La neurobiologia della dipendenza da farmaci

Presentazione sul tema: "La neurobiologia della dipendenza da farmaci"— Transcript della presentazione:

1 La neurobiologia della dipendenza da farmaci
6 marzo 2003 sono GB, sono medico e mi occupo di neuroanatomia e neurofisiologia all’universita’ di verona NON sono farmacologo, psicologo, sociologo… bene, allora di cosa parliamo?

2 meccanismi di azione delle droghe nel cervello
approccio razionale al dibattito e alla riflessione sul tema dell’uso di sostanze stupefacenti metodi e potenzialità della ricerca in ambito neuroscientifico meccanismi di azione delle droghe nel cervello

3 spunti per una riflessione
Definizione medico-clinica di tossicodipendenza (dal sito web della Società Italiana di Farmacologia) «l’uso compulsivo di sostanze dovuto alla necessità di evitare i disturbi psicofisici dell’astinenza ed associato ad una serie di alterazioni patologiche derivanti dall’esposizione cronica ad alte dosi delle sostanze stesse e dei loro contaminanti» Da una conferenza stampa del vice presidente del Consiglio, febbraio 2002 «Per noi la droga è droga: non c’è nessuna distinzione tra pesante o leggera»

4 un’altra dicotomia! dipendenza “psicologica” dipendenza “fisica”

5 La scienza dei bernoccoli cerebrali
Fermezza Benevolenza Imitazione Spiritualità Venerazione Speranza Coscienziosità Natura umana Comparazione Cautela Auto-stima Causalità Eventualità Continuità Idealismo Localizzazione Combattività Calcolo Costruttività La dottrina del diciannovesimo secolo detta frenologia riteneva che tratti di personalità quali la combattività, la spiritualità, la speranza, ecc. Fossero controllati da aree specifiche nel cervello, e che lo sviluppo di tali tratti provocasse l’espansione di tali aree che diventava visibile sotto forma di bernoccoli dovuti alla deformazione del cranio. Comportamenti alimentari Capacità amatorie

6 sensazioni somatiche movimento visione spaziale capacità di giudizio udito visione linguaggio percezione di oggetti coordinazione motoria emozioni

7 Riflesso patellare

8 vie nervose la sensazione di dolore
la risposta motoria allo stimolo dolorifico Pathway for sensation of pain and reaction to pain This is a long pathway, in which neurons make connections in both the brain and the spinal cord. Explain what happens when one slams a door on one's finger. First, nerve endings in the finger sense the injury to the finger (sensory neurons) and they send impulses along axons to the spinal cord (magenta pathway). Point to each part of the pathway as you explain the flow of information. The incoming axons form a synapse with neurons that project up to the brain. The neurons that travel up the spinal cord then form synapses with neurons in the thalamus, which is a part of the midbrain (magenta circle). The thalamus organizes this information and sends it to the sensory cortex (blue), which interprets the information as pain and directs the nearby motor cortex (orange) to send information back to the thalamus (green pathway). Again, the thalamus organizes this incoming information and sends signals down the spinal cord, which direct motor neurons to the finger and other parts of the body to react to the pain (e.g., shaking the finger or screaming "ouch!").

9 aree visive nel macaco le aree V1 e V2 hanno rappresentato un terreno molto fertile di ricerca, anche per la convergenza di informazioni provenienti dagli studi anatomici con i dati elettrofisiologici. Nel cervello di mammifero, tuttavia, sono state individuate numerose aree corticali [ricordare concetto di area] visive, cioè i cui neuroni vengono attivati (o inibiti) dalla presentazione di stimoli visivi.

