Pathophysiology of anxiety disorders

People who suffer anxiety disorders may have persistant irrational fears producing ongoing severe symtoms or have less irrational fears that produce an anxiety response above what one would expect as normal physiological symptoms. Current understanding indicates the difference between normal and pathological anxiety is based around abnormalities in the modulation of anxiety/fear pathways resulting in increased stimulatory output from the amygdala to the hypothalamus.

Three neurochemicals may be involved:-

• Noradrenaline (locus coeruleus circuits) - excitatory
• Seratonin (raphe nuclei circuits) - inhibitory
• GABA (pathways involving the cortex) - inhibitory

Noradrenergic Model

• Locus coeruleus (nuclei situated in the brainstem) is involved in enhancing physiological responses to fear and panic
• Principal brain site for noradrenaline synthesis and location of origins for most noradrenergic neurons. Noradrenergic neurons can stimulate glutamate neurons in the brain.
• The LC has an excitatory effect on many brain circuits and structures including the cortex, amygdala, hippocampus and the hypothalamus, at the same time it can be activate my inputs from the precortex and amygdala.
• In response to a perceived threat, LC stimulation can in turn prime structures to produce an autonomic response via the hypothalamus.
• In some GAD patients alpha2 NA receptors have been shown to be down-regulated through chronic noradrenergic activity. Alpha2 receptors when agonized by noradrenalin and adrenalin are generally inhibitory producing vasodilation instead of vasoconstriction importantly produce negative feedback inbihiting the LC and further noradrenaline release within the brain.
• In some SAD patients, there is an hyperactive adrenocortical response to psychologic stress.
• In conclusion the ANS of many patients is hypersensitive and over-reactive to various for example anxiogenic drugs more or less specific to the LC (e.g. yohibine - alpha2 adrenergic receptor antagonist) stimulate LC firing increasing NA release stimulating glutamate release and neural anxiety circuits and can produce feelings of anxiety. In comparison anxiolytic drugs (e.g. benzodiazipines) can inhibit LC firing.

Noradrenaline a2 adrenergic receptor & NA neurons of the brain

There are two different types of adrenoreceptor – the α and β receptors. The α receptors are further classified into α1 and α2 subtypes and the β receptors are further classified into β1, β2 and β3 subtypes. The α2 adrenoreceptors are widely distributed throughout the body and are found in adrenergic neurones, blood vessels, the pancreas and in smooth muscle. Coupled to inhibitory G-proteins,α2 adrenoreceptors have an inhibitory effect on neurotransmission when bound by an agonist.

GABA Model

• GABA (Gamma amino butyric acid) is the primary inhibitory neurotransmitter in the CNS
• GABAergic neurons has an inhibitory effect when they synapse onto other neurons
• If there is a hypofunction in GABAergic transmission in the brain, activity in cortical regions may be overly excitatory and insufficient modulation of anxiety may occur. The hippocampus also has a notably high number of GABA receptors
• Benzodiazepines and other similar anxiolytic drugs bind to an allosteric site on the GABA-A receptor augmenting the inhibitory effect of GABA on other neurons, reducing feelings of anxiety and anxiety response.
• Some current hypotheses and findings for GABA-A receptor involvement include abnormal sensitivity of the allosteric benzodiazepine binding sites to antagonization and decreased receptor binding in panic disorder. In GAD, decreased binding with benzodiazepines occured in the left temporal lobe. The role of endogenous benzodiazepines is a current research area

Seratonin Model

• 5-HT is mostly an inhibitory neurotransmitter 
• The raphe nuclei (brainstem) is the major point of origin of seratogenic neurons. These neurons project widely throughout brain.
• It is thought that seratogenic neurons are important in inhibiting the locus coeruleus and diminishing noradrenergic output.
• Noradrenalin may have a direct effect inhibiting 5HT release from pre-synaptic terminals.
• Abnormalities may occur at 5HT(1A/1D) autoreceptor, with their upregulation/increased sensitivity inhibiting presynaptic seratonin production and release
• Abnormalities at SERT
• Abnormalities of expression of post synaptic 5-HT receptors (e.g. fewer 1A vs more 2A/2C receptors)- the agonization of the 5HT2A receptor in the limbic system results in avoidance and anxious responses.