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 dopamine antagonists systemically dopamine antagonist in nucleus accumbens 6-OHDA lesion of mesolimbic projection DHβE into ventral tegmental area (VTA) nicotine self-administration in laboratory animals altered by:

Mesolimbic Dopamine System DHβE into VTA  time (min) dopamine (% of basal) * * * nic+DHβE 200 μM nic+DHβE 10 μM nicotine VTA manipulations alter nicotine- evoked dopamine release in ACC systemic nicotine

GABA Mechanisms VTA ACC GABA nAChRs exist on VTA GABA circuitry and dopamine neurons dopamine neurons are influenced by GABA- containing neurons

GABA Mechanisms GABA agonists into the VTA or administered systemically reduce self- administration of nicotine by animals GVG decreases nicotine-induced dopamine release in ACC and nicotine self-administration

Descending Glutamate Projections VTA glutamate GABA ACC mPFCx

Descending Glutamate Projections VTA glutamate GABA ACC mPFCx nicotine  GABA transmission nAChRs on GABA processes desensitize  GABA transmission nicotine  Glu transmission nAChRs on Glu processes desensitize less Glu transmission remains elevated facilitation of synaptic transmission

Preclinical Approaches- Excitation and Inhibition Produced by Nicotine

Brain Mechanisms in Summary VTA ACh glutamate GABA mesopontine nuclei glutamate GABA ACC mPFCx dopamine norepinephrine system cannabinoid system CRF system others …

Preclinical Approaches- Excitation 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 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 Transmission- Topiramate ( TOPAMAX)

Galantamine-Potentiation of Synaptic Transmission

Treatment Approaches- Preclinical 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 Approaches- Preclinical 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

Grant Positive Correlation with Craving in Left Amygdala/Perirhinal Cortex p<0.005, uncorrected. Extent = 10 pixels. N = 11

Alterations in Conditioned Cueing: Two Phases of a Second-Order Schedule Reinforcement

Pilla et al., 1999 D3 Partial Agonist Blocks Responses to Conditioned Cues

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

Session Responses Initiation Maintenance Extinction Saline Priming Drug Injection Testing Hypothetical Time Course in the Reinstatement Procedure Erb, Shaham & Stewart 1996

Nicotine Vaccine and Priming

DAS 431

Blockade of Stress-Induced Responses Medications Development for the Treatment of Abuse and Dependence

Footshock Stress-Induced Responses Medications Development for the Treatment of Abuse and Dependence

B. Heroin-trained rats A. Cocaine-trained rats Effects of SC Injections of the Non-Peptide CRF Antagonist, CP-154,526, on Stress-Induced Reinstatement Shaham et al Responses in 3 h (Active Lever) Veh 3015 * * Veh1530 Footshock (10 min) No stress * * CP-154,526 Dose (mg/kg, SC) No stress Footshock (15 min)

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

Source: Fowler, J.S. et al., Inhibition of monoamine oxidase in the brains of smokers. Nature 379, pp , February 22, Treatments for Nicotine Dependence Brain MAO B and Smoking Status

Treatments for Nicotine Dependence- MAO A Inhibition

Selegiline as a Possible Treatment

Selegiline for Smoking Cessation