Neurobiology and pharmacology of psychostimulants

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2 Department of Toxicology,University of Cagliari ; Institute of Neuroscience,CNR Centre for Studies on the Neurobiology of Dependence, MURST Neurobiology and pharmacology of psychostimulants Gaetano Di Chiara Strasbourg,2010

3 University of Cagliari - Department of Toxicology and CNR - Center for Neuropharmacology

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7 After Heimer et al

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9 After Gronevegen et al

10 Dialyzed areas

11 Preferential increase of DA in the NAc shell after i.v. cocaine Pontieri, Tanda, Orzi & Di Chiara, PNAS,1995

12 Selective increase of DA in the NAc shell after i.v.thc and heroin Tanda, Pontieri & Di Chiara, Science, 1997

13 Intravenous caffeine stimulates DA release in the prefrontal cortex(pfcx) but not in the nucleus accumbens shell/core Acquas, Tanda & Di Chiara, Neuropsychopharmacology, 2002

14 Wayne C. Drevets, M.D., Julie C. Price, Ph.D., David J. Kupfer, M.D., Paul E. Kinahan, Ph.D., Brian Lopresti, B.S., Daniel Holt, B.S., and Chester Mathis, Ph.D PET Measures of Amphetamine-Induced Dopamine Release in Ventral versus Dorsal Striatum NEUROPSYCHOPHARMACOLOGY 1999 VOL. 21, NO. 6

15 W.C. Drevets, C. Gautier, J.C. Price, D.J. Kupfer, P.E. Kinahan, A.A. Grace, J.L. Price, and C.A. Mathis Amphetamine-Induced Dopamine Release in Human Ventral Striatum Correlates with Euphoria Biol. Psychiatry 2001;49:81 96

16 Is NAc shell dopamine essential for drug reinforcement?

17 Addictive drugs preferentially increase extracellular dopamine in the NAc shell in a response contingent manner

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21 A.P. 1.7 A.P. 1.6 A.P. 1.2

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23 Lecca et al

24 Still Locomotion Sniffing upward Grooming Rearing Non-stereotyped activity Stereotyped activity Sniffing down Gnawing Head bobbing Licking

25 COCAINE Lecca et al, Psychopharmacol,2007

26 Full sensitization (i.e.both behavioural and biochemical) is induced by passive (response non-contingent) drug exposure

27 After Robinson and Berridge

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30 Cocaine-Lentivirus D1 sirna

31 Experimental Protocol EXPERIMENT I: 4μL x INJECTION/20 min EXPERIMENT II: 2X2μL x INJECTION/20 min LENTIVIRUS SiD1 LENTIVIRUS GFP NAc SHELL NAc CORE COCAINE (0.25 mg/kg x bolo) Self-Administration C H A L L E N G E HANDLING SURGERY RECOVERY ACQUISITION MAINTENANCE EXTINCTION FR1 FR5 Fos ASSAY

32 GFP expression 10X 40X

33 cfos immunohistochemistry of Lenti-D1 in the NAc shell Istologia Lenti-GFP SHELL Istologia Lenti-D1-Sils SHELL

34 Lenti-D1-Sils vs Lenti-GFP SHELL (AP: +1.5 from bregma)

35 cfos immunohistochemistry of lenti-d1 in the NAc core Lenti-GFP CORE Lenti-D1-Sils CORE

36 Exp 1 No effect of lenti-d1 in the NAc core on cocaine SA *: p<0.05 vs. inactive : p<0.05 vs. sid1

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41 Genetic and environmental influences on use and abuse/dependence of six different classes of illicit drugs High % of variance for use and for abuse/dependence accounted by genetic factors common to different drug classes Kendler et al,2003

42 Rat lines selectively bred for learning a two-way active avoidance Roman High Avoidance (RHA) Roman Low Avoidance (RLA)

43 Effect of Cocaine or Amphetamine on DA output in NAC Shell and in NAC Core of RHA and RLA rats Results are expressed as a percent of the respective basal values and are the mean ± S.E.M. of the number of animals shown in parentheses. Amphetamine or Cocaine were injected at the arrow. Solid symbols: P< 0.05 vs. the respective basal value; * P< 0.05 vs. the time-matched value for the NAC core of the RHA line; P< 0.05 vs. the time-matched value for the NAC shell of the RLA line.

44 Acquisition and Maintenance of Cocaine self-administration in RHA and RLA rats Escalating doses of cocaine (0.1, 0.2, and 0.4 mg/kg) were made available over four consecutive weeks. Data are presented as the mean ± S.E.M. number of active and inactive lever presses in each test session (n:8 rats/line). *P<0.05 vs the test session-matched active lever responding rate of the RLA line.