10 vie nervose Aree e vie visive

11 Circuiti del linguaggio
Questa mostra una serie di aree corticali che hanno in comune la proprietà di svolgere un ruolo fondamentale nella comprensione e nella produzione del linguaggio. L’area di Broca, per esempio, prende il nome dal neurologo francese che descrisse fra le altre cose, il caso di un paziente che capiva quello che sentiva, ma che non riusciva a parlare. Poteva canticchiare, fischiettare, pronunciare parole isolate, ma non un discorso di senso compiuto. L’esame autoptico di questo paziente rivelò un danno proprio in quest’area. Successivamente, un’altro studioso, Karl Wernicke descrisse un diverso tipo di afasia, consistente nell’incapacità di comprendere il linguaggio parlato, dovuta alla lesione di un’altra area corticale. Si noti come l’area di Wernicke sia in diretta prossimità di quest’ulteriore area, indicata in giallo, che rappresenta la corteccia uditiva primaria, ovvero la struttura corticale che per prima raccoglie ed elabora le informazioni sonore captate dall’orecchio. Wernicke ha formulato una teoria coerente (NO) C’e’ un altro aspetto interessante in questa immagine: frecce, ovvero circuiti... Ma insomma, parliamo di aree corticali responsabili di precise funzioni, parliamo di connessioni fra tali aree, ma cosa c’e’ in queste aree, e in cosa consistono queste connessioni? Di cosa è fatta questa materia così importante che la perdita anche di piccole quantità può provocare menomazioni gravissime o addirittura la morte?

12 The reward system Prima di tutto: come facciamo a sapere dell’esistenza nel cervello di un sistema della “ricompensa”?

13 reward system mm (“rinforzo positivo”)
Premendo la leva, il ratto si auto-somministra minuscole scariche elettriche che attivano una specifica area di cervello (“rinforzo positivo”)

14 nucleus accumbens

15 human accumbens & VTA Nucleus Accumbens (NAc) & Ventral Tegmental Area (VTA)

16 sistema dopaminergico
putamen nucleo caudato nucleo accumbens area tegmentale ventrale sostanza nera sistema dopaminergico

17 il circuito della “ricompensa”
Slide 11: The reward pathway Tell your audience that this is a view of the brain cut down the middle. An important part of the reward pathway is shown and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex via this pathway and it sends information to these structures via its neurons. The neurons of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex (point to each of these structures). Reiterate that this pathway is activated by a rewarding stimulus. [Note: the pathway shown here is not the only pathway activated by rewards, other structures are involved too, but only this part of the pathway is shown for simplicity.]

18 il circuito della “ricompensa”
Neurone dopaminergico alla corteccia frontale accumbens parleremo di questo, ma per parlare di questo dobbiamo avvicinarci... VTA

19 Describe the synapse and the process of chemical neurotransmission
Describe the synapse and the process of chemical neurotransmission. Indicate how vesicles containing a neurotransmitter, such as dopamine (the stars), move toward the presynaptic membrane as an electrical impulse arrives at the terminal. Describe the process of dopamine release (show how the vesicles fuse with the presynaptic membrane). Once inside the synaptic cleft, the dopamine can bind to specific proteins called dopamine receptors (in blue) on the membrane of a neighboring neuron. Introduce the idea that occupation of receptors by neurotransmitters causes various actions in the cell; activation or inhibition of enzymes, entry or exit of certain ions. State that you will describe how this happens in a few moments.

20 Sinapsi dopaminergica

21 Slide 6: Dopamine and the production of cyclic AMP Using the close-up view, explain what happens when dopamine binds to its receptor. When dopamine binds to its receptor, another protein called a G-protein (in pink) moves up close to the dopamine receptor. The G-protein signals an enzyme to produce cyclic adenosine monophosphate (cAMP) molecules (in green) inside the cell. [Sometimes the signal can decrease production of cAMP, depending on the kind of dopamine receptor and G-protein present.] Point to the dopamine receptor-G-protein/adenylate cyclase complex, and show how cAMP is generated when dopamine binds to its receptor. Indicate that cAMP (point to the cyclic-looking structures) controls many important functions in the cell including the ability of the cell to generate electrical impulses.

