Anxiety Disorders

Anxiety Disorders

* Panic disorder
o Can be induced by lactate or CO2 in PD sufferers (only occasionally in normal people)
o Increased activity in parahippocampal gyrus,
o Decreased activity in anterior temporal cortex & amygdala (seems odd!)
o May have 3, rather than 2, repeats of a section on chromosome 15
+ Also have joint laxity (bend too far)

* Treatments for panic disorder
o Benzodiazepines (e.g., Valium)
+ Increase frequency of Cl- channel openings in response to GABA
+ Have little or no effect alone: safer than barbiturates
+ Allopregnanolone = endogenous agonist at benzodiazepine binding site.
o Buspirone (Buspar): 5-HT1a agonist (GI/O)
o SSRIs: fluoxetine (Prozac), paroxetine (Paxil)

Benzodiazepine receptors in brain
PTSD
* Monozygotic > dizogotic concordance
o Genetics 1/3 of variance
* NMDA mechanisms in amygdala
o May mediate both the conditioning and the extinction
+ NMDA antagonists in amygdala prevent extinction
+ Hippocampus and PFC also lose effectiveness in extinction
* Not due to high levels of glucocorticoids:
o Usually PTSD sufferers have LOWER than normal cortisol levels, despite high CRH
+ Maybe it’s the high CRH that  symptoms
+ Or maybe it’s increased responsiveness to CRH or cortisol
* Individual differences in responsiveness to trauma
* Sometimes treated with β NE antagonists (propranolol) or protein synthesis inhibitors soon after the trauma or during recall of the trauma
OCD
* Increased metabolism in orbitofrontal cortex, cingulate, and caudate nuclei.
* Decreased REM latency (~ to depression)
* At least 2 gene polymorphisms:
o For BDNF, 5-HT2A receptor
* Treatment: SSRIs
Cingulotomy to treat OCD
Tourette’s Syndrome
* In many ways opposite Parkinson’s disease
* Treated with dopamine antagonists
* Monozygotic concordance: 53-77%; dizygotic concordance: 8-23%
* Witty Ticcy Ray (by Oliver Sacks): “We Touretters…are forced into levity by our Tourette’s and forced into gravity when we take Haldol….You have a natural balance: we must make the best of an artificial balance.”

THE NIGROSTRIATAL AND MESOLIMBIC DOPAMINE SYSTEMS
* Nigrostriatal and mesolimbic tracts are parallel.
o Begin in midbrain (substantia nigra & ventral tegmental area, VTA)
o End in dorsal (caudate & putamen) and ventral (N. accumbens) striatum
o Cortico-striato-pallido-thalamic-cortical loops

Nigrostriatal system
* Plans and triggers self-initiated movements
* Adjusts posture
* Degeneration  Parkinson’s disease
o Tremor at rest
o Difficulty initiating movements

Mesolimbic system
* Increases responsiveness to external and internal stimuli
* Motivation
* Motor activity
* Reward
* Drug addiction
* Schizophrenia
Nigrostriatal dopamine tract
Mesolimbic dopamine tract

Direct pathway
* Positive feedback loop
* Cortical areas that initiated the activity are further excited.
* 2 consecutive inhibitory influences
* Then an excitatory influence
* Stimulating the first inhibitory path inhibits the second inhibitory path: disinhibits the excitatory path.

Sensorimotor Cortex
Striatum
Direct pathway
* Stimulate putamen
* Inhibits GPi/SNr
via D1 receptors
Sensorimotor Cortex
Striatum
Direct Pathway
When putamen inhibits
GPi/SNr, VL/VA
is disinhibited.
Thus, VL/VA excites
sensory motor cortex.
Indirect Pathway
Negative feedback
Begins with 2
inhibitory paths:
1. Putamen to GPe
2. GPe to STN
Sensorimotor Cortex
Indirect Pathway
Those inhibitory paths disinhibit an excitatory path.
But that exc. path ends on another inhibitory path!
Function
* Direct path excites cortex; indirect path inhibits it: opposing functions.
* May “sharpen” influence on behavior
o (similar to “sharpening” receptive fields).
* May provide greater control over movement
o (similar to having both EPSPs and IPSPs on same neuron).

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

The Mesolimbic System
* Circuit is parallel to nigrostriatal system:
o Direct and indirect pathways
o Prefrontal cortex vs. sensory motor
o N. accumbens (ventral striatum), vs. caudate & putamen (dorsal striatum)
o Ventral pallidum vs. GPi and GPe
o Mediodorsal thalamus vs. VL/VA
Prefrontal Cortex
VP normally inhibits

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

Glutamate/DA balance in schizophrenia
* Cortical or hippocampal hypofunction may  decrease glutamate in NAcc and striatum
* decrease tonic DA release
* increase DA receptor sensitivity
* hyperresponsive to phasic input

Anxiety Disorders.ppt