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Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

There is a common assumption that alcohol produces impulsive behaviors, thereby increasing the preference for immediate over delayed rewards. An alternative explanation, provided by alcohol myopia theory, is that alcohol alters attentional processes such that intoxicated individuals respond exclusively to the most salient cues in their environment.We tested these two hypotheses in rats using standard (impulsivity) and modified (cue salience) versions of the delayed reinforcement task.In the impulsivity paradigm, rats were trained to choose between a small immediate reward (2 sucrose pellets) and a large delayed reward (12 sucrose pellets after 10 s) in a T-maze. In the cue salience paradigm, a light in one arm predicted either the small or the large reward, but the arm paired with the light varied across trials. In separate experiments, we examined how changes in delay to the large reward, alcohol administration, or alcohol combined with either a serotonin agonist [para-chloroamphetamine (pCA) at doses of 0.1, 0.4, 0.7, and 1.0 mg/kg, s.c.)] or a dopamine antagonist [cis-(Z)-flupenthixol dihydrochloride (alpha-flupenthixol) at doses of 0.0125, 0.025, 0.05, and 0.1 mg/kg, i.p.] affected performance in each task.Increasing the delay to the large reward increased impulsivity in both paradigms, but it had no effect on responding to a salient cue. Alcohol (0.6, 0.9, 1.2, and 1.8 g/kg, i.p.) increased the choice of the immediate reward and increased the choice of the lit arm, regardless of whether it signaled the small or the large reward. pCA selectively reduced alcohol-induced impulsivity, whereas alpha-flupenthixol selectively reduced responding to a salient cue.Rats, like humans, are influenced by cue salience when intoxicated. Although this alcohol myopia effect could explain alcohol-induced impulsivity, the two processes are probably distinct because they are mediated by dissociable pharmacological mechanisms.

Rats were rendered tolerant to ethanol or pentobarbital by daily oral administration. Motor impairments after test doses of ethanol or pentobarbital were measured prior to and at various times during chronic treatment in order to assess the degree of tolerance development. Chronic administration of p-chlorophenylalanine (p-CPA) in a dosage regimen which produced and maintained approximately 95% depletion of brain serotonin (5-HT) did not alter motor impairment after initial acute administration of ethanol or pentobarbital. However, the rate of tolerance development to the motor-impairing effects of both drugs was slowed down in p-CPA-treated rats, p-CPA did not appear to exert this effect by altering the disposition of ethanol or pentobarbital, since blood levels determined 20 min after administration of the test doses were similar in animals treated with p-CPA and in controls. These findings suggest that brain 5-HT may have a role in tolerance development to ethanol and pentobarbital.

Animals prenatally exposed to ethanol (ethanol-exposed animals) exhibit physiological and behavioral abnormalities consistent with altered 5-hyrdroxytryptamine (5-HT) function including lack of response inhibition and increased anxiety and aggression.The present study investigated the possibility that ethanol-exposed animals show alterations in 5-HT(1A) and 5-HT(2A) receptor function, two 5-HT receptor subtypes mediating these behaviors. We measured the physiological and behavioral responses to the 5-HT(1A) agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), and the 5-HT(2A/C)agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) (DOI), which provide indices for estimating central changes in 5-HT activity and receptor function.Female and male offspring from ethanol-exposed (E), pair-fed control (PF), and ad-libitum-fed control (C) dams were tested in adulthood. Animals were injected with 8-OH-DPAT or DOI to induce hypothermia and wet-dog shakes (WDS, a paroxysmal shudder of the head, neck and trunk), respectively, or with saline. In experiment 1, core temperatures were recorded immediately before injection of 8-OH-DPAT (0, 0.125 mg/kg or 0.500 mg/kg) and again at 30, 60, 90, 120 and 180 min post-injection. In experiment 2, the number of WDS were recorded in response to injection of DOI (0, 1 mg/kg).E females and males showed a greater hypothermic response to 8-OH-DPAT than PF and C animals. E females and males also showed less of a differential hypothermic response to low and high doses of 8-OH-DPAT than PF and C animals. In addition, in response to DOI, E females, but not males, showed a significantly greater rate of WDS than PF and C females.Our findings indicate that prenatal ethanol exposure alters 5-HT(1A) and 5-HT(2A) receptor function in adulthood and does so in a sex-specific manner. These findings have important implications for altered hormonal and behavioral responsiveness observed in ethanol-exposed animals.

