Repeated Ethanol Withdrawal Delays Development of Focal Seizures in Hippocampal Kindling

Withdrawal from chronic treatment with benzodiazepines is associated with increased neuronal excitability leading to anxiety, aversive effects and increased seizure sensitivity. After repeated withdrawal experiences, seizure sensitivity increases while withdrawal-induced anxiety and aversion decrease. We used autoradiographical methods employing [(3)H]Ro48 8587, a selective ligand for glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, to study withdrawal-induced changes in AMPA receptor binding in areas of the mouse brain postulated to be involved in these responses. Mice were given 21 days treatment with diazepam (15 mg/kg, s.c. in sesame oil) followed by withdrawal (single withdrawal) or three blocks of 7 days treatment interspersed with 3-day periods to allow washout of drug (repeated withdrawal). In keeping with heightened excitability in withdrawal from chronic diazepam treatment, the single withdrawal group showed, 72 h after their final dose of diazepam, increased [(3)H]Ro48 8587 binding in several brain areas associated with emotional responses or seizure activity, including hippocampal subfields, amygdalar and thalamic nuclei and motor cortex. In contrast, the repeated withdrawal group showed no changes in [(3)H]Ro48 8587 binding in any brain area studied. These observations are consistent with up-regulation of AMPA receptor-mediated transmission being important in withdrawal-induced anxiety and aversion but not in increased seizure sensitivity associated with repeated withdrawal. As changes in AMPA receptor subunit expression alter the functionality of the receptor, future studies will address this possibility.

Section: Hippocampal Structuresmentioning

confidence: 99%

α‐Amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor autoradiography in mouse brain after single and repeated withdrawal from diazepam

Allison

Pratt

Ripley

et al. 2005

“…There is substantial experimental support for common neuronal processes underlying withdrawal kindling, and both chemical (Stephens et al ., 2001; Ripley et al ., 2002) and amygdala (Pinel & Van Oot, 1975; Pinel et al ., 1975; Pinel, 1980; Carrington et al ., 1984) or superior colliculus kindling (McCown & Breese, 1990); in contrast, withdrawal kindling retards electrical kindling of hippocampus (Veatch & Gonzalez, 1997; Veatch & Gonzalez, 1999). Thus, increased seizure sensitivity resulting from repeated withdrawal from ethanol may reflect changes in synaptic efficiency in the amygdala resembling those underlying electrical kindling.…”

Section: Introductionmentioning

confidence: 99%

Aversive conditioning following repeated withdrawal from ethanol and epileptic kindling

Ripley

Brown

Dunworth

et al. 2003

Repeated withdrawal from ethanol, a procedure which resembles amygdala kindling in increasing seizure sensitivity, impairs the acquisition of fear conditioning (Stephens et al., 2001, Eur. J. Neurosci.,14, 2023-31). In contrast, rats previously kindled by repeated electrical stimulation of basolateral amygdala, or repeated administration of pentylenetetrazol, showed increased suppression of operant responding during the presentation of a stimulus conditioned to footshock when conditioning took place several weeks following the kindling experience. Neither form of kindling nor repeated ethanol withdrawal altered taste aversion conditioning, though rats treated chronically with ethanol and given a single withdrawal experience showed enhanced taste aversion conditioning. These results suggest that, despite evidence suggesting a common neuronal mechanism underlying seizure sensitivity following these types of kindling, they differ in their effects on fear conditioning.

“…In the case of alcohol withdrawal, the increased sensitivity to seizure‐inducing events has been likened to the process of epileptic kindling (Ballenger & Post, 1978), and in keeping with this idea, electrical kindling of the amygdala results in increased severity of seizures induced by withdrawal from chronic alcohol (Pinel et al ., 1975), while previous experience of alcohol withdrawal facilitates subsequent electrical kindling of the amygdala (Carrington et al ., 1984). In contrast, repeated ethanol withdrawal delays development of focal seizures in hippocampal kindling (Veatch & Gonzalez, 1999). Thus, increased seizure sensitivity resulting from repeated withdrawal from ethanol may reflect changes in synaptic efficiency resembling those underlying electrical kindling, specifically in the amygdala.…”

Section: Introductionmentioning

confidence: 99%

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

Stephens

Brown

Duka

et al. 2001

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.