Neurophysiology and Neurochemistry in PsychoGeriatrics

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PsychoGeriatrics Nicola Maggio, MD, PhD Sackler Faculty of

1 Tel Aviv University Sackler Faculty of Medicine CME in Psychiatry Neurophysiology and Neurochemistry in PsychoGeriatrics Nicola Maggio, MD, PhD Sackler Faculty of Medicine Tel Aviv University Department of Neurology The Chaim Sheba Medical Center

2 OUTLINE Synaptic Transmission Neuromodulation Basic Concepts of Neuropharmacology Neurochemistry in Psychogeriatrics

3 Synaptic Transmission

4 Synaptic Transmission Synaptic Transmission: chemical synapses Synaptic Transmission: electrical synapses

5 Synaptic Transmission Tripartite Synapse

6 Synaptic Transmission Multipartite Synapse Microglia Microglia in Synaptic Transmission

7 Synaptic Transmission Multipartite Synapse Microglia Microglia in Synaptic Pruning

8 Synaptic Transmission Multipartite Synapse Blood Brain Barrier The Neurovascular Unit

9 Synaptic Transmission Multipartite Synapse BBB opening

10 Dysfunctions of Synaptic Transmission Vascular Dementia

11 Dysfunctions of Synaptic Transmission Vascular Dementia

12 Dysfunctions of Synaptic Transmission Delirium in the elderly upon systemic conditions (i.e. infections, systemic inflammation, etc.)

13 Summary 1 The basic concept of synaptic transmission as the way of communication between a presynaptic and a postsynaptic partner has been changed in favor of a communication between multiple cellular elements that can influence each other both at physiological and pathophysiological levels.

14 Neuromodulation Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neurons.

15 Neuromodulation Neuromodulation is the physiological process by which a given neuron uses one or more neurotransmitters to regulate diverse populations of neurons. While classical synaptic transmission occurs between a presynaptic and a postsynaptic partner, neuromodulation occurs between subpopulation of neurons which influence the activity of other subpopulation of neurons. Neuromodulators can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain. Time scale of action is an additional difference between synaptic transmission and neuromodulation. While synaptic transmission is mainly operated through channels, neuromodulation occurs through metabotropic receptors.

16 G-proteins coupled receptors Effectors: camp; Phospholipase; Phosphodiesterases; Ion Channels.

17 Main Neuromodulators System Origin Targets Effects Norepinephrine Locus Coeruleus Spinal cord Thalamus Hypothalamus Striatum Neocortex Cingulate Gyrus Cingulum Hippocampus Amygdala Arousal Reward System Lateral Tegmental Field Hypothalamus

18 Main Neuromodulators System Origin Targets Effects Dopamine Mesocortical Mesolimbic Nigrostriatal Tuberoinfundibular All brain areas bearing dopamine receptors Motor System Reward System Cognition Endocrine Nausea

19 Main Neuromodulators System Origin Targets Effects Serotonin Caudal Dorsal Raphe Nucleus Rostral Dorsal Raphe Nucleus Deep Cerebellar Nuclei Cerebellar Cortex Spinal Cord Thalamus Striatum Hypothalamus Nucleus Accumbens Neocortex Cingulate Gyrus Cingulum Hippocampus Amygdala Increase: Mood Satiety Body Temperature Sleep Decrease: Nociception

20 Main Neuromodulators System Origin Targets Effects AcetylCholine Peduncolopontine Nucleus Mainly M1 receptors in: Brainstem Deep Cerebellar Nuclei Pontine Nuclei Locus Coeruleus Raphe Nucleus Lateral Reticular Nucleus Inferior Olive Thalamus Tectum Basal Ganglia Basal Forebrain Muscle and motor control systems Learning Short term memory Arousal Reward Basal Nucleus of Meynert Medial Septum Mainly M1 receptors in: Neocortex Mainly M1 receptors in: Hippocampus

21 Other Neuromodulators Opiods Endocannabinoids

22 Neuromodulation: Agonists/Antagonists An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist. A superagonist is a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%. This does not necessarily mean that it is more potent than the endogenous agonist, but is rather a comparison of the maximum possible response that can be produced inside the cell following receptor binding. Full agonists bind (have affinity for) and activate a receptor, producing full efficacy at that receptor. One example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at µ-opioid receptors throughout the central nervous system.

23 Neuromodulation: Agonists/Antagonists Partial agonists (such as buspirone, aripiprazole, buprenorphine, or norclozapine) also bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the opioid receptor with lower dependence and abuse potential. An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and inhibits the constitutive activity of the receptor. Inverse agonists exert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with antagonist. An example is the cannabinoid inverse agonist rimonabant. A co-agonist works with other co-agonists to produce the desired effect together. NMDA receptor activation requires the binding of both glutamate, glycine and D- serine co-agonists. An irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds. A selective agonist is selective for a specific type of receptor. E.g. buspirone is a selective agonist for serotonin 5-HT1A.

24 Neuromodulation: Agonists/Antagonists Competitive antagonists (also known as surmountable antagonists) reversibly bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor.

25 The Norepinephrine System Data regarding the effects of aging on the noradrenergic system are sparse and often contradictory. On the one hand, aging brains have reduced norepinephrine activity due to a decrease in the number of locus coeruleus neurons, as well as decreased activity of thyrosine hydroxylase and dopa decarboxylase, key enzymes in norepinephrine synthesis. Furthermore, both the concentration and activity of monoamine oxidase (MAO), the enzyme responsible for the presynaptic breakdown of norepinephrine increase with age. On the other hand, concentration of norepinephrine in cerebrospinal fluid (CSF) has been shown to increase with age and the concentration of norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) also increases in some areas of the aging brain.

