Accentuated decrease in social interaction in rats subjected to repeated ethanol withdrawals.

Since ballenger and Post (1978) summarized evidence that increased symptoms after multiple withdrawals from ethanol resemble a kindling process, a number of supportive clinical and animal studies have appeared. McCown and Breese (1990) were the first to report an increase in seizure susceptibility of the inferior colliculus after repeated ethanol withdrawals, which supported the kindling hypothesis. This effort demonstrated that seizures generated by electrical stimulation of the inferior colliculus could be elicited more easily in rats withdrawn repeatedly from ethanol, even though this increased sensitivity or sensitization was not observed in the amygdala (McCown and Breese, 1990). Thus, a key observation was that the adaptive changes due to repeated ethanol withdrawal could be different in different brain regions. In further support of this concept, Veatch and Gonzalez (1996, 1999, 2000) reported that several cycles of exposure to an ethanol inhalation chamber followed by an extended withdrawal period resulted in more electrical stimulation being required to kindle seizures from the hippocampus. On the other hand, mice exposed to an ethanol vapor chamber became more dependent with repeated exposures, as revealed by a decrease in seizure threshold or an increase in handling-induced convulsions (Becker and Hale, 1993; Becker et al., 1997, 1998; Jarvis and Becker, 1998). These examples provide convincing evidence for pathologic changes in brain function with repeated exposures to and withdrawals from ethanol. Others, including some studies in humans, have reported a similar sensitization process with repeated ethanol withdrawals (Brown et al., 1988; Holter et al., 1998; Maier and Pohorecky, 1989; Malcolm et al., 2000a,b; Meert and Huysmans, 1994; Ulrichsen et al., 1996, 1998). Thus, evidence supports the presence of a sensitization process in animals subjected to multiple withdrawals from ethanol. Of particular relevance to this article is the work of Spanagel and Holter (1999). They gave outbred rats access to water and three different concentrations of ethanol over prolonged periods. Periodically, the ethanol solutions were withdrawn. These authors noted that the rats increased their drinking of ethanol during these prolonged exposures and began to prefer the bottle containing the higher concentration of ethanol. Moreover, the animals exhibited anxiety-like behavior as indexed by the elevated plus maze (Holter et al., 1998; Spanagel and Holter, 1999). Although the anxiety-like behavior increased over time, the lengthy duration of these studies precludes detailed mechanistic investigations. The present article demonstrates that anxiety-like behavior can be induced by brief (15 days) exposures to ethanol and that the behavior can be accentuated if the exposure is cycled. A key behavioral pathology associated with ethanol withdrawal is anxiety (e.g., Criswell and Breese, 1992; File et al., 1989; Kampov-Polevoy et al., 2000; Knapp et al., 1998; Moy et al., 1997, 2000). However, except for the studies involving long-term access to alcohol (Holter et al., 1998; Spanagel and Holter, 1999), previous studies have not determined whether repeated withdrawals will sensitize animals to the anxiety associated with withdrawal. The social interaction test has been used widely to study anxiety-related behavior in rodents (e.g., File, 1993; File and Hyde, 1978; File et al., 1999; Gonzalez et al., 1998), including that related to withdrawal from drugs of abuse (Andrews et al., 1997; Costall et al., 1990; File et al., 1989; Irvine et al., 2001; Kampov-Polevoy et al., 2000). Thus, the social interaction test is well suited for determining whether changes in anxiety-related behavior occur during repeated exposures to and withdrawals from ethanol. The present study summarizes the findings of a three-cycle protocol of ethanol exposure and withdrawal on anxiety-like behavior, as measured by the social interaction test.