1. Alcohol and nicotine interactions: behavioural studies
Przemyslaw Bienkowski
Department of Pharmacology
Institute of Psychiatry and Neurology
Warsaw, Poland
IMAG’2006, Copenhagen, DK

2. Epidemiology Cigarette smoking and alcohol drinking goes together.
Istvan and Matarazzo (1984)
Glassman et al. (1990)
The National Household Survey on Drug Abuse ( )
The National Comorbidity Survey ( )
(reviewed by Anthony and Echeagaray-Wagner, 2000)
IMAG’2006, Copenhagen, DK

3. Epidemiology Most smokers consume alcohol.
The proportion of alcohol consumers using tobacco is smaller.
(Glassman et al.., 1990; Breslau, 1995; NHSDA; reviewed by Anthony and Echeagaray-Wagner, 2000)
"Gender studies"
Women with histories of regular smoking were five to six times more likely to report histories of alcohol dependence than non-smoker controls (11.5% vs. 2.1%).
Men with histories of regular smoking were two times more likely to report alcohol dependence than non-smoker controls (30.7% vs. 16.9%).
(The Australian twin panel; reviewed by Madden et al.., 2000)
IMAG’2006, Copenhagen, DK

4. Cigarette smoking and alcohol dependence
(according to the APA DSM-III-R criteria)
Number of alcohol-dependence symptoms
No. of symptoms 1 2 3 4 5 6
7-9*
Women
32.0
54.0
64.0
71.8
87.5
77.3
71.4
94.1
Men
36.6
50.6
56.3
59.2
61.4
68.4
75.9
83.3
Percentage of regular smokers (%) among
subjects with no symptoms of alcohol dependence
(Madden et al., 2000)
IMAG’2006, Copenhagen, DK

5. co-occurring use abuse dependence
Epidemiology
co-occurring use abuse dependence
correlation increases…
IMAG’2006, Copenhagen, DK

6. Smoking and drinking goes together because of
genetic & environmental factors.
alcohol dependence
nicotine dependence
common genetic factors
68%
genes: 60%
environment: 40%
True et al. (1999)
IMAG’2006, Copenhagen, DK

7. behavioural reactivity to ethanol and nicotine
True et al. (1999)
Bierut et al. (2000)
common factors
genes
environment
taste/olfactory responses
personality traits
metabolism of ethanol and nicotine
family problems
number and function of nicotinic receptors in the brain
stress
psychiatric disorders (depression, anxiety)
behavioural reactivity to ethanol and nicotine
sociocultural and economic influences (education, attitudes, taxes)

8. alcohol (A) => nicotine (N) nicotine (N) => alcohol (A)

9. Behavioural interactions between nicotine and alcohol
less specific
e.g. alcohol may increase impulsive behaviour and thus may disinhibit smoking behaviour in some individuals
more specific
e.g. nicotine may potentiate alcohol's rewarding properties or reduce its aversive effects

10. N - N - N - N - N - N =>>> A 
Effects of nicotine on alcohol drinking
N => A 
Acute nicotine injections decreased ethanol consumption in rats allowed to drink ethanol in the two-bottle choice procedure (e.g. Katner et al., 1997; Nadal et al., 1998; Dyr et al., 1999).
N - N - N - N - N - N =>>> A 
Chronic nicotine administration led to long-lasting increase in alcohol intake (Potthoff et al., 1983; Blomqvist et al., 1996; Smith et al., 1999; Le et al., 2000; Clark et al., 1998; 2001).
Effects of nicotine on alcohol reward ?

11. Effects of nicotine on the aversive effects of alcohol
conditioned taste aversion (CTA): an important mechanism promoting avoidance of spoiled or toxic foods
the CTA procedure adapted for experimental studies - alcohol "mimics" toxic effects of novel tasting fluids
(Baker and Cannon, 1982; Bienkowski et al., 1996,1997; Parker, 2003)

12. the conditioned taste aversion procedure
- acquisition phase
animals are trained to associate novel tasting fluid (e.g. 0.1% saccharin) with alcohol’s aversive effects,
alcohol injections occur after saccharin drinking sessions
- expression phase
conditioned avoidance of saccharin solutions in one-bottle or two-bottle tests
(Baker and Cannon, 1982; Bienkowski et al., 1996,1997; Parker, 2003)

13. Effects of acute nicotine administration on the aversive effects of alcohol
N => A 
In rats conditioned with ethanol, acute pre-treatment with nicotine attenuated the aversive stimulus effects of alcohol (Kunin et al., 1999).
Nicotine decreased the sedative effects of ethanol in humans (Perkins et al., 1997).

14. N - N - N - N - N - N =>>> A 
Effects of chronic pre-exposure to nicotine on the aversive effects of alcohol
N - N - N - N - N - N =>>> A 
Chronic pre-exposure to nicotine (3 x 0.6 mg/kg or 6 x 0.6 mg/kg) reduced the aversive effects of ethanol in the conditioned taste aversion procedure (Bienkowski et al., 1998; Kunin et al., 1999).

