Locomotor Stimulant Effects Of Ethanol Research Articles

Ethanol, But Not the Anxiolytic Drugs Buspirone and Diazepam, Produces a Conditioned Place Preference in Rats Exposed to Conditioned Fear Stress

The present study was designed to investigate the role of an anxiolytic effect in the development of a drug-associated place preference in rats exposed to conditioned fear stress, using the conditioned place-preference paradigm. The administration of a low dose of ethanol (300 mg/kg, IP) and the anxiolytic drugs, buspirone (1 and 2 mg/kg, IP) and diazepam (1.25 and 2.5 mg/kg, IP), did not produce a place preference in rats that were not exposed to conditioned fear stress. In rats that were exposed to conditioned fear stress, ethanol produced a significant place preference, while buspirone and diazepam failed to produce a place preference. In addition, ethanol, buspirone, and diazepam produced no place preference in rats treated with an anxiogenic dose of pentylenetetrazole (20 mg/kg, IP). A significant decrease in locomotor activity was observed in rats exposed to conditioned fear stress. Ethanol, but not buspirone and diazepam, significantly recovered or increased locomotor activity in rats exposed to conditioned fear stress. Further, the locomotor-stimulating effect of ethanol was markedly enhanced by repeated exposure to conditioned fear stress. These results suggest that the stimulating effect may be strongly related to the development of the rewarding effect of a low dose of ethanol under psychological stress, and that the conditioned place preference paradigm with conditioned fear stress may be useful for studying the rewarding mechanism of ethanol with regard to the interaction between ethanol and psychological stress.

Dizocilpine (MK-801) prevents the development of sensitization to ethanol in DBA/2J mice.

DBA/2J mice repeatedly exposed to ethanol (2 g/kg, i.p. every 48 h for 8 days) exhibit sensitization to the locomotor stimulant effects of ethanol. Pretreatment with the NMDA receptor antagonist dizocilpine (0.2-0.3 mg/kg, i.p.) completely prevents the development of sensitization. Thus, NMDA receptors appear to play an important role in behavioural sensitization to ethanol.

Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice.

Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA(A) and GABA(B) agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA(B) receptors, but not GABA(A) receptors, in development of sensitization to the locomotor stimulant effects of ethanol.

Duration of sensitization to the locomotor stimulant effects of ethanol in mice.

Behavioral sensitization to the psychomotor stimulant effects of some drugs can be quite persistent, lasting for weeks to months after cessation of drug exposure. We investigated the duration of sensitization to the locomotor stimulant effects of 2.0 g/kg ethanol (EtOH) and determined whether repeated EtOH administration would lead to alterations in blood EtOH clearance rates. Female mice were injected (IP) daily for up to 10 consecutive days with saline or EtOH. Baseline activity and acute EtOH locomotor responses were evaluated in Omnitech automated activity monitors (10-min test), with horizontal distance traveled as the measure of locomotion. Locomotor activity response to EtOH was reevaluated immediately after the final daily EtOH injection, and at 5-day intervals during which no EtOH was administered. Tail blood samples for determination of blood ethanol concentrations (BECs) were collected from EtOH-treated mice at the end of activity sessions. Sensitization lasted for up to 29 days, and in two of three of the behavioral sensitization studies, repeated EtOH treatment resulted in elevated BECs. There was no significant effect of repeated EtOH exposure on EtOH clearance rate in a study involving no behavioral testing. The demonstration of persistent behavioral sensitization may imply a lasting hypersensitivity of certain neural pathways to EtOH, thus increasing the reinforcing value of EtOH and the probability of relapse to EtOH drinking after abstinence.

Neurochemical Bases of Locomotion and Ethanol Stimulant Effects

The locomotor stimulant effect produced by alcohol (ethanol) is one of a large number of measurable ethanol effects. Ethanol-induced euphoria in humans and locomotor stimulation in rodents, a potential animal model of human euphoria, have long been recognized and the latter has been extensively characterized. Since the euphoria produced by ethanol may influence the development of uncontrolled or excessive alcohol use, a solid understanding of the neurochemical substrates underlying such effects is important. Such an understanding for spontaneous locomotion and for ethanol's stimulant effects is beginning to emerge. Herein we review what is known about three neurochemical substrates of locomotion and of ethanol's locomotor stimulant effects. Several lines of research have implicated dopaminergic, GABAergic, and glutamatergic neurotransmitter systems in determining these behaviors. A large collection of work is cited, which strongly implicates the above-mentioned neurotransmitter substances in the control of spontaneous locomotion. A smaller, but persuasive, body of evidence suggests that central nervous system processes utilizing these transmitters are involved in determining the effects of ethanol on locomotion. Particular emphasis has been placed on the mesolimbic ventral tegmental area to nucleus accumbens dopaminergic pathway, and on the ventral pallidum/substantia innominata, where GABA and glutamate have been found to play a role in altering the activity of this dopaminergic pathway. Research on ethanol and drug locomotor sensitization, increased responsiveness to the substance with repeated administration, is also reviewed as a process that may be important in the development of drug addiction.

Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization

The effect of the dopamine receptor antagonist haloperidol on the development of sensitization to ethanol-induced increases in locomotor activity was examined in DBA/2J mice. In Experiment 1, different groups of mice were given saline or ethanol (2 g/kg) immediately before each of four locomotor activity sessions (48-h intervals), and 1 h after pretreatment with saline, 0.10 or 0.15 mg/kg haloperidol. During a subsequent test, mice showed locomotor sensitization despite blockade of ethanol stimulated activity by haloperidol on the first conditioning trial. Moreover, test session activity was reduced in subjects that had previously received haloperidol, even though haloperidol was not present during testing. The second experiment examined the nature of the latter finding by comparing subjects that received equal exposure to haloperidol but differed in the pairing of its administration with the activity chambers. After four conditioning trials, each group was tested in the absence of haloperidol. Mice that had previously received haloperidol paired with the activity chambers were less active than control groups, suggesting development of a conditioned suppression of activity. Overall, these results suggest a dissociation of the neurobiological mechanisms that mediate the acute locomotor stimulant effects of ethanol and those mediating sensitization. Further, these studies illustrate the importance of antagonist-alone control groups that assess the possible influence of associative learning induced by the antagonist itself.

Ethanol sensitivity of brain NMDA receptors in mice selectively bred for differences in response to the low-dose locomotor stimulant effects of ethanol.

Brain NMDA receptor responses and their sensitivity to ethanol in vitro were determined in replicate lines of FAST and SLOW mice, selectively bred for differences in sensitivity to the locomotor stimulant effects of a low dose of ethanol. L-Glutamate-stimulated increases in the intracellular free calcium concentration (Cai) were determined in microsacs, a cell-free brain membrane preparation, isolated from hippocampus or cerebral cortex. Previous work showed that L-glutamate-stimulated increases in Cai in microsacs are mediated by activation of NMDA receptors. The concentration response for L-glutamate-stimulated increases in Cai did not differ between the lines in either hippocampal or cerebrocortical microsacs. Ethanol produced a concentration-dependent decrease in L-glutamate-stimulated increases in Cai in hippocampal and cerebrocortical microsacs from SLOW mice, but this effect of ethanol was reduced or absent in microsacs isolated from FAST mice. Resting Cai and the ability of a high ethanol concentration to increase resting Cai did not differ between the lines. These results suggest that differences in the sensitivity of brain NMDA receptors to the effects of ethanol determine, at least in part, differences in the locomotor stimulant effects of low doses of ethanol in FAST and SLOW mice. These differences are not due to ethanol effects on resting Cai.

Chronic effects of ethanol on central adenosine function of mice

Chronic ingestion of 5% ethanol had no significant effect on open field locomotor of NIH Swiss strain male mice, nor were the depressant effects of a non-selective adenosine receptor agonist, NECA, or the stimulant effects of a non-selective antagonist, caffeine significantly altered. The density of cerebral cortical A 1-adenosine receptors and of nitrendipine binding sites on calcium channels were significantly increased after chronic ethanol, while the density of striatal A 2a-adenosine receptors were unchanged. The locomotor stimulant effects of ethanol (2.5 g/kg) were slightly decreased after chronic ethanol, but were markedly reduced in mice after chronic caffeine ingestion. The results suggest some involvement of adenosine systems in the effects of ethanol.

Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization

Selectively bred FAST mice are highly susceptible, while SLOW mice are less susceptible, to the locomotor stimulant effects of ethanol. Heritability estimates indicate that approximately 15% of the variance in the FAST lines is of additive genetic origin, while low susceptibility is ostensibly nonheritable. Inbreeding has increased at the rate of 2% per generation, but fertility has been unaffected. Measurement reliability for sensitivity to this ethanol effect was high when measured in both circular (r = 0.6) and square (r = 0.7) open-fields. In addition, our results indicate that we have selected for differences in sensitivity to ethanol rather than for differences in habituation to the test environment. The difference in response to ethanol between FAST and SLOW mice extended to tests varying in duration, and to a range of ethanol doses. We conclude that the divergence between FAST and SLOW mice generalizes to related test parameters, and speculate that the genetic architecture underlying the locomotor stimulant response may be simpler than previously proposed.

Attenuation of the effects of ethanol on social behavior by alpha 2-adrenoceptor antagonists

In a social behavior test in mice ethanol (2 g/kg) significantly reduces the time spent in social interaction and increases locomotor activity. The relatively selective alpha 2-adrenoceptor antagonists atipamezole and idazoxan alone have no significant effect on either social interaction or locomotor activity in this test. However, when coadministered with 2 g/kg ethanol, atipamezole (0.3–3.0 mg/kg) significantly attenuated the ethanol-induced reduction in the time spent in social interaction without any effect on ethanol's locomotor stimulant action. Idazoxan (0.3–1.0 mg/kg) also showed a trend towards reversing the reduction in the time spent in social interaction although this was accompanied by a significant attenuation of the locomotor stimulant effect of ethanol. The results indicate that alpha 2-adrenoceptors may modulate ethanol's effects on social interaction in mice.