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Together the LC and Raphe nuclei form parts of the ascending reticular activating system that has projections throughout the CNS and are involved in mood, wakefulness, sleep cycles and arousal as well as pain modulation and a host of other maintenance functions such as meal patterning.
Together the LC and Raphe nuclei form parts of the ascending reticular activating system that has projections throughout the CNS and are involved in mood, wakefulness, sleep cycles and arousal as well as pain modulation and a host of other maintenance functions such as meal patterning.
The effect on neurotransmitter levels is quite rapid, but therapeutic effects take 3 weeks or more to become apparent. This is because although clomipramine and many other antidepressants (SRI, SSRI, TCA, atypical) have immediate effects on synaptic neurotransmission, the lasting corrections in mood are the result of intracellular changes and in receptor numbers. This is dependent on secondary messenger systems (cAMP, Ca<sup>2+</sup>, cGMP, IP<sub>3</sub>), gene expression and protein synthesis that take time to occur. Receptors for nor-adrenaline and serotonin are linked to metabotropic G-proteins that can induce changes in protein synthesis such as the up- and down-regulation of receptors. There are 14 known classes of 5-HT receptors, of these, in anxiety problems the 5-HT<sub>1</sub> receptor is the most relevant.
The effect on neurotransmitter levels is quite rapid, but therapeutic effects take 3 weeks or more to become apparent. This is because although clomipramine and many other antidepressants (SRI, selective serotonin reuptake inhibitor (SSRI), TCA, atypical) have immediate effects on synaptic neurotransmission, the lasting corrections in mood are the result of intracellular changes and in receptor numbers. This is dependent on secondary messenger systems (cAMP, Ca<sup>2+</sup>, cGMP, IP<sub>3</sub>), gene expression and protein synthesis that take time to occur. Receptors for nor-adrenaline and serotonin are linked to metabotropic G-proteins that can induce changes in protein synthesis such as the up- and down-regulation of receptors. There are 14 known classes of 5-HT receptors, of these, in anxiety problems the 5-HT<sub>1</sub> receptor is the most relevant.
For example, in states of anxiety and depression the following presynaptic changes are thought to occur:
For example, in states of anxiety and depression the following presynaptic changes are thought to occur:
{| class="wikitable"
{| class="wikitable"
|-
|-
! !! α2-Adr-autoreceptor !! α2-Adr-heteroreceptor !! 5-HT<sub>1A</sub>-autoreceptor
! !! α2-Adrenergic-autoreceptor !! α2-Adrenergic-heteroreceptor !! 5-HT<sub>1A</sub>-autoreceptor
|-
|-
| || Nor-adrenergic neuron || serotonergic neuron || serotonergic neuron
| || Nor-adrenergic neuron || serotonergic neuron || serotonergic neuron
{| class="wikitable"
{| class="wikitable"
|-
|-
! Drug !! Class !! 5-HT:NorAdrenaline Blocking ratio !! H<sub>1</sub> !! Ach (Muscarinic) Blockade
! Drug !! Class !! 5-HT:NorAdrenaline Blocking ratio !! H<sub>1</sub> Blockade !! Ach (Muscarinic) Blockade
|-
|-
| Amitriptyline || TCA || 1:4 || +++ || +++
| Amitriptyline || TCA || 1:4 || +++ || +++
==Adverse Effects==
==Adverse Effects==
{| class="wikitable"
|-
! H<sub>1</sub> Blockade !! Ach (Muscarinic) Blockade
|-
| Sedation, hypotension, increased appetite, weight gain, anti-allergic activity || Delirium, hyperthermia, insomnia, seizure induction, tachycardia, constipation, decreased bronchial secretion, blurred vision, narrow angle glaucoma (exacerbation), photophobia, dry mouth
|}
Amitriptyline also antagonises α2-adrenoceptors, which can also lead to agitation and tachycardia.
Amitriptyline also antagonises α2-adrenoceptors, which can also lead to agitation and tachycardia.
TCAs can also cause loss of libido [breeding animals] and mild corneal drying. They can cause galactorrhea through increased prolactin secretion [esp. cats].
TCAs can also cause loss of libido [breeding animals] and mild corneal drying. They can cause galactorrhea through increased prolactin secretion [esp. cats].
Finally, those TCAs that depend upon NorA reuptake inhibition for a part of their effect are sometimes associated with explosive emotional reactions including aggression. They should be used with some care.
Finally, those TCAs that depend upon NorAdrenaline reuptake inhibition for a part of their effect are sometimes associated with explosive emotional reactions including aggression. They should be used with some care.
'''Caution should be taken in if the animal suffers from any of the following pre-existing medical conditions:'''
*Heart disease, especially heart block and arrythmias.
*Heart disease, especially heart block and arrythmias.
*Diabetes: increases hyperglycaemia.
*Diabetes: increases hyperglycaemia.
*Hyperthyroidism [enhanced response to TCAs]
*Hyperthyroidism [enhanced response to TCAs]
'''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
*Morphine: enhanced analgesia and respiratory depression
*Morphine: enhanced analgesia and respiratory depression
*MAOIs: risk of serotonin syndrome, advise washout period of 2-3 weeks between treatment with these drugs.
*MAOIs: risk of serotonin syndrome, advise washout period of 2-3 weeks between treatment with these drugs.
*Fibre rich diets reduce availability of TCAs.
*Fibre rich diets reduce availability of TCAs.
If the drug is overdosed/combined with an inappropriate drug [see above] an increased sedation and degree of adverse effects as listed will be seen. If the drug dose is persistently high or the drug is combined with an MAOI, serotonin syndrome is a possibility:
If drug dose is persistently high or drug is combined with an MAOI, serotonin syndrome is a possibility:
*Gastrointestinal distress
*Gastrointestinal distress
*Head pain
*Head pain