tetrodotoxin and Alcoholism

Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naïve rats; this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. This reduction was restored by systemic administration of ceftriaxone, a β-lactam antibiotic known to increase GLT-1 expression. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1's function in the LHb is critical. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal.

Topics: Alcoholism; Amino Acid Transport System X-AG; Animals; Antidepressive Agents; Anxiety; Ceftriaxone; Central Nervous System Depressants; Depression; Ethanol; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Habenula; In Vitro Techniques; Kainic Acid; Male; Maze Learning; Nerve Tissue Proteins; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Substance Withdrawal Syndrome; Swimming; Tetrodotoxin

Ethanol, diethylether, halothane and enflurane inhibited the veratridine-dependent uptake of 24Na by synaptosomes isolated from rodent brain. The inhibitory action of ethanol was similar for uptake periods of 1 to 10 sec and also was observed with batrachotoxin-stimulated sodium uptake, demonstrating an inhibition of sodium influx through voltage-dependent channels. The inhibitory action of tetrodotoxin on sodium uptake was not altered by ethanol, indicating this site on the sodium channel was not altered by ethanol. The action of ethanol was selective for different brain regions and was more potent in inhibiting sodium uptake in cortex than in cerebellum. Investigation of the effects of temperature on veratridine-stimulated uptake and ethanol actions demonstrated that an increase in temperature (13 degrees-33 degrees C) decreased both the apparent KD of veratridine and the Vmax of the uptake. Ethanol decreased the apparent Vmax at all temperatures and decreased the apparent KD at low 13 degrees and 18 degrees C) but not at higher (30 degrees and 33 degrees C) temperatures. Thus, an increase in temperature mimicked some, but not all, of the effects of ethanol. These results, together with those from other studies, suggest that the disordering of membrane lipids by ethanol and other intoxicant-anesthetic drugs is an important factor in the inhibition of sodium channel function by these drugs.

Topics: Alcoholism; Anesthetics; Animals; Batrachotoxins; Brain; Electrochemistry; Ethanol; Humans; Ion Channels; Kinetics; Male; Mice; Mice, Inbred DBA; Ouabain; Rats; Rats, Inbred Strains; Serum Albumin, Bovine; Synaptosomes; Tetrodotoxin