Antagonism of the hypnotic effect of ethanol in mice by an alpha-1 adrenoceptor agonist

A lipid soluble alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587) antagonized the hypnotic effect of ethanol in C57Bl/6 and CD-1 mice. In Swiss-Webster mice the effect of St 587 was weak and in BALB/c mice this drug potentiated ethanol hypnosis. St 587 did not enhance the elimination of ethanol. Cirazoline, an alpha 1-adrenoceptor agonist which is more potent than St 587, was relatively more effective in antagonizing the ethanol-induced hypnosis. Though it appears that St 587 exerted its ethanol antagonism by virtue of its alpha 1-adrenoceptor agonistic effect, other contributing factors may also have to be considered. St 587 may prove to be of value in understanding the mechanism of action of ethanol and in the treatment of acute ethanol intoxication.     

Suitability of amfonelic acid-induced locomotor stimulation in mice as a model for the evaluation of classical and atypical antipsychotics

The potential usefulness of amfonelic acid ( AFA ), a selective dopamine (DA)-releasing agent, in quantitatively assessing the antidopaminergic and antipsychotic potencies of drugs, was evaluated. The procedure consisted of determining the ED50S of a number of neuroleptics in inhibiting the locomotor-stimulant effect of amfonelic acid in mice. These results were compared with the published data on the relative potencies of the neuroleptics to induce catalepsy in rats, to block drug-induced stereotypy and to alleviate psychotic symptoms clinically. It was observed that the amfonelic acid model was as good as, but not superior to, the other three procedures in identifying the potencies of classical antipsychotics. This model, however, was able to predict the clinical effectiveness of two atypical antipsychotics, thioridazine and clozapine, much more accurately than could be achieved by the other methods. Certain other atypical antipsychotics such as, mezilamine , RMI 81, 582, sulpiride and sultopride also produced a dose-related blockade of the amfonelic acid induced locomotor stimulation in mice. The antagonism to amfonelic acid exhibited by mezilamine was weaker, and that of RMI 81,582 was stronger than that of chlorpromazine. Only large doses of the two benzamides were effective in blocking the effect of amfonelic acid, sultopride being about 3 times more effective than sulpiride in this regard. Another analogue of benzamide, YM-09151-2, known to have the profile of a classical antipsychotic, was more effective than haloperidol in blocking the stimulant effect of amfonelic acid. Trebenzomine , which is considered to have the properties of an atypical antipsychotic, although this was proved otherwise when tested clinically, actually potentiated the response of mice to amfonelic acid. Apomorphine antagonized the stimulant effect of amfonelic acid, which could be attributed to its agonist activity at presynaptic DA receptors. Apomorphine has been reported to have clinical antipsychotic effects. Certain non-antipsychotic drugs such as prazosin (but not phenoxybenzamine), promethazine, methysergide, diazepam, as well as the gamm -aminobutyric acid agonists, muscimol and THIP, also inhibited the amfonelic acid-induced locomotor stimulation. In spite of this drawback, the present procedure should prove to be a useful animal model for the evaluation of the antipsychotic potencies of drugs. Its ability to identify the potential usefulness of atypical antipsychotics is noteworthy.     

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c,C57BL/6, and DBA/2 mice

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.     

Similarity between (+)-amphetamine and amfonelic acid

Rats, trained to discriminate the CNS stimulant (+)-amphetamine (1.0 mg/kg) from saline in a two-lever drug administration task, were challenged with various doses of the structurally dissimilar CNS stimulant amfonelic acid. Amfonelic acid was found to substitute for the amphetamine stimulus and was found to be 1.5 times more potent than amphetamine.     

