Transcript DI CHIARA GAETANO

DipartimentodiScienzeBiomediche,
UniversitàdegliStudidiCagliari;
IstitutodiNeuroscienze,ConsiglioNazionaledelleRicerche
Icannabinoidi sintetici:
aspettiepidemiologici,
neurobiologicieclinici
SITD,Roma,Novembre2016
Timesheet ofSynthetic Cannabinoids
Fattore&Fratta,2011
Synthetic cannabinoids arethemost prevalent class
ofnovel psychoactive substances (NPS)
Prevalence
Synthetic cannabinoids arethemost
commonly used novel psychoactive
substances inEuropeandtheUS.
Their useis morecommonin
adolescents:10%ofAmericanand6%of
European teenagershave used synthetic
cannabinoids.
Caution label
Low price ofsynthetic cannabinoids
Classical cannabinoids
Auwarter etal,2013
Non-classical cannabinoids
(cyclohexyl phenoles)
Indolecannabinoids
(JWH=JWHuffmann;AM=AlexandrosMakriyannis)
Increased CB1-receptoraffinity ofXLR-11pyrolytic derivative
McFarlane
Synthetic cannabinoid use
Synthetic cannabinoids areusually sold in2.5g
bags,and93%ofclients(n =39)smoked more
than one bag daily,and53%ofclientswere using
over5g(two bags)daily.
Mean daily useforall clientswas 4.6gdaily (SD
2.9g).Awiderange ofdifferent types/brands of
synthetic cannabinoids was used.
JWH-018
VIT E
JWH-018
GC-IT/MS
1-pentyl-3-(1-naphthoyl) indole
Potent agonist of CB1 (Ki, 9 nM)
and CB2 (Ki, 2.94 nM) receptors, ingredient of Spice.
Chin et al. (1999) J pharmacol Exp Ther 291: 837-844
Huffman et al. (2005) Bioorg Med Chem 13: 89-93
Auwärter et al. (2009) J Mass Spectrom 44 (5): 832-837
Uchiyama et al. (2009) Forensic Toxicol 27:61-66
Thechanging SPICEcomposition
CB1structure andmolecular fit ofagonists andantagonists
BB-22
5F-AKB48
STS-135
5F-PB22
Thirdgenerationcannabinoids
CB1receptor binding inrat brainhomogenates
DeLucaetal,2016
Electrophysiology ex vivo
Rostral
stim.
Whole cell patch-clamp
DA cell
Caudal
Stim.
JWH-018 decreases GABA A-mediated
post-synaptic currents in VTA DA neurons
JWH-018 preferentially increases
DA release in the NAc shell
0 . 1 2 5 m g / k g ip
0 . 2 5 m g / k g ip
PFCX
0 .5 m g / k g ip
NAc shell
NAc core
DA LEVELS (% OF BASAL)
+
§
*
§
175
175
150
150
125
125
125
100
100
100
JWH-018
0
§
*
§
*
175
§ § §
* *
150
*
JWH-018
60
120
0
JWH-018
60
120
0
60
TIME (min)
Solidsymbols:p<0.05vstherespectivebasalvalues;*:p<0.05vscore;§:p<0.05vsPFCX.
(Two-wayANOVA;atleastn=6pergroup).
o n e x t r a c e l l u l a r D A r e l e a s e
120
Blockade of JWH-018 effect on DA release
by SR 141716A and AM 251
175
*
150
Vehicle
SR 141716A
* *
* *
*
*
*
125
100
Vehicle
AM 251
175
150
*
*
*
125
100
JWH 0.25 mg/kg ip
JWH 0.25 mg/kg ip
0
DA LEVELS (% OF BASAL)
DA LEVELS (% OF BASAL)
NAc shell
60
120
0
60
TIME (min)
Solid symbols: p<0.05 vs the respective basal values; *: p<0.05 vs veh.
(Two-way ANOVA; at least n=5 per group).
120
JWH-018 does not increases DA release
in the NAc shell of CB1 KO mice
DA LEVELS (% OF BASAL)
NAc shell
CB1 +/+
CB1 -/-
175
*
150
*
*
125
*
100
JWH 0.3 mg/kg ip
0
60
120
180
TIME (min)
Solidsymbols:p<0.05vs therespectivebasalvalues;*:p<0.05vs CB1-/(Two-wayANOVA;atleastn=3pergroup).
I.V. drug self-administration
Responses per session
(nose-pokes)
Responding for i.v.JWH-018 IV:
acquisition, extinction and reacquisition
35
JWH-01 8
20 µ g/kg /inf
JWH-01 8
10 µg /kg /inf
30
VEHICLE
*
25
Acti ve
20
SR
Inac tive
*
15
10
*
*
*
*
*
§
*
**
** *
*
*
*
*
**
*
5
0
FR 1
0
5
10
FR 3
15
20
25
30
35
40
45
50
55
session
Consecutive sessions
10
J WH-018
10 µg/ kg/i nf
*p<0.05vsinactive;§ p<0.05vsJWH
200
JWH-0 18
20 µg/k g/inf
VEHICLE
9
8
(n
Prevalence ofpast year SCusebyadolescents
13-19,2011-2015
Cardiovascular stimulation byvagal inhibition
Withdrawal syndrome
Themost commonly reported problem as aresult of
synthetic cannabinoid usewas difficulty stopping
useduetothedevelopment ofwithdrawal
symptoms (n =41).
Withdrawal symptoms reported at theinitial
assessment included anxiety (n =29),moodswings
(n =30),nauseaandloss ofappetite(n =5).These
often occurred within 1–2hoflastuserequiring
repeated doses throughout theday.Clients
reported waking several times inthenighttosmoke
torelieve withdrawal symptoms.
Spice versusMarijuana
1) Nonuniform /uniform distribution ofactive principle
2) Unknown /known concentration ofactive principle
3) Highaffinity/low affinity active principle
4) Full-superagonist/partial agonist active principle
5) Unknown pyrolysis products
6) Continously changing /stable composition
7) Low price+high efficacy /highprice+relatively low
efficacy
ABCinterview toJWHuffmann:
‘’Legalize real Pot’’says fake Pot inventor’’
”These things (Spice )arenot near theproblem they are
intherest ofthecountrysimply because they canget
marijuana.Andmarijuanais not nearly as dangerous as
these compounds."
Aknowledgements
University of Cagliari
University of Ferrara
Mary De Luca
Miriam Melis
Pierluigi Caboni
Zisis Bimpisidis
Valentina Valentini
Grant/2013: INSIDE-018
Matteo Marti
Neurocentre Magendie
Giovanni Marsicano
Fulbright Research Scholar