Locomotor Stimulant Effects Of Ethanol Research Articles

GABAergic regulation of locomotion before and during an ethanol exposure in Drosophila melanogaster

Ethanol at low doses induces a locomotor stimulant response across a range of phylogenetically diverse species. In rodents, this response is commonly used as an index of ethanol’s disinhibitory, anxiolytic, or reinforcing effects, and its expression is regulated by signaling through a number of conserved neurotransmitter systems. In the current experiments, we asked whether ethanol-induced locomotor stimulation in the fruit fly Drosophila melanogaster might be mediated by ionotropic GABA receptors. We measured basal and ethanol-stimulated locomotion in flies expressing RNAi directed against three known subunits of ionotropic GABA receptors, and also examined the effects of picrotoxin feeding on these behaviors. We found that RNAi-mediated knockdown of a subunit of fly ionotropic GABA receptors, RDL, in all neurons resulted in an increased ethanol-induced locomotor stimulant response, while knockdown of two other subunits, LCCH3 and GRD, did not affect the responses. The effect of pan neuronal RDL knockdown was recapitulated with selective RDL knockdown in cholinergic neurons, and increased ethanol-induced locomotor stimulation was also seen by feeding the GABAA antagonist picrotoxin to flies prior to behavioral testing. However, the increase in ethanol-stimulated locomotion in each of these experiments was largely accounted for by decreased baseline activity. Our results indicate that ionotropic GABA receptors might be a conserved mediator of the locomotor stimulant effects of ethanol, but that alternative experimental approaches will be necessary to disentangle effects of GABAergic manipulations on baseline and ethanol-stimulated locomotion in flies.

Investigating the reciprocal relationships between locomotor sensitization to ethanol and PTSD-like clusters in DBA/2J mice

BackgroundPost-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal of this study was twofold. First to investigate whether PTSD reduces the threshold for the acquisition of ethanol sensitization in an animal model of PTSD. Then to investigate whether ethanol sensitization modulates the expression of PTSD. Methods152 female inbred DBA/2 J mice were submitted to an inescapable footshock paradigm to induce a PTSD-like condition (PTSDLC) and to a paradigm of locomotor sensitization to ethanol. In a first experiment, mice were submitted to the PTSDLC and then repeatedly injected with either saline, 1 g/kg ethanol or 2 g/kg ethanol. Their sensitization to the locomotor stimulant effects of ethanol was then tested in an open field. In a second experiment, mice were first sensitized to the locomotor stimulant effects of ethanol and then tested for their behavioral response to PTSDLC. ResultsIn the first experiment, PTSDLC failed to induce a significant locomotor sensitization at the subthreshold dose of 1 g/kg ethanol. However, with 2 g/kg ethanol, a stronger ethanol sensitization was observed in mice submitted to the footshock relative to the control group. In the second experiment, ethanol sensitization increased only some of the behavioral clusters of PTSDLC, namely the fear generalization in a new context. ConclusionPTSDLC did not reduce the dose threshold for the acquisition of ethanol sensitization but strengthened the development of ethanol sensitization with effective doses. This suggests that PTSD might interact with one of the mechanisms underlying the development of alcohol sensitization. When the relationship between ethanol sensitization and PTSDLC is tested in the reverse direction, the present study only shows a significant effect of ethanol administration on the “sensitized fear” PTSD cluster.

Chronic tolerance to ethanol-induced sedation: Implication for age-related differences in locomotor sensitization

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance.

