistent with clinical observations, showing a time course of delayed therapeutic effect which parallels slow-onset of antidepressant-induced clinical activity.

Distribution of the norepinephrine transporter (NET) in human brain

In rats the norepinephrine transporter (NET) has been localized mainly in the locus ceruleus and dorsal raphe nuclei.¹²⁷

Using the tritiated ligand described earlier, ³H-nisoxetine, the localization of NET was extended to the human brain.
An early study focused on binding of the tritiated ligand to the dorsal raphe nuclei and the locus ceruleus.¹²⁷
- Specificity of ³H-nisoxetine was assessed using desipramine which inhibited 3H-nisoxetine binding. Desipramine, a NET-specific ligand, competitively inhibits nisoxetine binding.

**Specific binding of [³H]nisoxetine to NETs at an example level in human brain¹²⁷**


"Digitized autoradiograms of the specific binding of [³H]nisoxetine to NETs at multiple levels along the rostral– caudal axis of the human dorsal raphe and locus coeruleus."¹²⁷ This example section was 6mm from the frenulum in the caudal direction.¹²⁷ The image represents specific ³H-nisoxetine binding, derived by subtracting non-specific binding (i.e. binding that occurs in the presence of the specific NET inhibitor desipramine, e.g.) from total binding.

**Brain schematics highlighting the locations of the locus coeruleus and dorsal raphe nucleus (top image) ¹²⁸and associated noradrenergic pathways (bottom image)¹²⁹**

Studies utilizing ³H-nisoxetine have focused on norepinephrine transporters (NETs) localized within human locus ceruleus and raphe nuclei.

However, other techniques have proven necessary for evaluation of transporter distribution outside of these regions.¹³⁰

The principal other method is that of positron emission tomography (PET), utilizing a derivative of the antidepressant reboxetine.
- Reboxetine is classified as a norepinephrine reuptake inhibitor which does not inhibit serotonin reuptake.
The ligand used in PET scans identifying the norepinephrine transporter is a ¹⁸F derivative, O-[¹⁸F]fluoromethyl di-deuterated analog of (S,S) [¹¹C]MeNER, (S,S)-[¹⁸F]FMeNER-D₂.

**Comparative Structures of reboxetine and the positron emitter reboxetine derivative used in PET¹³⁰**

Reboxetine	(S,S)-[¹⁸F]FMeNER-D₂, PET scan probe, a reboxetine derivative.

(S,S)-[¹⁸F]FMeNER-D₂ has exhibited selective binding to NETS in monkey brain and exhibits and in vitro affinity constant in the nanomolar (nM) range (Ki = 3.1 x 10^-9 M).¹³⁰

Specific binding was again defined as total binding minus binding occurring even in the presence of excess of desipramine.
Intense binding was noted in the locus ceruleus using PET scans, confirming earlier findings with ³H-nisoxetine.
- Setting the locus ceruleus binding intensity as 100%, binding and the anterior pons was about 10%, temporal cortex 12%, insular cortex about 10% with cerebellar gray matter binding at about 15%.¹³⁰

**Human brain autoradiography illustrating NET localization, using a PET scan probe specific for the norepinephrine transporter.¹³⁰**

Human brain autoradiography using the PET ligand (S,S)-[¹⁸F]FMeNER-D₂. Highest intensity is noted in the locus ceruleus and binding is also seen in temporal cortex (TC), cerebellum (Ce), and Pons (Po).	Non-specific binding, to sites other than the NET transporter is assessed by incubating the brain slices with the PET probe in the presence of high concentrations of desipramine. In this setup the higher concentrations of desipramine should occupy the NET sites and any other binding observed is attributed to non-NET, i.e. non-specific sites.

Autoradiography involves placing photographic emulsion (film) directly in contact with a brain slice in this case.
- The brain slice has been previously exposed to a radioactive emitter which has bound specifically to the site of interest, in this case the norepinephrine transporter.
- The particle emitted by the tagged ligand exposes the film grains located near the ligand, thus identifying the binding site with associated anatomy.

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