22 Autosomministrazione di dopamina
Il ratto si autosomministrerà dopamina... Ma solo se questa viene iniettata in VTA o accumbens Non si ottiene lo stesso effetto con altri neurotrasmettitori mm Slide 8: Reward: drug self-administration Introduce the concept of positive reinforcement or reward. Explain that rats will press a bar to get an injection of cocaine or heroin (self-administration - shown on the left). The rat keeps pressing to get more cocaine or heroin because the drugs make the rat feel so good. This is called positive reinforcement, or reward. Natural rewards include food, water and sex - each is required to maintain survival of our species. Animals and people will continue to exhibit a behavior that is rewarding - and they will cease that behavior when the reward is no longer present. Explain that there is actually a part of the brain that is activated by natural rewards and by artificial rewards such as addictive drugs. This part of the brain is called the reward system. Neuroscientists have been able to pinpoint the exact parts of the brain involved, with the help of the rats. Point to the cartoon on the right and explain that rats will also self-administer addictive drugs directly into their brains -but only into a specific area of the reward system. If the injection needle is moved less than a millimeter away from this crucial area, the rat won't press the lever for more drug. So based on information from working with the rats, scientists have drawn a map of the brain, and located the structures and pathways that are activated when an addictive drug is taken voluntarily. Tell the students that you will show them this "map".

23 area tegmentale ventrale
nucleo accumbens reward circuit

24 Slide 11: The reward pathway Tell your audience that this is a view of the brain cut down the middle. An important part of the reward pathway is shown and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex via this pathway and it sends information to these structures via its neurons. The neurons of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex (point to each of these structures). Reiterate that this pathway is activated by a rewarding stimulus. [Note: the pathway shown here is not the only pathway activated by rewards, other structures are involved too, but only this part of the pathway is shown for simplicity.] oggi sappiamo che la stimolazione provoca un aumento della quantità di dopamina rilasciata dai neuroni dell’area VTA nell’accumbens

25 L’importanza della dopamina
In seguito all’autostimolazione, una maggiore quantità di dopamina viene rilasciata nel circuito Se il rilascio di dopamina viene impedito (o con un farmaco o lesionando il circuito) il ratto non preme la barra Dunque ora conosciamo (alcune delle) strutture anatomiche e le sostanze chimiche implicate nel sistema della ricompensa The importance of the neurotransmitter dopamine has been determined in these experiments because scientists can measure an increased release of dopamine in the reward pathway after the rat receives the reward. And, if the dopamine release is prevented (either with a drug or by destroying the pathway), the rat won't press the bar for the electrical jolt. So with the help of the rats, scientists figured out the specific brain areas as well as the neurochemicals involved in the reward pathway.

26 Le ricompense “naturali”
Cibo Bevande Sesso Cure parentali Ecc. Slide 10: Natural rewards Natural rewards such as food, water, sex and nurturing allow the organism to feel pleasure when eating, drinking, procreating and being nurtured. Such pleasurable feelings reinforce the behavior so that it will be repeated. Each of these behaviors is required for the survival of the species. Remind your audience that there is a pathway in the brain that is responsible for rewarding behaviors. This can be viewed in more detail in the next slide.

27 neocorteccia putamen nucleo caudato sostanza nera habit learning

28 Il sistema della “ricompensa”…
… e il fenomeno della dipendenza Slide 9: The reward pathway and addiction Introduce the concept of reward. Humans, as well as other organisms engage in behaviors that are rewarding; the pleasurable feelings provide positive reinforcement so that the behavior is repeated. There are natural rewards as well as artificial rewards, such as drugs.

29 Autosomministrazione di farmaci
somministrazione “intracerebrale” di una piccola quantità dello stesso farmaco. il principio attivo agisce solo nell’area interessata dall’iniezione somministrazione “sistemica” di una soluzione contenente un farmaco come la cocaina. il principio attivo diffonde nell’intero cervello attraverso la circolazione ematica mm Slide 8: Reward: drug self-administration Introduce the concept of positive reinforcement or reward. Explain that rats will press a bar to get an injection of cocaine or heroin (self-administration - shown on the left). The rat keeps pressing to get more cocaine or heroin because the drugs make the rat feel so good. This is called positive reinforcement, or reward. Natural rewards include food, water and sex - each is required to maintain survival of our species. Animals and people will continue to exhibit a behavior that is rewarding - and they will cease that behavior when the reward is no longer present. Explain that there is actually a part of the brain that is activated by natural rewards and by artificial rewards such as addictive drugs. This part of the brain is called the reward system. Neuroscientists have been able to pinpoint the exact parts of the brain involved, with the help of the rats. Point to the cartoon on the right and explain that rats will also self-administer addictive drugs directly into their brains -but only into a specific area of the reward system. If the injection needle is moved less than a millimeter away from this crucial area, the rat won't press the lever for more drug. So based on information from working with the rats, scientists have drawn a map of the brain, and located the structures and pathways that are activated when an addictive drug is taken voluntarily. Tell the students that you will show them this "map".