GABAB receptor activation attenuates the stimulant but not mesolimbic dopamine response to ethanol in FAST mice

Neural processes influenced by γ-aminobutyric acid B (GABAB) receptors appear to contribute to acute ethanol sensitivity, including the difference between lines of mice bred for extreme sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effect of ethanol. One goal of the current study was to determine whether selection of the FAST and SLOW lines resulted in changes in GABAB receptor function, since the lines differ in sensitivity to the GABAB receptor agonist baclofen and baclofen attenuates the stimulant response to ethanol in FAST mice. A second goal was to determine whether the baclofen-induced reduction in ethanol stimulation in FAST mice is associated with an attenuation of the mesolimbic dopamine response to ethanol. In Experiment 1, the FAST and SLOW lines were found to not differ in GABAB receptor function (measured by baclofen-stimulated [35S]GTPγS binding) in whole brain or in several regional preparations, except in the striatum in one of the two replicate sets of selected lines. In Experiment 2, baclofen-induced attenuation of the locomotor stimulant response to ethanol in FAST mice was not accompanied by a reduction in dopamine levels in the nucleus accumbens, as measured by microdialysis. These data suggest that, overall, GABAB receptor function does not play an integral role in the genetic difference in ethanol sensitivity between the FAST and SLOW lines. Further, although GABAB receptors do modulate the locomotor stimulant response to ethanol in FAST mice, this effect does not appear to be due to a reduction in tonic dopamine signaling in the nucleus accumbens.

Taok2 controls behavioral response to ethanol in mice

Despite recent advances in the understanding of ethanol's biological action, many of the molecular targets of ethanol and mechanisms behind ethanol's effect on behavior remain poorly understood. In an effort to identify novel genes, the products of which regulate behavioral responses to ethanol, we recently identified a mutation in the dtao gene that confers resistance to the locomotor stimulating effect of ethanol in Drosophila. dtao encodes a member of the Ste20 family of serine/threonine kinases implicated in MAP kinase signaling pathways. In this study, we report that conditional ablation of the mouse dtao homolog, Taok2, constitutively and specifically in the nervous system, results in strain-specific and overlapping alterations in ethanol-dependent behaviors. These data suggest a functional conservation of dtao and Taok2 in mediating ethanol's biological action and identify Taok2 as a putative candidate gene for ethanol use disorders in humans.

Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation

BackgroundCo-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse. MethodsLocomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains. ResultsThe effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone. ConclusionsThese data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.

Chronic tolerance to the locomotor stimulating effect of ethanol in preweanling rats as a function of social stress

During early stages of development rats are highly sensitive to the locomotor stimulating effect of relatively high ethanol doses, an effect strongly modulated by social stress. This ethanol effect can be modulated by pharmacological treatments that also can attenuate the development of ethanol-induced locomotor sensitization in mice. By the end of the preweanling period the mechanisms underlying sensitization induced by psychostimulants are functional. The aim of the present study was to analyze the locomotor response to ethanol in preweanling rats as a function of repeated exposure to the drug under two different social conditions. Subjects were treated with ethanol between postnatal days 15 and 18 after being isolated for four hours (Experiment 1a) or simply residing in their home-cage (Experiment 1b). After two days of withdrawal locomotor response to ethanol was assessed in both social conditions. In Experiment 2 naïve rats were tested in terms of ethanol-induced activation of the locomotor response in both social conditions. Results from the present study showed no evidence of locomotor sensitization in preweanling rats in any of the social conditions. Instead we observed behavioral tolerance to the stimulating effect of ethanol in animals trained in the home-cage condition, in which subjects trained with ethanol showed sedation in response to ethanol at testing. Overall these results contribute to the understanding of the sensitivity of rats to the acute and chronic locomotor response to ethanol in an ontogenetic period characterized by high sensitivity to ethanol.

Cilnidipine, an L/N-type calcium channel blocker prevents acquisition and expression of ethanol-induced locomotor sensitization in mice

Several evidences indicated the involvement of L- and N-type calcium channels in behavioral effects of drugs of abuse, including ethanol. Calcium channels are implicated in ethanol-induced behaviors and neurochemical responses. Calcium channel antagonists block the psychostimulants induced behavioral sensitization. Recently, it is demonstrated that L-, N- and T-type calcium channel blockers attenuate the acute locomotor stimulant effects of ethanol. However, no evidence indicated the role of calcium channels in ethanol-induced psychomotor sensitization. Therefore, present study evaluated the influence of cilnidipine, an L/N-type calcium channel blocker on acquisition and expression of ethanol-induced locomotor sensitization. The results revealed that cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) attenuates the expression of sensitization to locomotor stimulant effect of ethanol (2.0g/kg, i.p.), whereas pre- treatment of cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) during development of sensitization blocks acquisition and attenuates expression of sensitization to locomotor stimulant effect of ethanol. Cilnidipine per se did not influence locomotor activity in tested doses. Further, cilnidipine had no influence on effect of ethanol on rotarod performance. These results support the hypothesis that neuroadaptive changes in calcium channels participate in the acquisition and the expression of ethanol-induced locomotor sensitization.

