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Examination of Age-Related Cholinergic Activity during Nicotine Exposure and Withdrawal

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The University of Texas at El Paso Examination of Age-Related Cholinergic Activity during Nicotine Exposure and Withdrawal Luis M Carcoba, M.D, Ph.D. – PowerPoint PPT presentation

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Title: Examination of Age-Related Cholinergic Activity during Nicotine Exposure and Withdrawal


1
Examination of Age-Related Cholinergic Activity
during Nicotine Exposure and Withdrawal
The University of Texas at El Paso
  • Luis M Carcoba, M.D, Ph.D.
  • University of Texas at El Paso
  • Department of Psychology
  • CHARLES R. DREW UNIVERSITY OF MEDICINE AND
    SCIENCE
  • 9th Drug Abuse Research Symposium
  • September 12, 2014

2
Introduction (Adolescents
Tobacco Use)
  • Although the prevalence of smoking among the
    general population has generally decreased over
    recent years, there has been a steady rise in the
    rate of smoking behavior among adolescents.
  • Adolescents are particularly vulnerable to
    tobacco abuse, and they are more likely to
    initiate tobacco use and continue to use tobacco
    products as adults. As a result, they are at
    greater risk of smoking-related diseases caused
    by long-term tobacco use.
  • Studies have demonstrated that adolescent rodents
    display fewer physical symptoms of nicotine
    withdrawal as compared with adult rats (ODell et
    al. 2006 Shram et al. 2008) and mice (Kota et
    al. 2007).
  • Also, the rewarding effects of nicotine are
    enhanced during the adolescent period of
    development (Torres et al., 2008).

3
Introduction (Nicotine
Withdrawal Syndrome)
  • It is well-accepted that relapse to smoking
    behavior is due, in large part, to negative
    reinforcement processes that maintain smoking
    behavior and relapse behavior in order to avoid
    the negative consequences of withdrawal.
  • Current treatment strategies focus on alleviating
    withdrawal. However, the role of withdrawal in
    smoking behavior during adolescence is presently
    unclear.

4

What We Know ? There are more than 4,000
chemicals found in the smoke of tobacco products.
Of these, nicotine, first identified in the early
1800s, is the primary reinforcing component of
tobacco.
5
What We Know ?
Koob GF (2005). The neurocircuitry of addiction
implications for treatment. Clin Neurosci Res 5
89101.
6
Role of ACh in NAcc
  • The behavioral mechanisms of nicotine are
    mediated, in large part, in the nucleus accumbens
    (NAcc), a terminal region of mesolimbic pathway
    where dopamine levels are increased following
    nicotine administration and decreased during
    withdrawal from this drug (Corrigall, 1991, 1992
    Mansvelder and McGehee, 2002 Watkins et al.,
    2000).

7
Role of ACh in NAcc
  • The nucleus accumbens (NAcc) has been implicated
    in modulating the reinforcing properties of drugs
    of abuse playing a role in the aversive aspects
    of drug withdrawal as reported during diazepam
    and morphine withdrawal.

8
Role of ACh in NAcc
  • Recent work in our laboratory focused on
    developmental differences to nicotine withdrawal
    demonstrated that adolescent rats exhibit lesser
    withdrawal-associated deficits in NAcc dopamine
    as compared to nicotine-dependent adults
    (Natividad et al., 2010).

9
Role of ACh in NAcc
  • Our initial studies focused on NAcc dopamine were
    a logical first step towards understanding the
    mechanisms of nicotine withdrawal given the
    importance of dopamine in mediating the
    behavioral effects of nicotine.
  • However, the mechanisms of nicotine withdrawal
    also appear to involve cholinergic transmission
    in the NAcc, since nicotine withdrawal produces
    increased ACh levels in this brain region of
    adult rats experiencing nicotine withdrawal (Rada
    et al., 2001).
  • Given the potential role of cholinergic systems
    in mediating age differences to withdrawal, the
    present study compared ACh levels in the NAcc of
    adolescent and adult rats during precipitated
    withdrawal.

10
Methods
  • Rats were divided in three groups
  • Adolescents
  • (PND 2830)
  • Adults
  • (PND 6075)
  • Pre Exposed
  • (PND 95)
  • Study Design
  • Pump Implant
  • Probe Implant
  • Assess Nacc ACh during Withdrawal

11
Nicotine Withdrawal in Rats
  • Study Design
  • Pump Implant
  • Probe Implant
  • Assess Nacc ACh during Withdrawal
  • To measure ACh activity rats were prepared with
    osmotic pumps delivering an equivalent nicotine
    dose in these age groups

Dependence Induction Administration of
nicotine via subcutaneous osmotic pumps for 7-14
days Withdrawal Spontaneous withdrawal
Removal of nicotine pump Precipitated
withdrawal Administration of the nicotinic
antagonist mecamylamine
12
Nicotine Withdrawal in Rats
  • Study Design
  • Pump Implant
  • Probe Implant
  • Assess Nacc ACh during Withdrawal
  • Following 13 days of nicotine exposure, rats were
    implanted with microdialysis probes in the NAcc.

Bregma 1.70 mm (Paxinos and Watson, 1998).
13
Nicotine Withdrawal in Rats
  • Study Design
  • Pump Implant
  • Probe Implant
  • Assess Nacc ACh during Withdrawal
  • Following 13 days of nicotine exposure, rats were
    implanted with microdialysis probes in the NAcc.

14
Nicotine Withdrawal in Rats
  • Study Design
  • Pump Implant
  • Probe Implant
  • Assess Nacc ACh during Withdrawal
  • Next day, dialysis samples were collected during
    baseline and following systemic administration of
    the nicotinic-receptor antagonist mecamylamine.
    ACh was quantified from 10-µl samples injected
    into a HPLC system

15
Baseline levels of ACH are higher in adolescent
rats
16
Extracellular Levels Ach (mM)
17
Extracellular Levels Ach (mM)
18
Extracellular Levels Ach (mM)
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22
Conclusions
  • Age Differences
  • Baseline levels of ACh were higher in adolescent
    versus adult rats.
  • During withdrawal, both groups displayed similar
    levels of ACh. This suggests that behavioral
    differences observed in nicotine exposed animals
    are not ACh-mediated.
  • Pre-exposure to Nicotine Effects
  • Baseline levels of ACh were slightly increased
    by adolescent nicotine
    exposure.
  • During withdrawal, the increases in ACh levels
    observed in naïve adults were blunted by
    adolescent nicotine exposure.

23
Questions ?
24
Acknowledgments Collaborators Dr. Laura E
ODell Dr. James Orfila Dr. ODell Lab Financial
Support from -Vulnerability Issues in Drug
Abuse (VIDA) Program -Research Incentive funds
from UTEP -National Institute on Drug Abuse
(R01-DA-021274)
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