The current study extends prior work demonstrating that nicotine ameliorates ethanol-induced deficits in fear conditioning (Gould and Lommock, 2003
; Gulick and Gould, 2008
; Gulick and Gould, 2009
) by demonstrating that nicotine also ameliorates ethanol deficits in learning the PMDAT. The PMDAT differs from fear conditioning on several measures. First, the PMDAT is an operant task in which mice learn to avoid an area of the maze, whereas fear conditioning is a traditional classical conditioning paradigm. In addition, the PMDAT does not use shocks to train the mice. Thus, the interactive effects of ethanol and nicotine on learning generalize across different types of learning. Interestingly, in the present study saline-treated mice showed a consistant decrease in locomotion between training day and testing day. This decrease may reflect habituation. Adminstration of higher doses of ethanol at training blocked the development of this habituation and nicotine prevented this ethanol-associated change in behavior. These interactive effects on locomotion at testing occurred even though nicotine and ethanol were administered at training, suggesting that ethanol and nicotine interact at training to produce long-term changes in behavior. Nicotine has also been shown to ameliorate ethanol-induced deficits in other cognitive processes. For example, ethanol-associated deficits in reference and working memory measured in the 8-arm radial maze were prevented by nicotine pretreatment (Tracy et al., 1999
). In addition, testing day administration of nicotine decreased ethanol-induced impairments in memory retrieval for passive avoidance (Rezayof et al., 2008
). Thus, ethanol produced deficits in both learning the PMDAT and in habituation, but at different doses; and nicotine reversed both deficits. These findings, along with prior research, indicate that nicotine can counter maladaptive effects of alcohol on learning and cognitive processes.
The ability of nicotine to reverse deficits in learning the PMDAT did not depend on changes in anxiety or locomotion. Specifically, the dose of nicotine used in the co-administration experiments did not produce any consistant effects on locomotor activity or anxiety but did reverse learning deficits induced by 1.0 and 1.4 g/kg ethanol. In addition, the 1.0 g/kg dose of ethanol altered learning but did not alter locomotor activity or anxiety, further suggesting that the ability of nicotine to ameliorate learning deficits associated with this dose of ethanol is not due to effects on anxiety or locomotion.
This is also the first study to examine the effects of nicotine on learning, anxiety and locomotion within the same subjects and the same task. Although previous research has demonstrated that nicotine enhances learning in other tasks (Gould and Wehner, 1999
; Hahn et al., 2002
; Rezvani and Levin, 2003
), nicotine did not enhance learning the PMDAT. In fact, the highest dose of nicotine produced a state-dependent learning deficit that was absent when nicotine was administered before testing as well as training, whereas the ethanol-induced learning deficit was attenuated but still significant when ethanol was administered on both days. Thus, the impairment of learning by nicotine may be due to state-dependent changes, but this was not the case for ethanol. Furthermore, the lack of enhancement of learning in the PMDAT by nicotine may be due to the specificity of nicotine enhancement of learning. We have previously shown that the doses of nicotine used here enhance hippocampus-dependent learning but not simple tone-shock associative learning that is hippocampus-independent (Gould et al., 2004
; Gould and Higgins, 2003
). Thus, learning in the PMDAT may not be critically dependent on the hippocampus; however, this needs further investigation.
Nicotine administration did not alter locomotor activity in the PMDAT on training day but did produce a slight, though inconsistent, anxiogenic effect. Previous studies examining the effects of nicotine on anxiety have likewise met with variable results (Biala and Budzynska, 2006
; Costall et al., 1989
). Using similar dose ranges to that of the current study, Costall and colleagues (1989)
found that acute nicotine decreased anxiety in a light-dark box, while Biala and Budzynska (2006)
found that acute nicotine increased anxiety in the elevated plus-maze. Although factors such as mouse strain (Costall and colleagues used BKW mice and Biala and Budzynska used Swiss mice), and methodological differences may contribute to the differential effects of nicotine across studies, nicotine may also have variable effects on anxiety depending on the task being examined.
Nicotine did reduce the anxiolytic effects of 1.4 g/kg ethanol assessed at training but did not alter the anxiolytic effects of the highest dose of ethanol. Previous work found that nicotine reduced the anxiolytic effects of ethanol in adolescent mice tested in the elevated plus-maze but one month after nicotine and ethanol exposure, these mice showed an anxiogenic response (Abreu-Villaca et al., 2008
). Another study found that ethanol and nicotine worked synergistically to decrease anxiety measured with the mirrored chamber task but this effect was dependent on genotype as mice bred for short sleep times after alcohol administration showed this effect and mice bred for long sleep times did not (Cao et al., 1993
). Thus, alcohol and nicotine clearly interact to alter anxiety but the effects may depend on genetics and perhaps on how anxiety is assessed.
The current results replicate previous work demonstrating that ethanol disruption of learning in the PMDAT was independent of the effects of ethanol on anxiety or locomotion (Kameda et al., 2007
) and show that this finding extends across different strains of mice, as we used C57BL/6 mice and Kameda and colleagues used Swiss mice. The finding that a wide range of ethanol doses impairs learning is consistent with previous research (Bammer and Chesher, 1982
; Gibson, 1985
; Gould, 2003
; Higgins et al., 1992
; Kameda et al., 2007
; Weitemier and Ryabinin, 2003
); however, in the PMDAT study by Kameda and colleagues (2007)
, learning was altered by lower doses of ethanol than those used in the current study. This disparity may be due to strain or methodological differences; Kameda and colleagues used a 10-minute training session, whereas the current study used a 5-minute session to reduce ceiling effects that could obscure any potential enhancement of learning. Nonetheless, ethanol clearly disrupts learning.
Ethanol also dose-dependently decreased anxiety in the current study, which is in agreement with previous literature on the anxiolytic effects of ethanol (Blanchard et al., 1993
; Durcan and Lister, 1988
; Gallate et al., 2003
; Kameda et al., 2007
). The anxiolytic effects of ethanol in the current study were weaker than the effect observed by Kameda and colleagues (2007)
; again, this may be due to genetic or methodological differences. We also found that a moderate dose of ethanol stimulated locomotion. This result is similar to a previous report that in the PMDAT moderate doses of ethanol stimulate, while higher doses depress, motor activity (Kameda et al., 2007
). Overall, ethanol disrupted learning (1.0–2.6 g/kg ethanol), decreased anxiety (1.4–2.6 g/kg ethanol), and increased locomotor activity (1.4 g/kg ethanol), but these effects occurred at different doses.
In conclusion, nicotine ameliorates ethanol induced deficits across a wide range of cognitive processes. This effect of nicotine could contribute to the high incidence of co-use and abuse of alcohol and tobacco products as individuals attempt to reduce cognitive impairments associated with alcohol use. However, recent work suggests that tolerance for this effect of nicotine occurs with chronic administration and cessation of chronic nicotine administration itself can produce cognitive deficits (Gulick and Gould, 2008
). The ability of acute nicotine to reverse learning deficits appears to be independent of changes in anxiety and locomotion. Finally, the effects of nicotine and alcohol administered alone on learning, anxiety, and locomotion were also independent.