30 la ricompensa dello sniffatore…

31 sinapsi dopaminergica

32 normale ricaptazione della dopamina

33 blocco del reuptake

34 aumento di produzione di cAMP

35 ruolo del sistema dopaminergico
attraverso una varietà di meccanismi, tutte le cosiddette droghe provocano un’attivazione anomala del circuito della ricompensa, caratterizzata da un’eccesso di attività dopaminergica

36 dall’uso all’abuso

37 lobo temporale mediale
squire & knowlton memoria dichiarativa (esplicita) non dichiarativa (implicita) fatti eventi abilità abitudini apprendimento associativo elementare apprendimento non associativo priming ippocampo lobo temporale mediale diencefalo risposte emotive muscolatura scheletrica striato corteccia motoria cervelletto vie riflesse amigdala neocorteccia cervelletto

38 plasticità sinaptica associativa
due tipi di “memoria” plasticità sinaptica associativa abitudini (habits) adattamenti non associativi abituazione sensibilizzazione

39 dotata di circa 20000 neuroni...
Aplysia californica

40 abituazione del riflesso di retrazione della branchia

41 esempio di meccanismo di tolleranza

42 facilitazione presinaptica nella sensibilizzazione del riflesso di retrazione della branchia

43 plasticità sinaptica associativa (LTP/LTD)

44 terminologia tolleranza o assuefazione sensibilizzazione dipendenza
sindrome di astinenza addiction

45 tolleranza o assuefazione
In seguito a esposizione prolungata, l’organismo non risponde più alla sostanza come all’inizio Per ottenere lo stesso effetto sono necessarie dosi maggiori della sostanza

46 sensibilizzazione La risposta dell’organismo cresce d’intensità con l’esposizione ripetuta Molte sostanze possono dare luogo sia a tolleranza che a sensibilizzazione

47 dipendenza Sindrome di astinenza
L’organismo reagisce alla presenza prolungata della sostanza incorporandola nei suoi meccanismi omeostatici L’improvvisa sottrazione della sostanza provoca uno scompenso in tali meccanismi che dà luogo a un insieme di sintomi: Sindrome di astinenza

48 addiction Uno stato dell’organismo caratterizzato da comportamenti compulsivi, finalizzati all’assunzione di una certa sostanza La capacità di controllare tali comportamenti e di limitare l’assunzione della sostanza è diminuita o abolita anche a costo di…

49 fenomeni e terminologia
withdrawal (s. astinenza) dipendenza tolleranza o assuefazione sensibilizzazione ricerca e uso compulsivo addiction apprendimento associativo ricadute

50 classi delle sostanze di abuso
Nicotina Etanolo Stimolanti Cocaina Anfetamine e altre droghe di sintesi Oppioidi Eroina Morfina Cannabinoidi

51 Eroina

52 Esempio importante nel nostro caso di terminale sinaptico contenente uno speciale neurotrasmettitore, la dopamina,… recettori… Vi anticipo che l’occupazione di recettori da parte di neurotrasmettitori provoca diverse cose nella cellula, incluse l’attivazione e l’inibizione di enzimi e l’ingresso e l’uscita di certi ioni. Fra un’attimo vi diro’ come questo avviene. Slide 4: The synapse and synaptic neurotransmission Describe the synapse and the process of chemical neurotransmission. Indicate how vesicles containing a neurotransmitter, such as dopamine (the stars), move toward the presynaptic membrane as an electrical impulse arrives at the terminal. Describe the process of dopamine release (show how the vesicles fuse with the presynaptic membrane). Once inside the synaptic cleft, the dopamine can bind to specific proteins called dopamine receptors (in blue) on the membrane of a neighboring neuron. Introduce the idea that occupation of receptors by neurotransmitters causes various actions in the cell; activation or inhibition of enzymes, entry or exit of certain ions. State that you will describe how this happens in a few moments.

