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Ethanol affects many functions of the brain and peripheral organs. Here we show that ethanol opens G-protein-activated, inwardly rectifying K + (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate. At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK1/2 and cardiac-type GIRK1/4 channels without interaction with G proteins or second messengers. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol.

Abstract  A family history of alcoholism has been demonstrated to be an important factor affecting cognitive function. However, no studies have yet been conducted to compare cognitive recovery of family history‐positive (FH+) and family history‐negative (FH–) alcoholics in the subacute withdrawal period. To tackle this problem, a neuropsychological test battery consisting of six computerized tests was administered to 19 FH+ and 20 FH– alcoholics at 2 and 7 weeks after abstinence. At 2 weeks after abstinence, overall performance of both FH+ and FH– groups was significantly poorer than that of healthy controls. At 7 weeks, these performances tended to recover, but in Trail Making A and Figure Position, performances of FH+ alcoholics remained worse than those of controls, while those of FH– alcoholics did not. Thus cognitive recovery during the subacute withdrawal period was worse among FH+ alcoholics than FH– alcoholics, and this finding should be considered when planning alcohol rehabilitation programs.

SummaryMechanism of central actions of antidepressants were studied in experimental animals.Tests were made on general behavior, anticonvulsant activity in maximal electroshock seizure, antireserpinic action, antagonistic action to methamphetamine‐excitation, anesthesia induced by hexobarbital, hypertension due to noradrenalin, hypotension induced by acetylcholine, anti‐tremorine action and antagonism for physostigmine in unanesthetized mice and rabbits. In these tests, it seemed that the mechanism of antidepressants is related to the changes of biogenic amines in the brain and to the central autonomic functions. Namely, imipramine, amitriptyline and nialamide were related intimately to the changes of biogenic amine and to the inhibitory effects of parasympathetic functions. Diazepam was connected with the tranquilizing effects and the inhibitory effects of parasympathetic functions, and dimethylaminoethanol had no relation to the autonomic functions.

It is the first and important practice for the study of the psychotropic drugs to observe the spontaneous movement of animals. Although many methods have been known for measuring the spontaneous movements, most of them are to find the change of motor activity of a single animal. Many investigators reported the automatic measurement of the motor activity. Photoelectric method was first used by Siegel et al. (1), which was improved by Dews et al. (2) in mice. Takagi et al. (3) traced the spontaneous movement of a mouse using a modified photoelectric apparatus. The central nervous system stimulant effect of 2-dimethylaminoethanol (DMAE) was first reported by Pfeiffer et al. (4) and had been confirmed by Konigsmark et al. (5), Himwich (6) and Brown and Gangloff (7). It was also confirmed by clinical trials. Pfeiffer et al. (8) proposed the hypothesis that DMAE played the role of a precursor of acetylcholine in the central nervous system. Groth et al. (9) found that DMAE was incorporated in the mouse brain more rapidly than choline and probably converted to brain choline. However, Pepeu et al. (10) and Kiplinger et al. (11) had different views from that of Pfeiffer. In this paper, we have developed a method of recording the spontaneous activity of grouped mice, in order to take an accurate measurement of a little change of motor activity by drugs. We investigated the effect of DMAE and its acyl esters on the spontaneous movement of the grouped and/or individual mice.

(R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.

The effects of injection of various purinoceptor agonists into the hypothalamic paraventricular nucleus in water-loaded and ethanol-anesthetized rats were investigated. Adenosine triphosphate (ATP), beta,gamma-methyleneadenosine 5'-triphosphate (AMP-PCP) and beta,gamma-imidoadenosine 5'-triphosphate (AMP-PNP) potently decreased the outflow of urine in a time- and dose-dependent manner. The ED50 values were approx 70 and 37 nmol for ATP and AMP-PCP, respectively. Adenosine diphosphate (ADP), AMP and adenosine reduced the outflow of urine much less than ATP. Adenosine triphosphate induced concomitant increases in the osmotic pressure of the urine and in the level of arginine-vasopressin (AVP) in plasma. The antidiuretic effect of ATP was blocked by prior injection of quinidine (a P2-purinoceptor antagonist) into the paraventricular nucleus, but not by the prior injection of theophylline (a P1-purinoceptor antagonist). The effect of ATP was also blocked by intravenous injection of an AVP(V1V2)-receptor antagonist, d(CH2)5-D-Tyr(Et)VAVP. The results suggest that ATP injected into the paraventricular nucleus may stimulate a purinoceptor, releasing AVP and inducing the antidiuretic effect through renal AVP(V2) receptors.

AbstractOromandibular dystonia is a focal dystonia involving the masticatory and tongue muscles, causing difficulties in speech or mastication. We treated 13 patients with this condition by injecting diluted lidocaine and alcohol intramuscularly. This method is aimed at reducing muscle spindle afferent activity. The symptoms had been resistant to other therapies such as pharmacotherapy or dental treatment. All patients showed clinical improvement after this therapy with reduced EMG activities in the affected muscles, whereas control injection of normal saline gave no changes in EMG activities. The overall subjective improvement was 57.7 ± 25.1% (mean ± standard deviation) in a self‐rating scale. The mean response of the jaw elevator muscles (70 ± 13.1%) was significantly higher (p < 0.02, t test) than that of the depressor muscles (38 ± 28.4%). Despite the precise mechanism being unknown, this difference might be related to the smaller number of muscle spindles in the depressor than the elevator muscles. This therapy is useful for the treatment of drug‐resistant oromandibular dystonia.

Cerebellar alterations are a hallmark of Fetal Alcohol Spectrum Disorders and are thought to be responsible for deficits in fine motor control, motor learning, balance, and higher cognitive functions. These deficits are, in part, a consequence of dysfunction of cerebellar circuits. Although the effect of developmental ethanol exposure on Purkinje and granule cells has been previously characterized, its actions on other cerebellar neuronal populations are not fully understood. Here, we assessed the impact of repeated ethanol exposure on the number of inhibitory neurons in the cerebellar vermis. We exposed pregnant mice to ethanol in vapor inhalation chambers during gestational days 12-19 and offspring during postnatal days 2-9. We used transgenic mice expressing the fluorescent protein, Venus, in GABAergic/glycinergic neurons. Using unbiased stereology techniques, we detected a reduction in Venus positive neurons in the molecular and granule cell layers of lobule II in the ethanol exposed group at postnatal day 16. In contrast, ethanol produced a more widespread reduction in Purkinje cell numbers that involved lobules II, IV-V and IX. We also found a reduction in the volume of lobules II, IV-V, VI-VII, IX and X in ethanol-exposed pups. These findings indicate that second and third trimester-equivalent ethanol exposure has a greater impact on Purkinje cells than interneurons in the developing cerebellar vermis. The decrease in the volume of most lobules could be a consequence of a reduction in cell numbers, dendritic arborizations, or axonal projections.