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1. Jaak Panksepp xxx Excerpta by: Gottfried Treviranus AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSInternational Master in Affective Neuroscience Florence 2004

2. AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICS -Eurocertificate MSc – Course in Affective and Anxiety Disorders Florence 2004 Excerpta by G. Treviranus !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! „psychology that shall be a natural science“ will “represent psychical processes as quantitatively determinate states of“„neurons“ (Waldeyer 1891) „thus making psychical processes perspicuous andfree from contradiction.“ Sigmund Freud‘sProject for a Scientific Psychology (1895) ?????????????????????????????????????????????????

3.  Neurochemical Systematics:

6. = AFTERTHOUGHT

7. Central theme:  40 years after Freud‘s project as a twen, transmitter research started (ACh), revealing several dozens of many more systems cascades of biochemical events convert chemical dialects (visualized by immuno-cytochemistry etc.) back to electrical ones we start to understand, how primitive emotions arise from specific neurochemistries AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

8. DNA: the source of mental life (1)  Central DOGMA of molecular biology:(nearly) all construction information for mammals are found in DNA of every cell (10,000 genes)  brains express most: ~ 50%  brains & bodies of mammals have  homologies human uniqueness Appx. A „... Human Origin“ AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

9. DNA: the source of mental life (2) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus DNA  transcription  RNA  translation   PROTEIN  BRAIN    everything else                 environment permeates all of this

10. Brief synopsis of Neurotransmitter & ReceptorSynthesis (1) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • (+) neuropeptides cleaved off from protein • (+) like ACh, by joining of fragments • (+) modified amino acids • stored in protective vesicles: pulsed liberation • (-) enzymatic degradation • (-) presynaptic reuptake transporter • (-) passive dissipation = diffusion & volume transport • (-)slow degradation (peptides)

11. Brief synopsis ofNeurotransmitter & Receptor Synthesis (2.1) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • receptors linger for days in membrane • invertebrate homologies  old phylogeny • some thread in & out 7 x ... (R 5-HT) • brain receptors for peripheral hormones • & for immune signals like cytokines • ACh-receptors: muscarinic♫Gviscero- • emotional; nicotinic♫X+ skeletal muscle

12. Brief synopsis ofNeurotransmitter & Receptor Synthesis (2.2) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • in & out 7 x : 7-transmembrane domain receptors >1000 GPCRs known: GDP GTP activation

13. Brief synopsis ofNeurotransmitter & Receptor Synthesis (2.3) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • G-Proteien-Coupled-Receptor

14. The GCRPdendrogram

15. Z(t) :outward translocation channel occupied by 3K+ ions 50% of the time Relative K+ density along the pore Z(t) :reentry of a translocating ion

16. Discovery of Synaptic Transmission Chemistries (1) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Nobel 1936 acetylcholine transmission Dale & Loewi Nobel 1970 S.T. mechanisms Axelrod, v.Euler & Katz Nobel 1977 neuropeptides Wallow Guillemin Schally Neuropeptides = 3 – 40+ amino acid chain TSH = first brain peptide: widely expressed often:1st hormones  also neuropeptides

17. Exaptation change of function of a preserved system („gill arches to jaw“)Peptide:PeripheralCentral function

18. Discovery of Synaptic Transmission Chemistries (3) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Neuropeptides (4)  peptides are digested drug transporters are being developed (Partridge) --- other classes of drugs seems difficult to make EXCEPTIONAL CASE: b-endorphin on m-receptor simulated by alkaloids (morphine, heroin)

19. Neurochemical Coding of Psychobehavioural Processes(1) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Pervasivetransmitters: what do they do in specific areas of the brain ? suppressors: 5-HT GABA&  facilitators: Glutamate NE DA But crosstalk! E.g. - Glutamatergic receptors on GABAergic inhibitory interneurons

20. Neurochemical Coding of Psychobehavioural Processes(2i) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GABA-systems

21. Neurochemical Coding of Psychobehavioural Processes(2ii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GABAA-receptor

22. Neurochemical Coding of Psychobehavioural Processes(12iii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GABAA-receptor http://www.wehi.edu.au/media/images/mps_workshop/gabaaall.jpg

23. Neurochemical Coding of Psychobehavioural Processes(12iii) . AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Allostery the binding of A and B to an allosteric proteinare coupled– influencing each other - and this kind of conformational coupling is known as allostery Jacques Monod Nobel laureate Medicine1965 1920 - 1976