28 Like many other biologically active substances, norepinephrine exerts its effects by binding to and activating receptors located on the surface of cells. Two broad families of norepinephrine receptors have been identified, known as alpha and beta adrenergic receptors. Alpha receptors are divided into subtypes α 1 and α 2 ; beta receptors into subtypes β 1, β 2, and β 3. All of these function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Alpha-2 receptors usually have inhibitory effects, but many are located presynaptically (i.e., on the surface of the cells that release norepinephrine), so the net effect of alpha-2 activation is often a decrease in the amount of norepinephrine released. Alpha-1 receptors and all three types of beta receptors usually have excitatory effects.

29 The Dopamine System

31 Like many other biologically active substances, dopamine exerts its effects by binding to and activating receptors located on the surface of cells. In mammals, five subtypes of dopamine receptors have been identified, labeled D1 through D5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Dopamine receptors in mammals can be divided into two families, known as D1-like and D2-like. For receptors located on neurons in the nervous system, the ultimate effect of D1-like activation (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like activation (D2, D3, and D4) is usually inhibition of the target neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory: its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1 receptors are the most numerous dopamine receptors in the human nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels

33 The Serotonin System

34 Binding profile of serotonin Receptor K i (nm) [18] Receptor function [Note 1] 5-HT 1 receptor family signals via G i/o inhibition of adenylyl cyclase. Receptor K i (nm) [18] Receptor function [Note 1] Memory(agonists ); learning (agonists ); 5-HT 1 receptor family signals via G i/o inhibition of adenylyl cyclase. anxiety (agonists ); depression (agonists ); Memory positive, negative, (agonists and ); cognitive 5-HT 1A 5-HT 1A symptoms learning [vague] of (agonists schizophrenia ); anxiety (partial (agonists ); analgesia depression (agonists ); positive, ); negative, aggression and cognitive (agonists symptoms ); dopamine of schizophrenia release in the prefrontal (partial agonists cortex (agonists ); analgesia ); (agonists serotonin ); release aggression and synthesis (agonists (agonists ); ) dopamine release in the prefrontal cortex 5-HT 5-HT 1B B 4.32 Vasoconstriction Vasoconstriction (agonists (agonists ); ); aggression aggression (agonists (agonists ); ); bone bone mass mass ( ). ( ). Serotonin Serotonin autoreceptor. autoreceptor. 5-HT 5-HT 1D 1D Vasoconstriction (agonists ) Vasoconstriction (agonists ) 5-HT 1E HT 1E 5-HT 1F HT 1F 10 Binding profile of serotonin (agonists ); serotonin release and synthesis (agonists )

35 5-HT 2 receptor family signals via G q activation of phospholipase C. Psychedelia (agonists ; antagonists ); depression (agonists & antagonists ); anxiety (antagonists ); 5-HT 2A positive and negative symptoms of schizophrenia (antagonists ); norepinephrine release from the locus coeruleus (antagonists ); glutamate release in the prefrontal cortex Cardiovascular functioning (agonists increase risk of 5-HT 2B 8.71 pulmonary hypertension), empathy (via the spindle neurons or Von Economo neurons [19] ) Dopamine release into the mesocorticolimbic pathway (agonists ); acetylcholine release in the prefrontal 5-HT 2C 5.02 cortex (agonists ); appetite (agonists ); antipsychotic effects (agonists ); antidepressant effects (agonists & antagonists ) Other 5-HT receptors 5-HT 3? Emesis (agonists ); anxiolysis (antagonists ) Movement of food across the GI tract (agonists ); 5-HT memory & learning (agonists ); antidepressant effects (agonists ). Signalling via G αs activation of adenylyl cyclase.

36 5-HT 5A HT HT Memory consolidation. [20] Signals via G i/o inhibition of adenylyl cyclase Cognition (antagonists ); antidepressant effects (agonists & antagonists ). G s signalling via activating adenylyl cyclase. Cognition (antagonists ); antidepressant effects (antagonists ). Acts by G s signalling via activating adenylyl cyclase.

38 Post mortem studies indicate a decrease of 5HT 2 receptors with aging in the cortex but not in the hypothalamus or striatum. An age-related decrease in receptor activity in the caudate, putamen and frontal cortex has been shown by PET. These changes in serotonin system are believed to underlie the changes in sleep, emotion and memory observed in old patients.

39 The Cholinergic System

42 The Opioids System

A significant loss in availability and structure of endogenous opioid neurotransmitters has been observed with aging expecially in the frontal lobes, hippocampus

44 A significant loss in availability and structure of endogenous opioid neurotransmitters has been observed with aging expecially in the frontal lobes, hippocampus and striatum. This causes an upregulation of the receptors and thus expose elderly patients to a high risk of side effects when exposed to drugs containing opioids.

45 The Endocannabinoids System

50 Summary Multiple modulators controlling different aspects of behavior exist within the brain, each having a peculiar mechanism of action through activation of specific receptors.

51 Novel approaches for manipulating synaptic transmission and neuromodulation

54 Thanks

- Neurotransmitters Of The Brain -

- Neurotransmitters Of The Brain - INTRODUCTION Synapsis: a specialized connection between two neurons that permits the transmission of signals in a one-way fashion (presynaptic postsynaptic). Types of