53 GABA endorfina

54 GABA morfina

55

56 L’azione dell’eroina nel cervello
Slide 15: Localization of opiate binding sites within the brain and spinal cord When a person injects heroin (or morphine), the drug travels quickly to the brain through the bloodstream. Actually, heroin can reach the brain just as quickly if it is smoked (see description of slide #25). Abusers also snort heroin to avoid problems with needles. In this case, the heroin doesn't reach the brain as quickly as if it were injected or smoked, but its effects can last longer. Once in the brain, the heroin is converted to morphine by enzymes; the morphine binds to opiate receptors in certain areas of the brain. Point to the areas where opiates bind (green dots). Part of the cerebral cortex, the VTA, nucleus accumbens, thalamus, brainstem and spinal cord are highlighted. Show that the morphine binds to opiate receptors that are concentrated in areas within the reward pathway (including the VTA, nucleus accumbens and cortex). Morphine also binds to areas involved in the pain pathway (including the thalamus, brainstem and spinal cord). Binding of morphine to areas in the pain pathway leads to analgesia

57 I recettori per la morfina si trovano in notevoli quantità nei centri che si trovano lungo il circuito della ricompensa

58 regioni nel SNC che mediano lo sviluppo di tolleranza alla morfina
Slide 20: Brain regions mediating the development of morphine tolerance The development of tolerance to the analgesic effects of morphine involves different areas of the brain separate from those in the reward pathway. Point to the 2 areas involved here, the thalamus, and the spinal cord (green dots). Both of these areas are important in sending pain messages and are responsible for the analgesic effects of morphine. The parts of the reward pathway involved in heroin (morphine) addiction are shown for comparison.

59 aree cerebrali che mediano lo sviluppo della dipendenza da morfina
Slide 22: Brain regions mediating the development of morphine dependence The development of dependence to morphine also involves specific areas of the brain, separate from the reward pathway. In this case, point to the thalamus and the brainstem (green dots). The parts of the reward pathway involved in heroin (morphine) addiction are shown for comparison. Many of the withdrawal symptoms from heroin or morphine are generated when the opiate receptors in the thalamus and brainstem are deprived of morphine. aree cerebrali che mediano lo sviluppo della dipendenza da morfina

60 Cocaina

61 La ricompensa dello sniffatore
la cocaina provoca un aumento dell’attività del nucleo accumbens e quindi un aumento del numero di impulsi nervosi verso la corteccia prefrontale. Slide 24: The action of cocaine Cocaine is also an addictive drug, and like heroin, not all users become addicted. However, with the advent of crack cocaine (the free base), the rate of addiction to cocaine has increased considerably. Slide 26: Localization of cocaine "binding sites" When a person smokes or snorts cocaine, it reaches all areas of the brain, but it binds to sites in some very specific areas. These are highlighted with the yellow dots; the VTA, the nucleus accumbens and the caudate nucleus (the largest structure). Point out that cocaine binds especially in the reward areas that you have just discussed. The binding of cocaine in other areas such as the caudate nucleus can explain other effects such as increased stereotypic (or repetitive) behaviors (pacing, nail-biting, scratching, etc..) Slide 15: Summary; cocaine binding in nucleus accumbens and activation of reward pathway Show the "big picture". As a result of cocaine's actions in the nucleus accumbens (point to the sprinkles of cocaine in the nuc. acc.), there are increased impulses leaving the nucleus accumbens to activate the reward system. Indicate that with continued use of cocaine, the body relies on this drug to maintain rewarding feelings. The person is no longer able to feel the positive reinforcement or pleasurable feelings of natural rewards (food, water, sex). Slide 28: Cocaine dependence and activation of the reward pathway Review where cocaine binds within the reward pathway (the VTA and the nucleus accumbens). As a result of cocaine's actions in the nucleus accumbens (point to the dots of cocaine in the VTA and nucleus accumbens), there are increased impulses leaving the nucleus accumbens to activate the reward system. This pathway can be activated even in the absence of cocaine, i.e. during craving. Indicate that with repeated use of cocaine, the body relies on this drug to maintain rewarding feelings. The person is no longer able to feel the positive reinforcement or pleasurable feelings of natural rewards (i.e. food, water, sex)--the person is only able to feel pleasure from the cocaine. Thus the user becomes dependent and when the cocaine is no longer present, anhedonia (inability to feel pleasure) and depression emerge as part of a withdrawal syndrome. To avoid this, the user goes back to the cocaine. Unlike the example for morphine, the cocaine addiction (i.e. craving) and the dependence (i.e. anhedonia) both involve structures in the reward pathway. La ricompensa dello sniffatore