24. Neurochemical Coding of Psychobehavioural Processes(2iv) • GABAA-receptor is part of a membrane chloride channel complex. GABA on the receptor opens the channel for Cl - • opening for Cl -can have 3 effectsdepending on the [Cl-] gradient & membrane potential: • most commonly: Cl- flux inward hyperpolarisation • Cl - flux outward depolarisation • No Cl- flux  no change in membrane potential • All 3reduce neuronal excitabilty by impeding generation or propagationof action potential AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

25. Neurochemical Coding of Psychobehavioural Processes(2v) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GABAA-receptor

26. Neurochemical Coding of Psychobehavioural Processes(2vi) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GABAA-receptor

27. Neurochemical Coding of Psychobehavioural Processes(3.1) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus  facilitators: Glutamate

28. On theNeurochemical Coding of Psychobehavioural Processes (3) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus  peptide & steroid neuromodula-tors often have more precise emotional & behavioural effects    this allows modelswhich oversimplify...but allow for  experimental predictionsinter-facing with psychology

29. Neurochemical Systematics (1) : nearly unmodified amino acids amino acids modified by enzymes amino acid chains (neuropeptides) miscellanea: ACh gaseous NOfatty acid-derived PGE2metabolic intermediaries ... 4 transmitter categories AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

30. Neurochemical Systematics (2) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus  i)nearly unmodified amino acids: Glutamate – the most abundant excitatory transmitter of body & brain it‘s catabolic glutamic acid decarboxylase(GAD) product GABA is the most abundant inhibitory transmitter in the brain only ii)glycine etc.: are difficult to study bc. too many effects, BBBs microinjections

31. Neurochemical Systematics (3) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus i)AA modified by enzymes biogenic amines: Tryptophane (indole double-ring): indoleamines: +OH > 5-HTP > - COOH >5-HT Tyrosinecatecholamines:

32. Neurochemical Systematics (4) • ii)Amino acids modified by enzymes = biogenic amines: Tyrosine (catechol C6-ring) catecholamines: • Tyr+OH >L-DOPA >- COOH > • DOPAMINE + OH (DA–b-H)NE ≡NOREPINEPHRINE + CH3 (PNMT*) > EPINEPHRINE caudal brain stem C1& C2: *) phenylethanolamin-N-methyltransferase AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

33. Neurochemical Systematics (5) iii)AA modified by enzymes= biogenic amines:  /  :Try  uptake= rate limitingstep Try +OH >5-HTP >- COOH >5-HTbrain /  ----------------------------------------------------------  /  :Tyr  uptakerate limitingstep  Tyrosine hydroxylase = rate limiting step : Tyr+OH >L-DOPA >- COOH >DAbrain =/  AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

34. Neurochemicbal Systematics (6) iv)AA modified by enzymes= biogenic amines: Try+OH >5-HTPprecursor loading> - COOH aromatic AA decarboxylase >5-HTbrain -------------------------------------------------------Tyr +OH >L-DOPA precursor loading> - COOH aromatic AA decarboxylase >DAbrain-- for Mb.Parkinson restoration ---  by DA-synthesis in serotonergic nerves ? AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

35. Neurochemical Systematics (7) i)amino acid chains (neuropeptides) ① brain opioides: endorphins, enkephalins, dynorphins, exogenic: caseomorphine, .. ② pituitary gland: oxytocin,vasopressin, ACTH, prolactin ③hypothalamicreleasers: CRF, LH-RH, TRH AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

36. Neurochemical Systematics (8) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus ii)amino acid chains (neuropeptides) ④gastric peptides: CCK, bombesin,VIP, ... ⑤ pituitary gland: oxytocin,vasopressin, ACTH, prolactin with active uptake BBB ⑥ many others: galanin, SP, CGRP, NPY, ... ⑦ ANP modulates CRF causes (lactate) panic attacks --------------------------------------------------------- most neuropeptides are digested & kept off by BBB !