Chronic ethanol exposure during adolescence alters the behavioral responsiveness to ethanol in adult mice

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present experiments was to characterize changes in the behavioral effects of ethanol in adult female Swiss mice after a chronic ethanol exposure during adolescence, extending from postnatal day 28 to postnatal day 42. After a chronic ethanol exposure during adolescence (daily injections of 0, 2.5 or 4g/kg ethanol for 14 consecutive days), adult mice were tested at postnatal day 63. The locomotor stimulant effects of ethanol, together with ethanol sensitization were tested in experiment 1. In experiment 2, the sedative effects of ethanol were assessed with the loss of righting reflex procedure. Finally, in experiment 3, the anxiolytic effects of ethanol were tested with the light/dark box test. Adult mice chronically exposed to ethanol during adolescence showed a lower basal locomotor activity, but higher locomotor stimulant effects of ethanol than non-exposed mice. Additionally, these adult mice developed higher rates of ethanol sensitization after chronic re-exposure to ethanol in adulthood. Adult mice exposed to ethanol during adolescence also had a stronger tolerance to the sedative effects of high ethanol doses, although they showed no evidence of changes in the anxiolytic effects of ethanol. These results are in agreement with the thesis that chronic alcohol consumption during adolescence, especially in high amounts, increases the risk of later alcohol-related disorders.

Insulin attenuates the acquisition and expression of ethanol-induced locomotor sensitization in DBA/2J mice

AimEthanol-induced locomotor sensitization is a behavioral manifestation of physiological responses to repeated ethanol exposures. While ethanol exerts direct effects on multiple neurotransmitter systems in the brain, ethanol-induced changes in metabolic state, including acute hyperglycemia and inhibition of insulin signaling, also have plausible roles in the expression of ethanol-related behaviors through direct and indirect effects on brain function. The current experiments examined whether insulin administration or the resultant hypoglycemia might attenuate the development of sensitization to the locomotor stimulant effect of ethanol. Main methodsMale and female DBA/2J mice received daily injections of 5 or 10IU/kg insulin before or after a stimulating dose of ethanol and subsequent testing in an automated activity monitor. Blood glucose levels were determined upon the completion of the experiments. Key findingsInsulin injected prior to ethanol blunted the acute stimulant response as well as the acquisition and expression of locomotor sensitization, while insulin given after ethanol did not affect the development of the sensitized response. In a separate experiment, mice given glucose concurrently with insulin developed ethanol-induced locomotor sensitization normally. SignificanceThese experiments suggest that insulin attenuates the development of ethanol-induced locomotor sensitization, and that blood glucose levels can largely account for this effect. Further studies of the role of ethanol-induced metabolic states should provide novel information on the expression of ethanol-related behaviors.

Mianserin, but not Ondansetron, reduces the locomotor stimulating effect of ethanol in preweanling rats

During infancy rats are highly sensitive to the locomotor stimulating effect of ethanol, an effect particularly observed when they are tested during the rising phase of the blood ethanol curve and in a novel environment. According to a recent study infant rats require some degree of stress to get stimulated after being challenged with ethanol. Ethanol-induced stimulation in preweanling rats required the activation of CRH-1 receptors. Considering these antecedents, we explored modulation of the acute stimulating effect of ethanol (2.5g/kg) by two anxiolytic drugs, Mianserin (2.5 or 5mg/kg) and Ondansetron (1 or 3mg/kg). Mianserin attenuated the stimulating effect of ethanol at a dose that did not affect locomotor activity in water-controls, likely acting through 5-HT2 receptors, while Ondansetron, a 5-HT3 antagonist, did not affect this response. These results are consistent with recent findings indicating that one of the mechanisms by which the CRH-1 receptor modulates anxiety depends on sensitization of the 5-HT2 receptor antagonist, and highlight the importance of stress as a modulator of the effects of ethanol during early developmental stages.