62 L’azione della cocaina nello striato
il nucleo caudato è coinvolto nella produzione di movimenti automatici, stereotipati Slide 24: The action of cocaine Cocaine is also an addictive drug, and like heroin, not all users become addicted. However, with the advent of crack cocaine (the free base), the rate of addiction to cocaine has increased considerably. Slide 26: Localization of cocaine "binding sites" When a person smokes or snorts cocaine, it reaches all areas of the brain, but it binds to sites in some very specific areas. These are highlighted with the yellow dots; the VTA, the nucleus accumbens and the caudate nucleus (the largest structure). Point out that cocaine binds especially in the reward areas that you have just discussed. The binding of cocaine in other areas such as the caudate nucleus can explain other effects such as increased stereotypic (or repetitive) behaviors (pacing, nail-biting, scratching, etc..)

63 Tetraidrocannabinolo(THC)

64

65

66 i siti di azione della marijuana

67 i meccanismi dell’addiction
è sufficiente il rinforzo positivo collegato all’attivazione del circuito della ricompensa per spiegare i fenomeni collegati all’addiction come la ricerca compulsiva della droga e le ricadute dopo lunghi periodi di astinenza?

68 plasticità sinaptica nello striato
corteccia nucleo caudato putamen sostanza nera plasticità sinaptica nello striato

69 fasi dell’addiction Fase Perché si assume la droga
Possibile substrato neuronale Iniziale Sperimentazione, automedicazione, pressione sociale ? Precoce e intermedia Memoria esplicita del piacere; aumento di valore di incentivo degli stimoli collegati alla droga Plasticità sinaptica di ippocampo, amigdala e proiezioni allo striato ventrale Sollievo o evitamento dei sintomi di astinenza Abituazione compensatoria in diverse regioni cerebrali Tardiva e ricadute Catene automatiche di stimolo-risposta (habits) Plasticità sinaptica di proiezioni neocorticali sullo striato dorsale

70 Dipendenza Addiction Cambiamenti “generici” nelle risposte comportamentali Apprendimento associativo Alterazioni presinaptiche del rilascio di neurotrasmettitore; Alterazioni postsinaptiche della trasduzione del segnale Plasticità strutturale di specifiche sinapsi glutamatergiche Abituazione compensatoria (tolleranza e sindrome di astinenza) Sensibilizzazione indipendente dal contesto; Sensibilizzazione da stress Risposte condizionate a stimoli collegati alla droga; Sensibilizzazione dipendente dal contesto; Suscettibilità alle ricadute;

71 3,4-metilenediossi-N-metilanfetamina

72 Slide 9: The Serotonin Neuron; The Major Target of Ecstasy
In order to help students understand how Ecstasy affects the function of serotonin neurons, it will be useful to review how neurotransmission takes place in a little more detail. You can explain serotonin neurotransmission as an example (serotonin is one of many neurotransmitters). This slide shows the connection between two neurons (the “synapse”). Serotonin is stored in small vesicles within the nerve terminal of a neuron. Electrical impulses (arising in the Raphe nucleus, for example) traveling down the axon toward the terminal cause the release of serotonin from small vesicles into the synaptic space. Point to the space between the terminal and the neighboring neuron. Once in the synaptic space, the serotonin binds to special proteins, called receptors, on the membrane of a neighboring neuron (this is usually at a dendrite or cell body). When serotonin binds to serotonin receptors (there are actually at least 14 types of serotonin receptors), it causes a change in the electrical properties of the receiving neuron that generally results in a decrease in its firing rate. Go to the next slide to explain how the action of serotonin is terminated.

73 Slide 10: Serotonin Transporters
Serotonin (in pink) is present in the synaptic space only for a limited amount of time. If it is not bound to the serotonin receptor, serotonin is removed from the synaptic space via special proteins called transporters (in green). The serotonin transporters are proteins located on the serotonin neuron terminals and they are in a unique position to transport serotonin from the synaptic space back into the neuron where it can be metabolized by enzymes. Explain to your students that the serotonin transporters are the primary targets for Ecstasy.

