1. Metabotropic Neurotransmitter Receptors

2. Dopamine Receptors

4. Dopamine receptors D1, D5 types D1 highest expressed DA receptor
Coupled to Gas
D2,3,4 types
D2 is the site of action for anti-psychotic drugs
Coupled to Gai and Gao
Primary AC in striatum is AC5
Activated by Gas and PKC
Inhibited by Gai/o and Ca2+

5. D2 autoreceptor D2 can be alternatively spliced to D2s and D2l
D2s acts as the inhibitory pre-synaptic autoreceptor
Inhibits synthesis and release of DA
D2l functions as an inhibitory post-synaptic receptor

7. Adrenergic Receptors a1-adrenergic receptors a2-adrenergic receptors
3 types, all coupled to Gaq/11 (PLC pathway)
a2-adrenergic receptors
3 types, coupled to Gai/o (inhibit AC)
Found pre-synaptically, acts as autoreceptor
b-adrenergic receptors
3 types, coupled to Gas (activate AC)
Often found on glia, where they reduce glutamate uptake and regulate glucose utilization

8. Functional Roles of adrenergic receptors
Hypothalamic
A1 in MPO area mediate wakefulness
Amygdala and HPC
A1 and B receptor activation promotes long term memory consolidation
A2 activation enhance working memory in PFC
A1 activation in PFC inhibits its function
Some anti-psychotic drugs antagonize A1 receptors—may act in PFC
Many anti-depressants (especially RI class) increase NE levels globally

9. CA Receptor Regulation
Agonist induced down regulation
Receptors are internalized after prolonged treatment with agonists
Reuptake inhibitors
Drugs like amphetamine
Denervation Supersensitivity (203 lab)
Physical ablation or chemical antagonism of receptor activation leads to increased receptor density and sensitivity

10. Muscarinic Ach Receptors

11. mAchR localization
M1-abundant post-synaptic (dendritic) receptor in the brain
M2 enriched in thalamus and brainstem, low levels elsewhere
Pre-synaptic autoreceptor
M3 low levels in cortex and HPC
M5 low levels in VTA, SN midbrain
M4 high levels in striatum (pre-synaptic)

13. Implications for disease
AD-loss of cholinergic neurons
Schizophrenia- reduced levels of M1 and M4
Genetic and pharmacological links
Parkinson’s disease
Links to nicotine protection
Regulation of pre-synaptic DA release
Balance of Ach and DA in Striatum regulates movement
Drug Addiction-M5 antagonists in VTA

14. Serotonin Receptors

15. Serotonin Receptors

17. 5-HT1A Gi/o coupled Cortex and hippocampus
Post-synaptic and somatodendritic autoreceptor functions
As autoreceptors, mechanism is via activation of K+ channels
Function in feeding, sexual behaviors, and body temperature, ACTH release
Agonists of 5-HT1A treat anxiety, and perhaps depression and schizophrenia too

18. 5-HT2 Family
Gq coupled
5-HT2A post-synaptic receptor found highest in PFC on both GABA and Glutamate neurons
Homeostatic functions (temperature)
Roles in cognition and mental illness
Antagonists are anti-psychotic
Agonists are hallucinogenic

19. 5-HT 4,6,7 receptors Gs coupled 5-HT4 5-HT6 5-HT7
Multiple splice isoforms
Not well studied
5-HT6
Target of anti-psychotic drugs and anti-depressants (striatum)
Antagonists increase Ach transmission, improve learning and memory
5-HT7
Sleep, circadian rhythms and mood (SCN)
Target of anti-psychotic drugs

21. Metabotropic Glutamate ReceptorsGi Gq

22. Functional Roles for mGluR
All 3 classes inhibit L-type voltage sensitive Ca2+ channels
mGluR activation also closes K+ channels, leading to slow repolarization (prolong excitation) HPC and cortex
Opposite effect in cerebellum
Pre-synaptic mGluRs are inhibitory-on both Glutamate and GABA neurons (Ca2+ channel)

23. Studies in knock-out mice
mGlu1 -/- mice-cerebellar ataxia
mGlu1 necessary for pruning of climbing fiber-Purkinje cell synapses during development
LTD is defective, poor motor learning
mGlu2 -/- mice- impaired LTD in HPC

24. Metabotropic GABAB receptors
2 members, R1 and R2, have been cloned
Function as a dimer, R1 binding GABA, R2 binding the G protein
4 known associated subunits regulate localization, function, and pharmacology
Inhibitory
Open K+ channels
Block Ca2+ channels (presynaptic inhibition)
Inhibit AC