Antagonism of alcohol hypnosis by blockade of prostaglandin synthesis and activity: genotype and time course effects

Pretreatment of mice with prostaglandin synthetase inhibitors (PGSI's) antagonizes alcohol-induced behaviors. This study examined genetic and time course factors of this effect and studied the effects of a putative prostaglandin antagonist (SC-19220) on ethanol sleep time. Long Sleep (LS) and Short Sleep (SS) mice, lines bred for differential response to an hypnotic dose of ethanol, showed a four-fold difference in their dose-response curves for indomethacin antagonism of ethanol-induced hypnosis. Females of both lines required higher amounts of indomethacin relative to males. Indomethacin pretreated animals regained the righting response at a higher blood ethanol concentration than did saline pretreated animals. In addition, indomethacin pretreatment failed to alter the rate of ethanol disappearance from blood. In general, both lines showed effects with low doses of indomethacin at early time points and with high doses of indomethacin at later time points. Indomethacin did not antagonize ethanol-induced hypnosis if given after ethanol. In C3H mice, pretreatment with low doses of SC-19220, a dibenzoxazepine derivative, produced a significant decrease in ethanol sleep time, moderate doses produced no effect, and high levels increased sleep time. These results further substantiate and expand our previous reports. Possible mechanisms for the biphasic effects of indomethacin treatment are presented and discussed.     

Dissociation between the locomotor and anxiolytic effects of acetaldehyde in the elevated plus-maze: Evidence that acetaldehyde is not involved in the anxiolytic effects of ethanol in mice

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects of the acute administration of acetaldehyde. In particular, the role of this metabolite in ethanol-induced anxiolytic effects has never been extensively tested. The aim of the present study was to characterize the anxiolytic effects of acetaldehyde in two strains of mice, C57BL/6J and CD1 mice with the elevated plus-maze procedure. The results show that acute injections of ethanol (1–2 g/kg) induced significant dose-dependent anxiolytic effects in both strains of mice. In contrast, acetaldehyde failed to produce any anxiolytic effect, although it induced a significant hypolocomotor effect at the highest doses. In an independent experiment, cyanamide, an aldehyde dehydrogenase inhibitor, prevented the locomotor stimulant effects of ethanol, although it failed to alter its anxiolytic effects. Together, the results of the present study indicate that acetaldehyde is not involved in ethanol-induced anxiolytic effects, although it may be involved in its sedative/hypolocomotor effects.     

Chronic desipramine enhances amphetamine-induced increases in interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramine and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine. Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 micrograms/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.     

Effects of antagonists of the various subtypes of dopamine receptors on the locomotor activity of C57BL mice induced by psychostimulators

The involvement of dopamine receptors of various subtypes in the mechanisms of locomotor hyperactivity caused by single administration of psychostimulants d-amphetamine and syndnocarb was studied in C57BL mice. Administered in a dose not influencing the spontaneous locomotor activity, SCH23390 and raclopride--selective antagonists of the D1 and D2 subtypes of dopamine receptors, respectively--abolished the hyperactivity induced by d-amphetamine, while not significantly changing the effect of sydnocarb. On the contrary, clozapine--antagonist of the D4 subtype of dopamine receptors--failed to reduce the stimulant action of d-amphetamine, but significantly decreased the effect of sydnocarb under the same experimental conditions.     

Does tolerance develop to the activating,as well as the depressant,effects of ethanol?

Genetically determined differences were demonstrated in the response of mice to low doses of ethanol. Ethanol (1.35 g/kg) produced an increase in locomotion in DBA/2 and BALB/c mice, but did not alter the locomotor activity of C57B1/6 mice. Chronic administration of ethanol produced tolerance to the sedative/hypnotic effects of high doses of ethanol in DBA/2 and BALB/c mice, but the equivalent chronic ethanol administration paradigm produced no tolerance to the activating effects of ethanol in these animals. C57B1/6 mice became tolerant to the hypnotic effects of ethanol, but no change in the behavior of these mice, given a low dose of ethanol, was noted after the mice were withdrawn from chronic feeding with ethanol-containing diets. The results indicate the presence of different mechanisms for tolerance development to the activating and depresant effects of ethanol, and indicate that strain-dependent differences in the activating effects of ethanol are not determined by an animal's greater sensitivity to the sedating effects of this drug.     

