Effects of intrahippocampal nicotine and neurosteroid administration on withdrawal in voluntary and chronic alcohol-drinking rats.
BACKGROUND
Previous studies have shown that 4.6 mug of nicotine administered to the hippocampus can deteriorate learning acquisition in alcohol-drinking rats. The aim of the present study was to research whether this nicotine dose can alter the alcohol withdrawal syndrome and whether the two neurosteroids, allopregnanolone (AlloP) and pregnenolone sulfate (PregS), at doses previously reported as anxiolytic and promnesic, respectively, can modulate these effects.


METHODS
We used a free-choice drinking procedure that involved providing the rats with an alcoholic solution (10% ethanol) at an early age. Alcohol and control rats were assigned randomly to six groups that received two consecutive intrahippocampal (dorsal CA1) injections once per week during three consecutive weeks after one hour of ethanol drinking. The first injection was nicotine (4.6 microg, 20 mM) or saline and the second injection was PregS (5 ng, 24 microM), AlloP (0.2 microg, 1.26 microM) or saline. Blood alcohol concentrations were assessed one week before the withdrawal testing. Locomotor activity and audiogenic seizures were tested during withdrawal after 110 days of voluntary ethanol consumption. Rats were injected immediately before the withdrawal testing.


RESULTS
AlloP induced a decrease in horizontal and vertical activities, suggesting that the dose tested has sedative effects. AlloP reversed the seizures induced by ethanol withdrawal and also the spontaneous audiogenic seizures induced by the acoustic stimulation in control rats. Moreover, AlloP decreased other alcohol withdrawal signs, such as tail stiffening and body rigidity. Intrahippocampal administration of nicotine or PregS, at the doses tested, did not effectively modify the expression of audiogenic seizures induced by alcohol withdrawal.


CONCLUSIONS
These results show that hippocampal GABAergic activity and AlloP have an important role in preventing convulsive behavior. The results also highlight the therapeutic potential of AlloP for reducing the alcohol withdrawal syndrome.
Martin-Garcia
Elena
E
Institut de Neurociències, Departament de Psicobiologia i Metodologia de les Ciències de la Salut, Universitat Autònoma de Barcelona, Barcelona, Spain.
Pallares
Marc
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000627:therapeutic use*; D011280:Pregnanolone / Q000627:therapeutic use*; D011284:Pregnenolone / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
C018370:pregnenolone sulfate; D000431:Ethanol; D009538:Nicotine; D011284:Pregnenolone; D011280:Pregnanolone