15. N - N - N - N - N - N =>>> A
Pre-exposure to nicotine (6 x 0.6 mg/kg) blocked ethanol-induced conditioned taste aversion (cross-tolerance; the NIC-Et group).
Similar effects were observed after pre-exposure to ethanol (tolerance; the Et-Et group).
In other studies, mice pre-exposed to nicotine showed tolerance to ethanol-induced hypothermia (Collins et al., 1988,1993).
Bienkowski et al., Eur. Neuropsychopharmacol. 8, 79-87; 1998.

16. N - N - N - N - N - N =>>> A 
Human subjects with histories of regular smoking rated themselves as significantly less intoxicated than did non-smokers receiving the same dose of alcohol.
This relationship persisted in women even when a history of alcohol drinking was controlled for (Madden et al., 1997).
"Thus, either acute or chronic cross-tolerance may exist between smoking and alcohol that leads to diminished response to alcohol in those who smoke.
Alternatively, common genetic mechanisms may lead to the increased probability that a person will become a regular smoker and to reduced propensity for intoxication after a given dose of alcohol."
(Madden et al., 1997)

17. Effects of alcohol on behavioural effects of nicotine - less explored
A - A - A =>>> N
Pre-exposure to alcohol eliminated the aversive stimulus effects of nicotine in the conditioned taste aversion procedure (Kunin et al., 1999).

18. N - N - N =>>> A  A - A - A =>>> N 
the conditioned taste aversion procedure – chronic pre-exposure experiments
symmetric interactions
N - N - N =>>> A 
A - A - A =>>> N 

19. Effects of alcohol on behavioural effects of nicotine
Animal studies on effects of ethanol on nicotine self-administration have not been conducted (published?) as yet.
In the conditioned place preference procedure, ethanol did not alter nicotine reward. The same low doses of alcohol potently blocked nicotine-induced seizures (Korkosz et al., 2006).
Strong effects of alcohol on smoking behaviour were observed in humans. After alcohol administration, smokers take more puffs, inhale smoke deeper and achieve higher levels of carbon monoxide (and nicotine) in the blood (Griffith et al., 1976; Hennigfield et al., 1984; Zacny et al., 1997). In contrast, effects of alcohol on the rewarding effects of nicotine are inconsistent (Glautier et al., 1996; Zacny et al., 1997; Rose et al., 2004; Perkins et al., 2005).

20. Conclusions & future directions
Chronic nicotine administration leads to long-lasting increase in alcohol consumption.
Early initiation of cigarette smoking may facilitate heavy drinking and development of alcohol abuse/dependence ?

21. Conclusions & future directions
Cross-tolerance between alcohol and nicotine has been found in the taste aversion procedure. Chronic pre-exposure to nicotine may attenuate the aversive effects of alcohol and vice versa.
Early initiation of smoking may facilitate heavy drinking and development of alcohol abuse/dependence ?

22. Future directions and hypotheses
to be tested: models of ethanol and nicotine co-abuse are needed
Effects of concurrent availability of alcohol and nicotine on the acquisition and maintenance of nicotine and alcohol self-administration should be tested in 'naturalistic' animal models.
Female (!) and male subjects at different stages of development should be tested.

23. Future directions and hypotheses
to be tested - role of sensory factors
Nicotine and ethanol, as all other drugs of abuse, needs appropriate vehicle (i.e. cigarette smoke and alcoholic beverages).
Gustatory and olfactory responses to cigarette smoke and alcoholic beverages may be correlated.
Genetically determined 'blindness' to bitter taste (Snyder, 1931) may promote beer/alcohol consumption and cigarette smoking in adolescents (Rogowski et al., unpublished)?

24. Thank you for your attention.

25. Effects of nicotine on the discriminative effects of alcohol
discriminative stimulus (DS) - any stimulus guiding our behaviour
alcohol may function as a discriminative stimulus
the drug discrimination procedure - animal and human model of subjective effects of drugs
(Jarbe, 1987; Colpaert, 1999)

26. N
A 
In rats trained to discriminate ethanol from its vehicle, nicotine did not substitute for ethanol
but
increased the discriminative stimulus properties of ethanol when the two drugs were given in combination (Signs and Schechter, 1986; Bienkowski et al., 1998).

27. Nicotine (0. 3 mg/kg, s. c. ) and diazepam (0. 5 mg/kg, i. p
Nicotine (0.3 mg/kg, s.c.) and diazepam (0.5 mg/kg, i.p.) enhanced the discriminative stimulus effects of ethanol in the rat.
Bienkowski et al., Pharmacol. Biochem. Behav. 60, 61-69; 1998.