37. Neurochemical Systematics (9) miscellaneous: Adenosine:coffee blocks thalamic sleep-rec.Steroids:cortisol, testosterone, E2, progeste-rone Neuro(active)steroids:steroids as neurorec.-ligands Gaseous:NO Immune signals:cytokines, INF Fatty acid derived: prostaglandins ACh Metabolic intermediaries? glucose, purines ... AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

38. NEUROSTATICS OF MAMMALIAN BRAIN AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus

39. Acetylcholine: Attentional & Action – System - (1) - AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus acetylCoA + choline > Choline-AcetylTransferaseChAT – Immunohistochemical mappingLevey‘83>Acetylcholine (ACh) >breakdown (also in non-ACh-neurons)by true mb Cholinesterase log4/s ↔ ACh survival 100ms

40. Acetylcholine: Attentional/Action – System (2ii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus ACh easy >1997 HPLCpmolFlentge ACh: 20% freein cell body & axon80% in terminal1:1labile & stable poolrelease toxins: b-bungarotoxin (Cobra) botulinum (log-12 g kills mouse) receptors: curare fast Na+ nicotinic atropineNslow muscarinic M

41. Acetylcholine: Attentional/Action – System (2ii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus CHOLINOTOXINS (1)B.Everitt, T.W.Robbins 1997 electrolytic lesions lesion fibres of pas-sage F(+++) i) excitatory amino acid infu-sion  lesions cell bodies myelin axons of passage ii)ibotenic acid R: NMDA  F(++) destroys non-ACh neurons – subst. innominata R: AMPA/kainate-exciting quisqualic acid + specificF(+) collateral damage ...

42. Acetylcholine: Attentional/Action – System (2iii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • CHOLINOTOXINS (2)B.Everitt, T.W.Robbins 1997 • R: AMPA/kainate-exciting quisqualic acid (+) specificF(+) R: AMPAAMPA(++) specific for nmbF(+)  R: low-affinity on ACh-neurons NFG 192IgG-saporin ☨ Wiley 1991 192IgG-saporinis +++ specific and has changed & refocussed concepts about ACh-systems

43. Acetylcholine: Attentional/Action – System (3) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus magnocell. Basal Cholinergic Forebrain system Brainstem cholinergic neurons Ch1MS Ch2vdB Ch4 Ch3hdB=nmb Ch6 LDTg Ch5 PPTg

44. Acetylcholine: Attentional/Action – System (4i) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Ch4 nbm Meynertbasal forebrain  higher info processing all over Cortex Ch1 MS, Ch2&3 v&hdBCh-5&6PPTg & LDTg  thalamic processing most of major somatic motor nucleipontine to (hypo)thalamic reticular fields   vigilance  Ch4 nbm Meynertbasal forebrain NO! Learning & Memory & Attention shifts un-changedCortex: ACh release visual etc.attention:divided & incremental↗not  „novelty“time of CSin HC Ch1 MS ? / Ch2 vhB & Ch3 hdBimpulsivity &early learning anterior cingulate cortex & post.: latelearning

45. Acetylcholine: Attentional/Action – System (4ii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus Brainstem cholinergic neurons:  Ch-5 PPTg  all thalamusCh-6LDTg   some thalamic nn.pontine to (hypo)thalamic reticular core fields   vigilance sleep/wake REM amygdalar ACh system ? retention of affective conditioning

46. Acetylcholine: Attentional/Action – System (4vi) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus CENTRAL ACh FUNCTIONS Everitt&Robbins Cambridge ´97  basal forebrainsignal/noise ratio  n.basalis-neocortical visual attention (not memory)  septo-hippocampal short-term spatial working memory,  ? by prolonging representations in HC ?

47. Acetylcholine: Attentional/Action – System (4v) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus • i) diagonal-band-cingulate cortex: response-rules by conditional discriminationii)diagonal-band-BFCSLEEPvia GABA inhibition of BFC n.basalis m-amygdala:retention of affective conditioning  i) brainstem-thala-mus: basic arousal ii)brainstem-mid-brain DA neurons:behavioural activation

48. Acetylcholine: Attentional/Action – System (5) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus muscarinic M1 - BLOCKERS (atropine, scopolamine)   attention most motivated behaviours memory... but M2 – BLOCKERS memory ACh EXCESS (by cholinesterase inhibitors)  muscarinic   ANS †

49. Acetylcholine: Attentional/Action – System (4iii) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus ACh attention arousal action tendencies  ACh micro- iontophoresis (or carbachol) in brain sites (byarousal) rage (cat) aggression vocalization drinking (rat)burst-firing single-firing;EEG synchronisation

50. Acetylcholine: Attentional/Action – System (6) AFFECTIVE NEUROSCIENCE – Jaak Panksepp - ch. 6: NEURODYNAMICSEurocertificate MSc – Course in Affective and Anxiety disorders Florence 2004 Excerpta by G. Treviranus GALANTAMINEtreats disor-ders at ACh-muscarinic transmis- sion  BLOCKS Acetylcholines-terase   action of ACh on ionophore cation transport ~ funnel & tunnel ~ BDZ on GABA-A or ~ aripiprazole on D2