Divergent reserpine effects on amfonelic acid and amphetamine stimulation of synaptosomal dopamine formation from phenylalanine

Some effects of a non-amphetamine central stimulant, amtbnelic acid, on the synaptosomal (P₂) formation and release of dopamine being produced continuously from [¹⁴C]phenylalanine substrate have been determined. How reserpine action may modify the effects of amfonelic acid and those of amphetamine (the latter was included for comparative purposes) was also examined. For these studies, P₂ preparation from rat caudate nuclei was incubated with [¹⁴C]phenylalanine with and without various drug additions, and the particulates were separated from the medium after incubation. The separated fractions were analyzed for labeled dopamine and for the synaptosomal content of the labeled substrate. Of the total labeled dopamine formed, the fraction that was present in the medium was determined and taken as a measure of the spontaneous release (no drug addition) or its enhancement by any addition. Amfonelic acid and amphetamine (0.91–18.2 μM) comparably stimulated the synthesis and release of [¹⁴C]dopamine. The addition of reserpine (1.8 μM) alone had an inhibitory effect on total synthesis and a stimulatory one on release. In the presence of reserpine, the synthesis stimulation by amphetamine was maintained or accentuated, but amfonelic acid induced an inhibitory effect additive to that due to reserpine alone. The release stimulations by amphetamine and amfonelic acid were comparable in the absence as well as in the presence of reserpine. Following reserpine pretreatments at 24 and 2 hr, amphetamine (9.1 μM) markedly stimulated, but AA (9.1 μM) affected nonsignificantly, the dopamine synthesis. The pretreatments did not abolish the release-enhancing effect of either stimulant. None of the drug additions resulted in a significant alteration of the paniculate [¹⁴C]phenylalanine substrate level. In summary, the results show that amfonelic acid, like amphetamine, may release continuously forming synaptosomal dopamine and stimulate dopamine synthesis. However, the synthesis stimulation by amfonelic acid, but not that by amphetamine, may he abolished by reserpine action, either in vitro or in vivo. The results suggest that. although amphetamine may stimulate by releasing the newly forming dopamine pool, a significant amfonelic acid action may he on the catecholamine storage system, and synaptosomal dopamine synthesis may be under the controlling influence of both the newly forming amine and the vesicular stores.     

The effect of doxepin on the central action of ethanol.

The effect of combined treatment with doxepin and ethanol was tested in mice, rats and rabbits. Doxepin was given in a single dose (5 or 10 mg/kg) or chronically (10 mg/kg/d for 21 days). Doxepin did not affect ethanol toxicity and ethanol-induced impairment of rota-rod performance, but potentiated ethanol-induced hypothermia (only acutely) and prolonged ethanol-induced sleep in mice. Given acutely it potentiated the inhibitory effect of ethanol on locomotor activity in mice, while given chronically it counteracted the ethanol-induced sedation. Doxepin did not interfere with ethanol-induced EEG effects in rabbits, and prevented the development of tolerance to hypothermic, but not to hypnotic effects of ethanol in rats. In general, the interference of doxepin with ethanol was more pronounced after single doses of the drug than after chronic treatment.     

Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (?) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or γ-acetylenic GABA caused a dose-dependent inhibition of the locomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (?) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for γ-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (?) baclofen may prove to be useful in the management of PCP intoxication.Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (?) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (?) baclofen and PCP. The possible use of (?) baclofen as an adjuvant to general anesthetic is discussed.     

Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.     

Different effects of amphetamine and amfonelic acid on peripheral and central catecholamine metabolism

