Chapter 5 Opener

1. Chapter 5 Opener

2. 5.1 Structural features of catecholamines

3. How enzymes affect the molecule • Hydroxylase adds a hydroxyl group (OH) • Decarboxylase removes a carboxyl group (COOH)

4. 5.2 Catecholamines are synthesized in a multi-step pathway

5. Synthesis of the catecholamines • Begins with the amino acid tyrosine • Obtained from dietary protein • Transported from blood to the brain • Dopamine neurons • contain only the first two enzymes • Tyrosine hydroxylase (TH) • Aromatic amino acid decarboxylase (AADC) • Norepinephrine neurons • Also contain • Dopamine β-hydoroxylase (DBH)

6. Conversion of tyrosine to DOPA is the slowest • Thus, tyrosine hydroxylase (TH) is the rate limiting enzyme. • Lots of DA or NE in a cell inhibits TH • High firing rates increases TH

7. Drugs that affect synthesis • Catecholamine formation can be increased by administration of a biochemical precursor • L-DOPA • Treatment for Parkinson’s Disease • Drugs that reduce catecholamine synthesis • Inhibit a synthesizing enzyme • AMPT (α-methyl-para-tyrosine) • Blocks TH (tyrosine hydroxylase) • Depletes catecholamines • Causes return of depressive symptoms in patients treated with antidepressants

8. Drugs that affect Storage • Catecholamines are stored in and released from synaptic vesicles • Provides a means of release • Several thousand molecules per vesicle • Protects neurotransmitter from degradation by enzymes in the terminal button.

9. VMAT • Vesicular monoamine transporter (VMAT) • A protein in the membrane of the vesicle • Pulls catecholamines into the vesicle • Reserpine blocks VMAT • DA and NE are thus not encased in a vesicle • Broken down by enzymes • Low levels of DA and NE • Causes sedation in animals • Depressive symptoms in humans • Effects can be reversed with DOPA • Led to the catecholamine theory of depression • Depression – too little catecholamine activity

10. 5.3 Catecholaminergic neurons use a vesicular monoamine transporter protein (VMAT2)

11. 5.4 Role of catecholamine depletion in the behavioral depressant effects of reserpine

12. Drugs that affect release of catecholamines • Normally nerve impulse reaches the terminal button • Causes exocytosis • Some drugs cause exocytosis independently of nerve firing • amphetamine and methamphetamine • Causes behavioral activation • Notice opposite effect of reserpine • Can cause stereotypy at high doses • Sniffing, licking, biting, repetitive head movement • In humans • increased alertness • energy • euphoria • insomnia

13. Drugs that affect autoreceptors • Work by inhibiting the amount of Ca++ that enters the terminal button in response to an action potential reaching the terminal button • Less DA or NE released when next action potential arives • D2 = DA autoreceptor • α2 = NE autoreceptor • Agonists of these receptors = decrease release • Antagonists of these receptors = increase release

14. 5.5 A typical dopaminergic neuron possesses autoreceptors on the membrane of its terminals

15. Drugs that affect the transporter • Transporters cause reuptake from the synapse • The neurotransmitter is then either repackaged in vesicle, or broken down by enzymes • Transporter blocking drugs • Tricyclic antidepressants • SSRIs • NSRIs • cocaine

16. 5.5 A typical dopaminergic neuron possesses autoreceptors on the membrane of its terminals

17. Drugs that affect metabolizing enzymes that break down catecholamines after reuptake • Catechol-O-methyltransferase (COMT) • Monoamine oxidase (MAO) • Breakdown of DA • Homovanillic acid (HVA) • Breakdown of NE • 3-methoxy-4-hydroxy-phenylglycol (MHPG) • Concentrations of these metabolites in blood and urine play a role in determining the involvement of DA and NE in mental disorders (e.g., depression and schizophrenia).

18. MAO and COMT inhibitors • MAO inhibitors • used to treat depression • COMT inhibitors • Often prescribed with L-DOPA in Parkinson’s disease to prevent the break down of L-DOPA prior to reaching the brain.

19. The A system = from the Swedes • A = cells that stain for NE or DA • A 1-7 = noradrenergic • A 8-16 = dopaminergic

20. Organization of the DA system • Three main pathways • 1. Nigrostratal tract (movement) • Starts in A9 – substantia nigra (in mesencephalon) • projects to the striatum (caudate and putamen).

21. 5.7 The ascending DA system can be divided into three pathways (Part 1)

22. Box 5.1 Parkinson’s Disease—A “Radical” Death of Dopaminergic Neurons? (Part 1)

23. Box 5.1 Parkinson’s Disease—A “Radical” Death of Dopaminergic Neurons? (Part 2)

24. 2. Mesolimbic dopamine pathway (reward) • Starts in A10 – ventral tegmental area (in mesencephalon. • Projects to limbic system (in particular nucleus accumbens and olfactory tubercules).

25. 5.7 The ascending DA system can be divided into three pathways (Part 2)

26. 3. Mesocortical dopamine pathway (reward) • Starts in A10 – VTA • To cortex (primarily prefrontal cortex)

27. 5.7 The ascending DA system can be divided into three pathways (Part 3)

28. 5 subtypes of dopamine receptors • D1 like • D1 and D5 • D2 like • D2, D3, and D4 • All are metabotropic receptors • Both families are largely found in the striatum and nucleus accumbens

29. D1 and D2 effects on cAMP • In general, increased postsynaptic DA receptor stimulation decreases nigrostriatal DA activity • D1 and D2 receptors work together • Synergistic relationship

30. D1 • D1 activation – Gs protein • increases cAMP synthesis • D1 receptor activation may be necessary for full expression of D2 effects

31. D2 • D2 activation – Gi protein • decreases cAMP synthesis • Autoreceptors inhibit DA synthesis and release • Post synaptic receptors slow firing rate • Inhibition of Ca++ entry • Opening of K+ channels

32. 5.9 Signaling mechanisms of D1 and D2 receptors

33. Agonists • D1 • SKF 38393 – elicits grooming behavior • D2 • Quinpirole – locomotion and sniffing • Antagonists • D1 • SCH 23390 – decreased activity • D2 • Haloperidol – decreased activity

34. 5.10 Catalepsy can be produced by DA receptor antagonists

35. Ascending noradrenergic system • Starts in the pons and medulla • A6 – locus coeruleus • Axons extend throughout the forebrain • Also cerebellum and spinal cord

36. 5.11 The locus coeruleus (LC) contains a dense cluster of noradenergic neurons

37. Sleeping or inactive rats • Slow firing of cells in LC • Novel sensory stimuli • Fast firing of cells in LC • Thus, LC may play a role in vigilance • Being alert to stimuli in the environment

38. 5.12 Role of the locus coeruleus in vigilance

39. α and β receptors • β1 and β2 receptors are like D1 • α2 similar to D2 • α1 works somewhat differently – phosphoinositide second messenger • Adrenergic agonists increase arousal and eating behavior • Adrenergic antagonists • Treat hypertension = α1 • Impotence = α2 • Increase parasympathetic; decrease sympathetic • Generalized anxiety disorder = β blockers • Reduce sympathetic response

40. α and β receptors • β1 and β2 receptors are like D1 – increase cAMP • α2 similar to D2 – decrease cAMP • α1 works somewhat differently – phosphoinositide second messenger • Adrenergic agonists increase arousal • Animals sleep less • Adrenergic antagonists • Treat hypertension = α1 • Impotence = α2 • Increase parasympathetic; decrease sympathetic • Generalized anxiety disorder = β blockers • Reduce sympathetic response