Neuropeptide Y signaling modulates the expression of ethanol-induced behavioral sensitization in mice

Neuropeptide Y (NPY) and protein kinase A (PKA) have been implicated in neurobiological responses to ethanol. We have previously reported that mutant mice lacking normal production of the RIIβ subunit of PKA (RIIβ-/- mice) show enhanced sensitivity to the locomotor stimulant effects of ethanol and increased behavioral sensitization relative to littermate wild-type RIIβ+/+ mice. We now report that RIIβ-/- mice also show increased NPY immunoreactivity in the nucleus accumbens (NAc) core and the ventral striatum relative to RIIβ+/+ mice. These observations suggest that elevated NPY signaling in the NAc and/or striatum may contribute to the increased sensitivity to ethanol-induced behavioral sensitization that is a characteristic of RIIβ-/- mice. Consistently, NPY-/- mice failed to display ethanol-induced behavioral sensitization that was evident in littermate NPY+/+ mice. To examine more directly the role of NPY in the locomotor stimulant effects of ethanol, we infused a recombinant adeno-associated virus (rAAV) into the region of the NAc core of DBA/2J mice. The rAAV-fibronectin (FIB)-NPY(13-36) vector expresses and constitutively secretes the NPY fragment NPY(13-36) (a selective Y(2) receptor agonist) from infected cells in vivo. Mice treated with the rAAV-FIB-NPY(13-36) vector exhibited reduced expression of ethanol-induced behavioral sensitization compared with mice treated with a control vector. Taken together, the current data provide the first evidence that NPY signaling in the NAc core and the Y(2) receptor modulate ethanol-induced behavioral sensitization.

Agmatine blocks ethanol-induced locomotor hyperactivity in male mice

Ethanol-induced locomotor activity is associated to rewarding effects of ethanol and ethanol dependence. Agmatine is a novel endogenous ligand at α 2-adrenoceptors, imidazoline and N-methyl- d-aspartate (NMDA) receptors, as well as a nitric oxide synthase (NOS) inhibitor. There is no evidence presented for the relationship between the acute locomotor stimulating effect of ethanol and agmatine. Thus, the present study investigated the effects of agmatine on acute ethanol-induced locomotor hyperactivity in mice. Adult male Swiss–Webster mice (26–36 g) were used as subjects. Locomotor activity of the mice was recorded for 30 min immediately following intraperitoneal administration of ethanol (0.5, 1 and 2 g/kg) or saline (n = 8 for each group). Agmatine (5, 10 and 20 mg/kg) or saline was administered intraperitoneally to another four individual groups (n = 8 for each group) of the mice 20 min before the ethanol injection. In these groups, locomotor activity was also recorded immediately following ethanol (0.5 g/kg) injection for 30 min. Ethanol (0.5 g/kg) produced some significant increases in locomotor activity of the mice. Agmatine (5–20 mg/kg) significantly blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity. These doses of agmatine did not affect the locomotor activity in naive mice when they were administered alone. Our results suggest that agmatine has an important role in ethanol-induced locomotor hyperactivity in mice. There may be a relationship between the addictive psychostimulant effects of the ethanol and central agmatinergic system.