The effects of amphetamine (AMPH) and a non-amphetamine stimulant, amfonelic acid (AFA), on catecholamine metabolism in peripheral sympathetic ganglia (superior cervical and celiac) and several brain regions (hypothalamus, caudate, olfactory tubercle and nucleus accumbens) were examined. The effects of the drugs on gross behavior measures (hyperactivity with some stereotypy) were similar. In the sympathetic ganglion (both intact and decentralized superior cervical ganglia included) AMPH significantly elevated dopamine, with a non-significant reduction in norepinephrine. Three, 4-dihydroxyphenylacetic acid (DOPAC) was significantly decreased, in the celiac ganglion, but not in the superior cervial ganglion. Amfonelic acid had no effect on catecholamines in the ganglia. The effect of AMPH on superior cervical ganglion SIF-cells dopamine concentration is therefore local and independent on the preganglionic nerve. In all the brain regions analyzed AMPH significantly increased norepinephrine and dopamine concentrations, with only minor effects on their metabolites (caudate and accumbens DOPAC decreased). Amfonelic acid, on the other hand primarily elevated dopamine metabolism. It decreased norepinephrine in the olfactory tubercle and accumbens, and increased 3-methoxy-4-hydroxyphenylglycol concentration in the hypothalamus. This latter suggests an influence of AFA on central noradrenergic neurons. At the doses used neither drug significantly altered caudate monoamine oxidase activity. Since desmethylimipramine produced different effects on catecholamine metabolism than AFA, it is unlikely that AFA works by blocking norepinephrine reuptake. Desmethylimipramine in contrast to AFA, reduced the metabolism of both norepinephrine and dopamine in the caudate and hypothalamus. Our results are consistent with the concept that AMPH acts to release amines and shuts down catecholaminergic neuronal firing, while AFA facilitates impulse-induced release and stimulates central catecholamine turnover. γ-Butyrolactone, which blocks dopaminergic impulse flow, antagonized the hyperactive effects of AFA but not its biochemical actions,suggesting that other transmitter systems are involved or that γ-butyrolactone produced a non-specific, generalized depression of activity. The stimulant effects of AMPH, AFA and desmethylimipramine do not appear to be directly related to their influence on central catecholamines.     

Genetic differences in naloxone enhancement of ethanol-induced conditioned taste aversion

The influence of the opioid system on acquisition of an ethanol-induced conditioned taste aversion was examined in alcohol-preferring and avoiding inbred strains of mice (C57BL/6J and DBA/2J). Fluid-deprived mice from each strain received either ethanol alone, naloxone alone, or both ethanol and naloxone immediately after access to a novel tasting fluid. Naloxone alone (1 or 3 mg/kg) did not induce a conditioned taste aversion in either strain of mice. Administration of ethanol (1.5 g/kg) to DBA/2J mice produced a moderate taste aversion that was not affected by co-administration of naloxone. Although ethanol administered alone (3 g/kg) did not cause a taste aversion in C57BL/6J mice, the combination of ethanol and the higher dose of naloxone produced a significant taste aversion that increased across trials. A second experiment addressed the possibility that naloxone failed to enhance the ethanol-induced condition taste aversion in DBA/2J mice due to a floor effect on consumption. A lower ethanol dose (1 g/kg) was given alone or in combination with naloxone (1 or 3 mg/kg). Again, ethanol produced a moderate conditioned taste aversion that was not potentiated by naloxone. Subsequent conditioning with a high ethanol dose produced further suppression of intake, confirming that naloxone's failure to enhance aversion on earlier trials was not due to a floor effect. These data demonstrate a strain specific interaction between the aversive effect of ethanol and naloxone. More specifically, the results indicate that blockade of opioid receptors enhances the aversive effect of ethanol in C57BL/6J but not DBA/2J mice, suggesting that genetically determined differences in the endogenous opioid system of alcohol-preferring mice may mitigate ethanol's aversive effect.     

Soporific action of ethanol in mice: possible role of biogenic amines

Ethanol-induced sleep time was measured in mice after administration of L-3,4-dihydroxyphenylalanine (L-DOPA), L-tryptophan (L-TP), DL-5-hydroxytryptophan (5-HTP), serotonin (5HT), DL-5-hydroxyindole-3-acetic acid (5HIAA), and DL-parachlorophenylalanine (pCPA), a serotonin depletor. The pCPA administration, with concomitant reduction of brain serotonin, had no effect on ethanol-induced sleep; TP, 5-HTP and 5HIAA failed also to significantly enhance ethanol sleep in mice. However, serotonin significantly enhanced sleeping time of mice administered an ineffective dose of ethanol. Pretreatment with L-DOPA produced a marked prolongation of ethanol narcosis with a concomitant large increase in whole brain dopamine (DA). Administration of L-DOPA and pCPA, together, produced a smaller augmentation of ethanol effects.     

