Animal Models and the Cognitive Effects of Ethanol

Merle G. Paule

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Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press/Taylor & Francis; 2006.

Animal Models of Cognitive Impairment.

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Chapter 5Animal Models and the Cognitive Effects of Ethanol

Merle G. Paule.

Author Information and Affiliations

Background

Ethanol (ethyl alcohol, alcohol) has been widely studied in many different formats and at many levels of complexity. Given the wealth of available information, this brief chapter cannot begin to recapitulate the literature on the many and varied facets of ethanol. For a solid introduction to the history of the use of ethanol as a research tool and details on its general absorption, distribution, metabolism, excretion, and toxicology, we refer the reader to the informative and interesting chapter in the recent edition of Goodman and Gilman [1].

Ethanol is unique among the psychoactive compounds available for human consumption: it is widely available, its use is legal and acceptable in many societies, and it takes relatively large (i.e., gram) quantities to exert pharmacological and other effects. Of all the psychoactive drugs available to humans, ethanol is implicated in the greatest number of accidents [2]. Decrements in human psychomotor performance appear to be due primarily to ethanol’s effects on cognitive (central) mechanisms rather than motor (peripheral) components [2], and tasks that are more complex are likelier to be affected by small doses. The consensus is that ethanol causes deterioration in driving skills at or below blood alcohol concentrations of 0.05 g/100 ml and that such impairment increases significantly as these levels increase [2].

Perhaps importantly, the psychotropic effects of ethanol change along a dose continuum; thus, it can be classified as a stimulant, an anxiolytic, a sedative, a muscle relaxant, a euphoriant, and a general anesthetic that can cause coma and death if a large enough dose is given. While many of these effects would, for other drugs, be considered “therapeutic effects,” the only recognized clinical use of systemically administered ethanol is the treatment of poisoning by methyl alcohol or ethylene glycol. Dehydrated ethanol might also be used via proximal injection to destroy nerves or ganglia to relieve long-lasting pain related to trigeminal neuralgia, inoperable cancer, etc. [1].

Ethanol is primarily a central nervous system (CNS) depressant; however, “behavioral disinhibition” as a result of the effects of ethanol on some brain areas/functions is often interpreted as “stimulation.” Some researchers [3] have presented convincing evidence that, at low doses and soon after exposure, ethanol acts along a continuum of stimulation leading to depression. The observations supporting this thesis [4] show that, in rats trained to discriminate pentobarbital from amphetamine using a two-choice lever-pressing procedure, ethanol produced a greater number of amphetamine-appropriate responses than pentobarbital-appropriate responses when testing occurred within 15 min of exposure. Tests on humans [4] show that relatively low doses of ethanol (0.33 g/kg) can actually enhance performance in reaction time and visual search tasks: the results of these tests showed that accuracy was improved while response speed was not affected. Still others report [5] that the dose of ethanol is important, with memory facilitation occurring at low doses but impairment predominating at moderate to heavy doses. In addition, the effects of ethanol on memory may be different on the ascending arm, as opposed to the descending arm, of the blood alcohol curve.

Chronic exposure to ethanol can lead to tolerance, physical dependence, and alcoholism, and a number of animal models have been developed to study aspects of these important consequences of continued ethanol exposure [6]. When such exposure occurs during pregnancy, offspring can suffer teratological outcomes in the form of the fetal alcohol syndrome (FAS) or the fetal alcohol effects syndrome (FAES). Prenatal ethanol exposures in animal models have been shown to produce data in good congruence with respect to qualitative endpoints observed in humans [7, 8]. The focus of this chapter, however, is to present information on the acute —rather than chronic — effects of ethanol on the function of the CNS.

Because of the disruptive and debilitating effects of ethanol on a multitude of cognitive functions in animals, acute ethanol intoxication is used as a model of amnesia in which the effects of antiamnestic compounds are assessed [9, 10]. Generally, animals are treated with significant doses of ethanol (e.g., 2.0 g/kg) prior to training in a variety of tasks in which ethanol disrupts aspects of learning, and then potential antiamnestic agents are given concomitantly to determine whether the effects of ethanol can be attenuated [9]. In addition, the involvement of specific anatomical substrates in ethanol-induced amnesia have been explored [11], with the hippocampal formation being strongly implicated. Ethanol has been shown to affect specific neurotransmitter levels (i.e., reduced glutamate levels in the dorsal hippocampus), and such changes sometimes have strong relationships with alterations in important aspects of cognitive function such as spatial memory deficits [11].

