Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcohol

Abstract

Repeated experience of withdrawal from chronic alcohol treatment increases sensitivity to seizures. It has been argued by analogy that negative affective consequences of withdrawal also sensitize, but repeated experience of withdrawal from another sedative-hypnotic drug, diazepam, results in amelioration of withdrawal anxiety and aversiveness. We tested whether giving rats repeated experience of withdrawal from alcohol altered their ability to acquire a conditioned emotional response (CER). Male Hooded Lister rats were fed a nutritionally complete liquid diet as their only food source. Different groups received control diet, or diet containing 7% ethanol. Rats receiving ethanol diet were fed for either 24 days (Single withdrawal, SWD), or 30 days, with two periods of 3 days, starting at day 11, and 21, in which they received control diet (Repeated withdrawal, RWD). All rats were fed lab chow at the end of their liquid diet feeding period. Starting 12 days after the final withdrawal, groups of Control, SWD and RWD rats were given pentylenetetrazole (PTZ; 30 mg/kg, i.p.) three times a week, and scored for seizures. The occurrence of two successive Stage 5 seizures was taken as the criterion for full PTZ kindling. Other groups of control, SWD and RWD rats were trained to operate levers to obtain food, and were then exposed, in a fully counterbalanced design, to light and tone stimuli which predicted unavoidable footshock (CS+), or which had no consequences (CS-). Rats consumed approximately 17.5 g/kg/day of ethanol, resulting in blood alcohol levels of approximately 100 mg/dL. Repeated administration of PTZ resulted in increasing seizure scores. RWD rats achieved kindling criterion faster than either Control or SWD rats. No differences were seen in the groups in flinch threshold to footshock (0.3 mA). At a shock intensity of 0.35 mA, Control, but not RWD or SWD rats showed significant suppression to the CS+ CS- presentation did not affect response rates. The three groups differed in their response to pairing the CS+ with increasing shock levels, the Controls remaining more sensitive to the CS+. SWD rats showed significant suppression of lever pressing during CS+ presentations only at 0.45 and 0.5 mA, and RWD rats only at 0.5 mA. Giving rats repeated experience of withdrawal from chronic ethanol results in increased sensitivity to PTZ kindling, but reduces their ability to acquire a CER. Withdrawal kindling of sensitivity to anxiogenic events does not seem to occur under circumstances which give rise to kindling of seizure sensitivity.

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

“…This theory of kindling seizure activity was subsequently supported by several clinical investigations (Booth and Blow 1993;Brown et al 1988;Lechtenberg and Worner 1990, 1991Worner 1996). Work in rats showing that repeated withdrawals from chronic alcohol facilitate inferior collicular kindling afforded critical support for the kindling hypothesis (McCown and Breese 1990), as did other animal studies that demonstrated enhanced seizure susceptibility following repeated withdrawals (Baker and Cannon 1979;Becker and Hale 1993;Becker et al 1997Becker et al , 1998Clemmesen and Hemmingsen 1984;Kokka et al 1993;Maier and Pohorecky 1989;Meert and Huysmans 1994;Ripley et al 2002;Stephens et al 2001;Ulrichsen et al 1995Ulrichsen et al , 1998. This concept of "kindling" of seizure activity following repeated detoxifications has been a major advance, as it provided an appreciation of the necessity of progressive adaptive change preceding withdrawal-induced seizure activity in alcoholics.…”

“…Reports indicate that multiple withdrawals from alcohol impair learning of a conditioned emotional response (CER; Stephens et al 2001;Ripley et al 2003Ripley et al , 2004, a result consistent with a persistent adaptive change. Based on these findings, Stephens et al (2001) argued that altered affective state is not likely to drive relapse.…”

“…Based on these findings, Stephens et al (2001) argued that altered affective state is not likely to drive relapse. This conclusion is seemingly contrary on the hypothesis being proposed (Fig.…”

“…3). A major consideration for interpretation is the absence of anxiety-like behavior 2 weeks following the repeated withdrawals (Overstreet et al 2002), the time period at which the CER is measured (Stephens et al 2001). In order to elicit anxietylike behavior at this later period after repeated withdrawals, animals have to be provoked by re-introduction to withdrawal from a subsequent ethanol challenge or to stress (Overstreet et al 2002;Fig.…”

Cognitive and emotional consequences of binge drinking: role of amygdala and prefrontal cortex

“…Many of the behavioural changes seen in binge drinkers can be modelled in the rodent (indeed, some of the deficits we have subsequently described in alcoholics were predicted on the basis of our prior rat studies (Stephens et al 2001(Stephens et al , 2005). Thus, the increased propensity to show seizures following several episodes of alcohol withdrawal has been routinely demonstrated (Becker & Veatch 2002).…”