Effects of L-ascorbic acid on ethanol-induced central nervous system depression in mice

Male Swiss-Webster mice were administered ethanol immediately before a motor coordination test. Controls and animals treated with 1, 2 or 3 g/kg, IP, of ethanol remained on a suspended meter stick for 240 +/- 0, 232 +/- 8, 93 +/- 2 and 75 +/- 5 sec, respectively. Blood ethanol levels at the end of the test period (4 min) or when the animal fell from the meter stick were 1.02 +/- 0.03, 2.13 +/- 0.09 and 2.24 +/- 0.07 mg/ml for the 1, 2 and 3 g/kg dose of ethanol, respectively. Thirty min prior to ethanol (2 g/kg, IP) animals received L-ascorbic acid in doses of 500 or 1000 mg/kg, IP. Both doses of L-ascorbic acid significantly enhanced the duration of time that the animals spent on the meter stick. When animals were given 1 g/kg, IP, of ethanol their rate of walking (cm/min) on the meter stick was significantly increased over controls. Administration of L-ascorbic acid (1000 mg/kg, IP) 30 min prior to ethanol (1 g/kg) did not change the rate of locomotion. In experiments on ethanol-induced hypnosis (sleep-time), animals received L-ascorbic acid (250, 500, 1000 or 1500 mg/kg, IP) or saline 30 min prior to ethanol (4 g/kg, IP). L-ascorbic acid increased the time of onset of hypnosis significantly at doses of 1000 and 1500 mg/kg. With these doses of L-ascorbic acid sleep duration and blood ethanol content were not altered. L-ascorbic acid, however, increased ethanol-induced hypnosis at a dose of 500 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apomorphine effects on behavioral response to ethanol in mice selectively bred for differential sensitivity to ethanol

Two lines of mice selectively bred for differences in response to a hypnotic dose of ethanol were administered apomorphine alone or in combination with ethanol. When administered by itself, apomorphine produced similar dose-dependent depression of locomotor activity and increases in stereotypy in the two lines. Doses of apomorphine (0.5 microM/kg and 2 microM/kg) thought to bind only presynaptic dopamine receptors blocked the slight locomotor activation to 1.5 g/kg ethanol in the ethanol-sensitive Long-Sleep (LS) mice; in the ethanol-insensitive Short-Sleep (SS) mice which show marked activation to all subhypnotic doses of ethanol, these doses of apomorphine only attenuated the activation. A higher apomorphine dose (8 microM/kg) antagonized the locomotor depressant effects of 2.0 and 2.5 g/kg of ethanol in LS mice but did not alter the shape of the SS ethanol dose response curve for locomotor activity. Apomorphine (2 and 8 microM/kg) potentiated ethanol-induced loss of the righting reflex in LS mice in a dose dependent fashion, but did not alter this soporific effect of ethanol in SS mice. These findings extend the data base suggesting a role for dopamine both in the mechanism(s) differentiating the LS and SS mice and the stimulant and intoxicating properties of ethanol.     

Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine

(+) Amphetamine was more potent than (?) amphetamine in causing persistent depletion of striatal dopamine in iprindole-treated rats. This effect of amphetamine was not mimicked by EXP561, a structurally related compound that is more potent than amphetamine as an inhibitor of dopamine uptake. The depletion of striatal dopamine at 1 week after amphetamine injection in iprindole-treated rats was prevented by amfonelic acid, an inhibitor of uptake into dopamine neurons. The depletion of dopamine by amphetamine was prevented when amfonelic acid was given at the same time as amphetamine or as long as 4 hr after amphetamine but not when amfonelic acid was given 24–48 hr after amphetamine. Amfonelic acid antagonized the depletion of dopamine by amphetamine but not the depletion of serotonin by p-chloroamphetamine; fluoxetine antagonized the depletion of serotonin by p-chloroamphetamine but not the depletion of dopamine by amphetamine. Pretreatment with α-methyltyrosine to block dopamine synthesis antagonized the persistent depletion of dopamine by amphetamine, but pretreatment with an inhibitor of monoamine oxidase to increase the dopamine concentration had no effect. The possibility that prolonged release of dopamine from intraneuronal storage granules leads to deleterious effects on dopamine neurons is discussed.