45 Cocaine-induced Reinstatement of drug-seeking behavior and Reacquisition of Cocaine self-administration in RHA and RLA rats Reinstatement. Data are presented as the mean ± S.E.M. number of active and inactive lever presses following an acute priming dose of cocaine [0 (saline); 2.5; 5; 10; mg/kg, i.p.; n:8 rats/line]. *P<0.05 vs the dose-matched RLA value; P<0.05 vs the line- and dosematched inactive lever value; #P<0.05 vs the line-matched saline value. Reacquisition. Cocaine (0.1 mg/kg/inf) was made contingently available over nine consecutive test sessions. Data are presented as the mean ± S.E.M. number of active and inactive lever presses in each test session (n:8 rats/line). *P<0.05 vs the test session-matched active lever responding rate of the RLA line

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47 Effect of repeated Fonzies feeding on DA output in PFCX and NAc shell dialysates Bassareo and Di Chiara, J. Neurosci. 1997

48 Effect of repeated Fonzies feeding on DA output in NAc shell and NAc core dialysates Bassareo, De Luca & Di Chiara, J.Neurosci.2002

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50 NAc shell DA responsiveness obeys pavlovian rules, consistently with a role in the acquisition of motivational properties by stimuli (incentive learning) NAc core DA responsiveness reflects motivational salience, consistently with a role in the expression of motivational properties by stimuli

51 Drug addiction as abnormal incentive motivation Excessive control over behaviour by drug-conditioned incentive stimuli Reduced control over behaviour by incentive stimuli conditioned to non-drug rewards

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53 Fonzies-filled box (the complex stimulus)

54 CONDITIONING PROTOCOL 3 days once a day FFB 10 min CONDITIONED: DRUG s.c. or PALATABLE FOOD UNCONDITIONED: 3 days once a day FFB 10 min Saline s.c. or STANDARD FOOD PSEUDOCONDITIONED: 3 days once a day DRUG s.c. or Saline s.c. FFB 10 min

55 Responsiveness of DA trasmission to FFB(CS) and Fonzies feeding

56 Response of NAc core and PFCX DA to a drug-cs 56

57 Responsiveness of NAc shell DA to FFB (CS) and morphine (1mg/Kg s.c.) (US) 57

58 The responsiveness of NAc shell DA to drug reward does not undergo single trial habituation as instead is the case of non-drug rewards

59 Drug-conditioned stimuli release DA in the NAc shell and amplify drug-induced stimulation of NAc shell DA

60 Key features of addiction 1) Excessive facilitation of drug seeking&taking by non-contingent drug-conditioned stimuli (drug incentives) 2) Enduring ability of drug incentives to reinstate drug seeking&taking 3) Control of behaviour by drug stimuli to the exclusion of non-drug ones

61 Pavlovian incentive learning model of drug addiction 1) Occurrence of contingencies between stimuli(contexts,cues) and drugs with hedonic and DA- activating properties 2) Dysadaptive stimulation of DA transmission by drugs 3) Acquisition of excessive incentive properties by drug incentives (abnormal pavlovian incentive learning ) Di Chiara, Drug &Alcohol Depend.,1995; J.Psychopharmacol.,1998; Behav.Brain Res,2002

62 Consequences of drug-induced abnormal pavlovian incentive learning 1)Reduced number of stimulus-drug associations needed for acquisition of incentive properties by stimuli 2)Increased number and impact of drug incentives 3) Increased resistance to extinction 4) Focussing on drug-related to the exclusion of non-drug stimuli 5) Enduring influence of drug-conditioned incentives on behaviour

63 A pavlovian incentive learning model of drug addiction 1) Reliable occurrence of contingencies between stimuli(contexts or cues) and drugs with hedonic and dopamine activating properties 2) Acquisition of excessive incentive properties by drug-conditioned stimuli (abnormal pavlovian incentive learning ) 3) Facilitation of instrumental responding for drugs by the occurrence of drug-conditioned stimuli (drug-incentives)

64 COLLABORATORS Ezio Carboni, Cristina Cadoni, GianLuigiTanda, Valentina Bassareo, Elio Acquas, Sandro Fenu, Mary De Luca Valentina Valentini Daniele Lecca Fabio Cacciapaglia Bruno Giros, INSERM Cecile Spielewoy,INSERM Gian Luigi Tanda,NIDA Steve Goldberg,NIDA Jean-Luc Dreyer, Fribourg Amine Bahi, Fribourg