74 Slide 11: Ecstasy and Serotonin Transporters
When Ecstasy binds to the serotonin transporters, more serotonin ends up in the synaptic space. This occurs for two reasons. First, Ecstasy can prevent the transporters from carrying serotonin back into the terminal. Second, Ecstasy can cause the transporters to work in reverse mode-- they actually bring serotonin from the terminal into the synaptic space. So, more serotonin is present in the synaptic space and more serotonin receptors become activated. This is the major short-term effect of Ecstasy that alters brain chemistry. While the serotonin system is the primary target for Ecstasy, Ecstasy has similar effects on the dopamine (another neurotranmsitter) system as well. Ecstasy can inhibit dopamine transporters and cause an increase in dopamine levels in the synaptic space (not shown here). To help students understand how the alteration in brain chemistry results in psychological changes, go to the next slide.

75 Slide 18: Long-term Effects in Monkeys
The loss of serotonin transporters, along with a decrease in serotonin, suggest that the serotonin neurons are damaged. While it is not possible to detect this directly in the brains of living humans, animal studies have revealed that this is the case. A very important experiment was performed in monkeys to determine if Ecstasy can actually damage neurons. Monkeys were given Ecstasy twice a day for 4 days (control monkeys were given saline). One group of monkeys’ brains were removed 2 weeks later for analysis and another group of monkeys lived for an additional 7 years before their brains were removed. Scientists examined the brains for the presence of serotonin. This slide shows the presence of serotonin in neurons of the neocortex from 3 typical monkeys. On the left, the monkey who did not receive any Ecstasy had a lot of serotonin (in pink) in the neocortex. Two weeks after a monkey received Ecstasy, most of the serotonin was gone (point to the middle panel), suggesting that the serotonin neuron terminals were destroyed (there was no destruction of the serotonin cell bodies arising back in the brainstem). Point to the right hand panel and show students that this damage appeared to be long-term because 7 years later there was some recovery, but it was not complete (in fact, the pattern of regrowth of serotonin terminals was abnormal - point out one of the areas where the pink lines are running sideways). Scientists found similar changes in limbic areas of the brain such as the hippocampus and amygdala. The monkey experiments are an important reminder that humans may suffer the same fate, although this still remains to be demonstrated. Tell the students how difficult it is to do this same kind of experiment in humans because it requires removing pieces of the brain to look for the loss of the serotonin neurons. Image courtesy of Dr. GA Ricaurte, Johns Hopkins University School of Medicine.

76 Slide 19: Ecstasy Causes Destruction of Serotonin Nerve Terminals
This slide illustrates the degeneration of serotonin nerve terminals after long-term or repeated use of Ecstasy (you can refer back to slide 9 to compare this degenerating terminal to a healthy terminal). Remind students that we have several pieces of evidence that support this effect of Ecstasy. Ecstasy users have lost serotonin, serotonin metabolites and serotonin transporters on serotonin neuron terminals. In contrast, the serotonin cell bodies are still intact but the genetic instructions from the nucleus for any regrowth of terminals may be abnormal Scientists have made a great deal of progress in understanding how Ecstasy might actually damage the serotonin terminals. The damage involves the production of oxygen radicals (unstable forms of oxygen), which are very destructive to proteins, lipids and DNA. The rich supply of mitochondria (which are a major source of oxygen radical formation) found in the terminals may cause the terminals to be especially sensitive to drugs like Ecstasy

77 e infine la più pericolosa di tutte

78 Nicotina

79 Nicotina gli animali usati negli esperimenti di autostimolazione non fanno differenza fra nicotina e cocaina la nicotina agisce aumentando i livelli di dopamina nel circuito della ricompensa (esattamente come cocaina, eroina e THC)

80 Fumo di sigaretta Una componente del fumo di sigaretta, ancora sconosciuta, inibisce le monoaminossidasi L’aumento di dopamina sarebbe alla base dell’altissima incidenza di fumo di sigaretta in: Soggetti che fanno uso di altre droghe (effetto potenziato!) Depressione e altre turbe psichiche MAO

81 La nicotina è una droga che induce
Addiction Assuefazione Dipendenza