Inhibitory effect of berberine on the motivational effects of ethanol in mice

It is believed that drug-induced rewarding effects play an important role in the development of substance dependence. Recently, berberine was reported to inhibit the rewarding effects of drugs of abuse such as cocaine, morphine, and nicotine. Berberine is also demonstrated to modulate the activity of several neurotransmitter systems like, dopamine, nitric oxide, serotonin, and NMDA, which are implicated in rewarding effects of ethanol. Hence, we hypothesized that berberine may modulate the ethanol-induced rewarding effects. Therefore, we studied the effect of berberine on locomotor sensitization, conditioned place preference (CPP), and ethanol drinking preference in mice. The results revealed that acute administration of berberine (2.5, 5, and 10 mg/kg, i.p.) dose dependently reduced locomotor stimulant effect of acute ethanol and expression of sensitization to locomotor stimulant effect of ethanol. Further, pretreatment with berberine (2.5, 5, and 10 mg/kg, i.p.) prior to each dose of ethanol, blocked the development as well as expression of sensitization to locomotor stimulant effect of ethanol. In another set of experiment, treatment with berberine (5 and 10 mg/kg, i.p.) reduced the induction and expression of ethanol-induced CPP in mice. In addition, berberine in these doses also reduced preference to ethanol drinking over water, but did not alter the general reward. In conclusion, the results of the present study revealed that berberine attenuates ethanol-induced rewarding effects in mice and that could be attributed to its neuro-modulatory action.

Inhibitory influence of mecamylamine on the development and the expression of ethanol-induced locomotor sensitization in mice

Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5–2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanol-induced locomotor sensitization.

Ethanol‐ and cocaine‐induced locomotion are genetically related to increases in accumbal dopamine

Neuroanatomical research suggests that interactions between dopamine and glutamate within the mesolimbic dopamine system are involved in both drug-induced locomotor stimulation and addiction. Therefore, genetically determined differences in the locomotor responses to ethanol and cocaine may be related to differences in the effects of these drugs on this system. To test this, we measured drug-induced changes in dopamine and glutamate within the nucleus accumbens (NAcc), a major target of mesolimbic dopamine neurons, using in vivo microdialysis in selectively bred FAST and SLOW mouse lines, which were bred for extreme sensitivity (FAST) and insensitivity (SLOW) to the locomotor stimulant effects of ethanol. These mice also show a genetically correlated difference in stimulant response to cocaine (FAST > SLOW). Single injections of ethanol (2 g/kg) or cocaine (40 mg/kg) resulted in larger increases in dopamine within the NAcc in FAST compared with SLOW mice. There was no effect of either drug on NAcc glutamate levels. These experiments indicate that response of the mesolimbic dopamine system is genetically correlated with sensitivity to ethanol- and cocaine-induced locomotion. Because increased sensitivity to the stimulating effects of ethanol appears to be associated with greater risk for alcohol abuse, genetically determined differences in the mesolimbic dopamine response to ethanol may represent a critical underlying mechanism for increased genetic risk for alcoholism.

Infusions of acetaldehyde into the arcuate nucleus of the hypothalamus induce motor activity in rats

Aims The hypothalamic arcuate nucleus (ARH) is one of the brain regions with the highest levels of catalase expression. Acetaldehyde, metabolized from ethanol in the CNS through the actions of catalase, has a role in the behavioral effects observed after ethanol administration. In previous studies acetaldehyde injected in the lateral ventricles or in the substantia nigra reticulata (SNR) mimicked the behavioral stimulant effects of centrally administered ethanol. Main methods In the present study we assessed the effects of acetaldehyde administered either into the ARH into a dorsal control or into the third ventricle on locomotion and rearing observed in 30 min sessions in an open field. Key findings Acetaldehyde injected into the ARH induced horizontal locomotion and rearing for 20 min. In contrast, administration of acetaldehyde into a control site dorsal to the ARH did not have any effect on locomotion. Although acetaldehyde administration into the third ventricle also induced locomotion, the time course for the effect in this area was different from the time course following ARH injections. Acetaldehyde in the ARH produced a long lasting induction of locomotion, while with intraventricular injections the effects disappeared after 5 min. Significance The present results are consistent with previous studies demonstrating that acetaldehyde is an active metabolite of ethanol, which can have locomotor stimulant properties when administered in the ventricular system of the brain or into specific brain nuclei. Some brain nuclei rich in catalase (i.e.; SNR and ARH) could be mediating some of the locomotor stimulant effects of ethanol through its conversion to acetaldehyde.

