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Multiple Neuronal Systems Thought to be Involved in Nicotine Dependence Frank Vocci, Ph.D. Director Division of Treatment Research and Development National Institute on Drug Abuse Nicotinic Cholinergic Receptors • nAChRs span the cell membrane • binding of nicotine / other ligands alters configuration • permeability to ions changes Nicotine Partial Agonist Treatments for Nicotine Dependence • Inhibition of nicotine metabolism • Based on observations of differences in nicotine metabolism ( CYP 2A6) and risk of dependence formation – Pianezza et al Nature (1998) • Clinical study with Methoxsalen ( CYP2A6 inhibitor ) reduced CO and smoking – Sellers et al CPT (2000) Mesolimbic Dopamine System nicotine self-administration in laboratory animals altered by: dopamine antagonists systemically dopamine antagonist in nucleus accumbens 6-OHDA lesion of mesolimbic projection DHβE into ventral tegmental area (VTA) Mesolimbic Dopamine System dopamine (% of basal) VTA manipulations alter nicotineevoked dopamine release in ACC 300 250 nic+DHβE 200 μM nic+DHβE 10 μM nicotine systemic nicotine 200 150 100 * * * --------------------------------------------------- 50 0 -40 -20 0 20 40 60 80 100 120 140 160 time (min) DHβE into VTA GABA Mechanisms dopamine neurons are influenced by GABAcontaining neurons nAChRs exist on VTA GABA circuitry and dopamine neurons ACC VTA GABA GABA Mechanisms • GABA agonists into the VTA or administered systemically reduce selfadministration of nicotine by animals • GVG decreases nicotine-induced dopamine release in ACC and nicotine self-administration Descending Glutamate Projections mPFCx glutamate GABA ACC VTA Descending Glutamate Projections mPFCx glutamate • nicotine GABA transmission • nAChRs on GABA processes desensitize • GABA transmission VTA GABA facilitation of synaptic transmission ACC • nicotine Glu transmission • nAChRs on Glu processes desensitize less • Glu transmission remains elevated Preclinical ApproachesExcitation and Inhibition Produced by Nicotine Brain Mechanisms in Summary mPFCx norepinephrine system glutamate cannabinoid system CRF system dopamine VTA others … GABA ACC mesopontine nuclei GABA glutamate ACh Preclinical ApproachesExcitation and Inhibition Produced by Nicotine • Three approaches are apparent in terms of modulation of nicotine – Reduce the glutamatergic excitation through blockade of glutamate receptors… or – Increase the GABAergic inhibition by increasing GABA or administering GABA-like drugs – Reduce glutamate excitation and increase GABA activity Modulation of Glutamatergic Transmission by an MGluR5 Antagonist GVG ( GABA B) and Nicotine Vigabatrin and Smoking Cessation • Visual Field Defects have been reported in @ 30 % of individuals taking between 110 and 1500 grams of vigabatrin • Effects may start as a bi-concave nasal lesion and progress to concentric circles • Would have to be relegated to smokers who had failed to quit with other behavioral and pharmacological means • Would have a time-limited therapy;e.g., facilitation of smoking cessation Simultaneous Modulation of GABAergic TransmissionTopiramate ( TOPAMAX) Galantamine-Potentiation of Synaptic Transmission Treatment ApproachesPreclinical Studies • Based on altering neurobiological processes that may be involved in maintenance of dependence or reinstatement • Nicotine or smoking –related cues • Nicotine-priming • Stress- induced increases in nicotine intake • Effects on frontal cortex inhibitory systems Treatment ApproachesPreclinical Studies • Based on altering neurobiological processes that may be involved in maintenance of dependence or reinstatement • Nicotine or smoking –related cues • Nicotine-priming • Stress- induced increases in nicotine intake • Effects on frontal cortex inhibitory systems Positive Correlation with Craving in Left Amygdala/Perirhinal Cortex p<0.005, uncorrected. Extent = 10 pixels. N = 11 Grant Alterations in Conditioned Cueing: Two Phases of a Second-Order Schedule Reinforcement D3 Partial Agonist Blocks Responses to Conditioned Cues Pilla et al., 1999 Priming • “Priming” is a function of the rate and extent of drug into the CNS • Reducing rate and extent of uptake could block priming … and relapse • Pharmacological alterations of priming mechanisms Hypothetical Time Course in the Reinstatement Procedure Responses Maintenance Initiation Priming Drug Injection Saline Extinction Testing Session Erb, Shaham & Stewart 1996 Nicotine Vaccine and Priming DAS 431 Medications Development for the Treatment of Abuse and Dependence Blockade of Stress-Induced Responses Medications Development for the Treatment of Abuse and Dependence Footshock Stress-Induced Responses Effects of SC Injections of the Non-Peptide CRF Antagonist, CP-154,526, on Stress-Induced Reinstatement Responses in 3 h (Active Lever) A. Cocaine-trained rats B. Heroin-trained rats 60 45 No stress Footshock (15 min) No stress Footshock (10 min) * 30 * 15 0 Veh 15 * * 30 Veh 15 30 CP-154,526 Dose (mg/kg, SC) Shaham et al Medications Development for Smoking Cessation • Multiple clinical targets available that go beyond manipulation of the nicotinic cholinergic system • Decisions on which clinical targets to pursue • Multiple preclinical targets in discovery and preclinical testing that need priority ranking Treatments for Nicotine Dependence • MAO inhibitors • Noted that a constituent in cigarette smoke is an MAO ( A and B) inhibitor- Fowler et al PNAS (1996) and Fowler et al Nature (1996) • Suggests that MAO inhibition may assist smokers in quitting Treatments for Nicotine Dependence Brain MAO B and Smoking Status Source: Fowler, J.S. et al., Inhibition of monoamine oxidase in the brains of smokers. Nature 379, pp. 733-736, February 22, 1996. Treatments for Nicotine Dependence- MAO A Inhibition Selegiline as a Possible Treatment Selegiline for Smoking Cessation