Drug-associated environmental stimuli elicit craving in humans and drug-seeking in animals.We tested the hypothesis that Pavlovian-conditioned alcohol-seeking is mediated by dopamine, using rats from two vendors.Male, Long-Evans rats (220-240 g) from Charles River (St-Constant, QC, Canada) and Harlan Laboratories (Indianapolis, IN, USA) received 21 sessions of intermittent, 24-h access to ethanol (15 %, v/v) and water in the home-cage. Subsequently, rats were trained to discriminate between one conditioned stimulus (CS+) that was paired with ethanol (0.2 ml per CS+) and a second stimulus (CS-) that was not. Entries into a fluid port where ethanol was delivered were recorded. Next, rats were exposed to a different context where cues and ethanol were withheld. At test, responding to the CS+ and CS- without ethanol was assessed in the second, non-alcohol context. Injections (1 ml/kg; s.c.) of the dopamine D1-receptor antagonist SCH 23390 (0, 3.33, and 10 μg/kg) or dopamine D2-receptor antagonist eticlopride (0, 5, and 10 μg/kg) were administered before test.Home-cage alcohol consumption was higher in Harlan rats than Charles River rats. At test, saline-treated rats responded more to the alcohol-predictive CS+ than the CS-. While SCH 23390 attenuated CS+ responding in rats from both vendors, eticlopride reduced CS+ responding in Harlan rats only. Subsequently, SCH 23390 but not eticlopride attenuated CS+ responding when the CS+ was again paired with ethanol.These results indicate important differences in alcohol consumption in Long-Evans rats from different suppliers, and highlight a novel role for dopamine in Pavlovian-conditioned alcohol-seeking.

The possible involvement of catecholamines (CA) in the mediation of acetaldehyde's conditioned taste aversion (CTA) was examined by testing the effects of alpha-methyl-para-tyrosine (AMPT, a tyrosine hydroxylase inhibitor) on the CTAs produced by acetaldehyde. AMPT blocked the acquisition of the CTA normally produced by a low dose of acetaldehyde (0.2 g/kg), but had no significant effect on CTA produced by a high dose of acetaldehyde (0.3 g/kg). In a second study, acetaldehyde's role in the CTA produced by ethanol was investigated using the pre-exposure conditioned taste aversion paradigm. Pre-exposure to acetaldehyde (both doses) blocked the ethanol CTAs but when pre-exposure with acetaldehyde was coupled with AMPT, only the larger dose of acetaldehyde blocked the ethanol aversion. These results suggest that while the CTA to the low dose of acetaldehyde may be primarily central and catecholamine-mediated, the mechanism underlying the high dose CTA is probably peripheral and emetic in nature. These findings support the conclusion that acetaldehyde may be mediating many of the actions of ethanol.

The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug.Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol.We used the place preference paradigm to measure the rewarding effects of cocaine (20 mg/kg), morphine (5 or 10 mg/Kg), or ethanol (20%) in adult (PND 75) male Dcc haploinsufficient mice or their wild-type litter mates. In a second experiment, we compared in these two genotypes, in vivo dopamine release in the nucleus accumbens after a single i.p. injection of morphine (10 mg/kg).We found reduced morphine-induced dopamine release in the nucleus accumbens of Dcc haploinsufficient male mice, but, contrary to the effects of stimulant drugs, there is no effect of genotype on morphine-induced conditioned preference.These findings show that reduced drug-induced mesolimbic dopamine in Dcc haploinsufficient male mice protects specifically against the rewarding effects of stimulant drugs, but not against the rewarding properties of morphine and ethanol. These results suggest that these drugs exert their rewarding effect via different brain circuits.

The zebrafish has become an increasingly popular animal model for investigating ethanol's actions in the brain and its effects on behavior. Acute exposure to ethanol in zebrafish has been shown to induce a dose-dependent increase of locomotor activity, to reduce fear- and anxiety-related behavioral responses, and to increase the levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC).The objective of the present study was to investigate the role of dopamine D1 receptors (D1-R) in ethanol-induced locomotor activity in zebrafish.Zebrafish were pre-treated with SCH-23390 (0 or 1 mg/L bath concentration), a D1-R antagonist, and subsequently exposed to ethanol (0, 0.25, 0.5, 1.0 % v/v). To explore potential underlying mechanisms, we quantified levels of dopamine, DOPAC, serotonin, and 5-HIAA from whole-brain tissue using high-precision liquid chromatography.We found pre-treatment with the D1-R antagonist to attenuate locomotor activity independent of ethanol concentration. Furthermore, unlike ethanol, D1-R antagonism did not alter behavioral responses associated with fear and anxiety. Pre-treatment with SCH-23390 decreased levels of dopamine and DOPAC, but this effect was also independent of ethanol concentration. The D1-R antagonist also reduced serotonin and 5-hydroxyindole acetic acid (5-HIAA) levels.These results suggest a multifaceted and at least partially independent role of dopamine D1 receptors in ethanol-induced locomotor activity and anxiety-related responses as well as in the functioning of the dopaminergic and serotoninergic neurotransmitter systems in zebrafish.