Involvement of A2A receptors in anxiolytic, locomotor and motivational properties of ethanol in mice

We have shown previously that mice lacking the adenosine A2A receptor (A2AR) generated on a CD1 background self-administer more ethanol and exhibit hyposensitivity to acute ethanol. We aimed to investigate if the increased propensity of A2A(-/-) mice to consume ethanol is associated with an altered sensitivity in the motivational properties of ethanol in the conditioned place preference (CPP) and conditioned taste aversion (CTA) paradigms and with an altered development of sensitization to the locomotor effects of ethanol. We also tested their sensitivity to the anxiolytic effects of ethanol. Our results show that A2A(-/-) mice produced on a CD1 background displayed a reduced ethanol-induced CPP and an increased sensitivity to the anxiolytic and locomotorstimulant effects of ethanol, but they did not show alteration in ethanol-induced CTA and locomotor sensitization. Ethanol-induced CPP, ethanol consumption and the locomotor effects of ethanol were also tested in A2A(-/-) mice produced on a C57BL/6J background. Our results emphasized the importance of the genetic background because alteration in ethanol consumption and preference, ethanol-induced CPP and locomotor-stimulant effects were not found in knockout mice produced on the alcohol-preferring C57BL/6J genetic background. Finally, the A2AR agonist, 2-p-(2-carboxyethyl)-phenylethylamino-50-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680), reduced ethanol consumption and preference in C57BL/6J mice. In conclusion, A2AR deficiency in mice generated on a CD1 background leads to high ethanol consumption that is associated with an increased sensitivity to the locomotor-stimulant/anxiolytic effects of ethanol and a decrease in ethanol-induced CPP.

Effects of cyanamide and acetaldehyde accumulation on the locomotor stimulant and sedative effects of ethanol in mice

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase.

Corticotropin releasing factor-1 receptor antagonist, CP-154,526, blocks the expression of ethanol-induced behavioral sensitization in DBA/2J mice

Rationale Manipulation of glucocorticoid receptor signaling has been shown to alter the acquisition and expression of ethanol-induced locomotor sensitization in mice. It is unknown if other components of the hypothalamic–pituitary–adrenal (HPA)-axis modulate locomotor sensitization resulting from repeated ethanol administration. In the present investigation, we determined if pretreatment with an i.p. injection of CP-154,526, a selective corticotropin releasing factor (CRF) type-1 receptor antagonist, would block the acquisition and/or expression of ethanol-induced locomotor sensitization in male DBA/2J mice. Methods To assess the role of the CRF 1 receptor in the acquisition of behavioral sensitization, mice were pretreated with an i.p. injection of CP-154,526 30 min before each of 10 sensitizing i.p. injections of ethanol. To determine the role of the CRF 1 receptor in modulating the expression of ethanol-induced sensitization, mice that had previously been sensitized to the locomotor stimulant effects of ethanol were pretreated with CP-154,526 30 min before an i.p. injection of ethanol on the test day. In a third study, ethanol-naïve mice were pretreated with CP-154,526 30 min before an initial i.p. injection of ethanol to determine the combined effects of the CRF 1 receptor antagonist and ethanol on locomotor activity. Blood ethanol concentrations were assessed at the termination of sensitization studies. Results Pretreatment with CP-154,526 blocked the expression of ethanol-induced locomotor sensitization in DBA/2J mice but did not prevent the acquisition of sensitization. The ability of CP-154,526 to block the expression of ethanol-induced locomotor sensitization was not attributable to alterations in blood ethanol levels or possible sedative effects produced by the combined administration of CP-154,526 and ethanol. Conclusions These data provide novel evidence that CRF 1 receptor signaling modulates the expression of ethanol-induced locomotor sensitization, and add to a growing literature suggesting a role for neurochemicals and hormones associated with the HPA-axis in behavioral sensitization resulting from repeated exposure to drugs of abuse.