Changes

==Mechanism of Action==

==Mechanism of Action==

Tricyclic group of antidepressants (TCA) are chemically similar to phenothiazines. Amitriptyline and clomipramine are examples of drugs of this type, with clomipramine also being classed as a serotonin re-uptake inhibitor due to its modest serotonergic selectivity.  

The tricyclic group of antidepressants (TCA) are chemically similar to phenothiazines. Amitriptyline and clomipramine are examples of drugs of this type, with clomipramine also being classed as a serotonin re-uptake inhibitor (SRI) due to its modest serotonergic selectivity.  

TCAs have three major effects which vary in degree depending on the specific drug used. These are:  

TCAs have three major effects which vary in degree depending on the specific drug used. These are:  

Together the LC and Raphe nuclei form parts of the ascending reticular activating system that has projections throughout the CNS and is 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 is 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 serotonergic antidepressants (SRI, selective serotonin reuptake inhibitor (SSRI), TCA, atypical) have immediate effects on synaptic neurotransmission, the lasting changes in emotional response are the result of intracellular changes and in altered receptor expression. This is dependent on secondary messenger systems (cAMP, Ca²⁺, cGMP, IP₃), 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-HT₁ 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 serotonergic antidepressants (SRI, selective serotonin reuptake inhibitor (SSRI), TCA and atypical) have immediate effects on synaptic neurotransmission, the lasting changes in emotional response are the result of intracellular changes and in altered receptor expression. This is dependent on secondary messenger systems (cAMP, Ca²⁺, cGMP, IP₃), 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-HT₁ 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:

*Increase in serotonin in the synaptic cleft.

*Increase in serotonin in the synaptic cleft.

*Increase in stimulation of postsynaptic 5-HT_1A1A-receptors, leading to an elevation of mood (mechanism unknown)

*Increase in stimulation of postsynaptic 5-HT_1A receptors, leading to an elevation of mood (mechanism unknown).

*Increase in CREB and BDNF, leading to normally CNS adaptation to external events

*Increase in CREB and BDNF, leading to normally CNS adaptation to external events.

The exact reason why CREB, BDNF and other neurotropic factors are central to resolving depression and anxiety is to date unclear but it is thought to relate to adaptability of the CNS to external events.

The exact reason why CREB, BDNF and other neurotropic factors are central to resolving depression and anxiety is to date unclear but it is thought to relate to adaptability of the CNS to external events.

Clomipramine and TCAs are far more safely and commonly used in behavioural pharmacology in comparison to benzodiazepines, phenothiazines, barbiturates and sympathomimetic agents.

Clomipramine and TCAs are far more safely and commonly used in behavioural pharmacology in comparison to benzodiazepines, phenothiazines, barbiturates and sympathomimetic agents.

===Selective serotonin reuptake inhibitors (SSRIs)===

===Selective Serotonin Reuptake Inhibitors (SSRIs)===

SSRIs are a group of drugs that all have a greater effect on serotonin reuptake than noradrenaline reuptake. Unlike TCAs, which are named on the basis of chemical structure, the SSRIs are named according to their primary effect on serotonin reuptake. The ratio of serotonin reuptake selectivity in favour varies from around 15:1 (fluoxetine) to more than 150:1 (sertraline). Along with increasing serotonergic selectivity, SSRI drugs also show fewer effects on other neurotransmitter systems. In particular, they are less anticholinergic than TCAs.

SSRIs are a group of drugs that all have a greater effect on serotonin reuptake than noradrenaline reuptake. Unlike TCAs, which are named on the basis of chemical structure, the SSRIs are named according to their primary effect on serotonin reuptake. The ratio of serotonin reuptake selectivity in favour varies from around 15:1 (fluoxetine) to more than 150:1 (sertraline). Along with increasing serotonergic selectivity, SSRI drugs also show fewer effects on other neurotransmitter systems. In particular, they are less anticholinergic than TCAs.

Numerous models of anxiety have been tested in animals. Many are not apparently reliable detectors of anxiolytic effect, and have not been applied to more modern anxiolytic/antidepressant drugs like SSRIs/SRIs. Those in which there is a response to TCA/SRI and SSRI drugs include:

Numerous models of anxiety have been tested in animals. Many are not apparently reliable detectors of anxiolytic effect, and have not been applied to more modern anxiolytic/antidepressant drugs like SSRIs/SRIs. Those in which there is a response to TCA/SRI and SSRI drugs include:

*Approach-avoidance conflict (Stretched approach posture test).

*Approach-avoidance conflict (stretched approach posture test).

*Separation distress vocalisation (guinea pig isolation calls, rat pup isolation ultrasonic vocalisation).

*Separation distress vocalisation (guinea pig isolation calls, rat pup isolation ultrasonic vocalisation).

*Defensive burying in rodents (only some 5-HT reuptake inhibitors)

*Defensive burying in rodents (only some 5-HT reuptake inhibitors).

Interestingly no effect has been found in those tests (so far performed) that involve conditioned fear potentiated startle responses.

Interestingly no effect has been found in those tests (so far performed) that involve conditioned fear potentiated startle responses.

The blocking ratio indicates the relative effect of the agent on reuptake of serotonin vs. noradrenaline. Fluoxetine is 3 times more selective for serotonin than clomipramine. Clomipramine was the first TCA whose ratio favours serotonin reuptake inhibition, and hence its title of non-selective serotonin reuptake inhibitor (SRI). The level of anticholinergic effect is usually also decreased with increasing serotonergic selectivity.

The blocking ratio indicates the relative effect of the agent on reuptake of serotonin vs. noradrenaline. Fluoxetine is 3 times more selective for serotonin than clomipramine. Clomipramine was the first TCA whose ratio favours serotonin reuptake inhibition, hence its title of non-selective serotonin reuptake inhibitor (SRI). The level of anticholinergic effect is usually also decreased with increasing serotonergic selectivity.

===Medical cautions===

===Medical Cautions===

'''Caution should be taken if the animal suffers from any of the following pre-existing medical conditions:'''

'''Caution should be taken if the animal suffers from any of the following pre-existing medical conditions:'''

*Heart disease, especially heart block and arrythmias <ref>Pouchelon, J. L., Martel, E., Champeroux, P., Richard, S. & King, J. N. (2000). Effect of clomipramine hydrochloride on the electrocardiogram and heart rate of dogs. American Journal of Veterinary Research, in press.</ref><ref>Reich, M. R., Ohad, D. G., Overall, K. L. & Dunham, A. E. (2000). Electrocardiographic assessment of antianxiety medication in dogs and correlation with drug serum concentration. Journal of the American Veterinary Medical Association 216, 1571–5.</ref>

*Heart disease, especially heart block and arrythmias <ref>Pouchelon, J. L., Martel, E., Champeroux, P., Richard, S. & King, J. N. (2000). Effect of clomipramine hydrochloride on the electrocardiogram and heart rate of dogs. American Journal of Veterinary Research, in press.</ref><ref>Reich, M. R., Ohad, D. G., Overall, K. L. & Dunham, A. E. (2000). Electrocardiographic assessment of antianxiety medication in dogs and correlation with drug serum concentration. Journal of the American Veterinary Medical Association 216, 1571–5.</ref>

==References==

==References==

<references/>

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[[Category:Pharmacological Approach to Problem Behaviour]]

[[Category:Pharmacological Approach to Problem Behaviour]]

[[Category:JBowen reviewed]]

[[Category:JBowen reviewed]]