Behavioral Effects in Animal Models

Relevance

The metabolism of ethanol by a variety of animals (e.g., squirrel monkeys) is generally similar to that of humans [12]. In addition, the effects of ethanol on similar behaviors — such as eye tracking — are similar in both monkeys and humans [13]. Thus, animal models can provide relevant information about specific effects of ethanol that might be expected to manifest in humans. This is particularly true when the tasks utilized are appropriate for use in both the animal models and humans [14, 15].

Mechanism(s) of Action of Ethanol

Subjective Effects: Drug Discrimination Studies

While the cellular/receptor mechanisms underlying ethanol’s effects on neuronal function can be studied in vitro using a variety of neurotransmitter-receptor binding techniques, its psychoactive properties provide opportunity for extensive assessment using whole-animal models. Psychoactive compounds are thought to produce relatively specific interoceptive cues to which both human and animal subjects can attend. Both animals and people can be trained to make a specific response (e.g., press the rightmost of two response levers) in the presence of one drug (e.g., ethanol) and another response (press the leftmost lever) in the absence of that drug or in the presence of another drug. Once reliable responding has been established (the correct lever for the given drug condition is selected a high percentage of the time), then the ability of other compounds to substitute or generalize to the training drug(s) can be assessed. Such drug-discrimination studies have proved invaluable in providing insight into the neural substrates via which centrally acting drugs exert their effects. In addition, data obtained from drug-discrimination studies in animals have been found to be in good accord with those obtained in humans, in that findings are qualitatively similar across species and that potency relationships are quantitatively similar between most, but not all, other species and humans [16, 17]. Thus, data obtained from animal studies can be relevant to the human condition.

In rats trained to discriminate ethanol or pentobarbital from the “no drug” condition, both drugs substituted for each other, thus demonstrating the similarity, if not equivalence, of the internal or interoceptive cue of both agents and, thus, the mechanism of action. However, rats could also be trained to discriminate each drug from the other, demonstrating that the two drugs do differ in their interoceptive cues [18]. Other studies in rats showed that low doses of ethanol (0.10 g/kg) substituted more for amphetamine than pentobarbital, while higher doses of ethanol (0.20 g/kg) substituted for pentobarbital [3]. These results demonstrate that there are dose-dependent effects on different neurochemical systems and that biphasic effects can be observed. In squirrel monkeys trained to discriminate ethanol from saline, several ethanolic drinks (bourbon, gin, beer, vodka, and red wine) and both pentobarbital and barbital substituted for ethanol, whereas morphine did not [19]. Thus, ethanol shares properties with a variety of ethanolic drinks but not with the opiate, morphine. Interestingly, several other ethanolic drinks (cognac, scotch, and tequila) engendered a response different from that of ethanol, suggesting differences salient enough from the training dose of ethanol (1.6 g/kg) to be detected by some subjects. In novel drug-discrimination experiments in rats examining the early “excitatory” phase of ethanol’s “subjective” effects (i.e., 6 min after administration) and the later or “sedative” phase (30 min after administration), it was demonstrated that the mu-opiate-receptor antagonist naloxone significantly attenuated discrimination of ethanol’s excitatory stimulus effects but not its sedative effects [20]. These data clearly indicate that the behavioral effects of ethanol are complicated and vary as a function of time after exposure.

Opioids

In studies to explore the potential role of endogenous opioid systems in the discriminative stimulus of ethanol, a series of opioid antagonists was administered to rats trained to discriminate ethanol from saline [21]. Of the two mu-opioid-receptor antagonists tested (naloxone and cyprodime), only naloxone — and only at a high dose — partially, but significantly, antagonized the ethanol cue; cyprodime was without effect. The delta-opioid-receptor antagonist naltrindole and the kappa-opioid-receptor antagonist norbinaltorphimine were both without effect in altering the ethanol cue; thus, it appears that, at most, the ethanol interoceptive stimulus is minimally dependent on its interaction with endogenous opioid systems.

Dopamine and Serotonin

In rats trained to discriminate ethanol from saline, a variety of dopaminergic and serotonergic agonists and antagonists were used to explore the involvement of these two systems in ethanol’s effects [22]. None of the dopaminergic treatments utilized had an effect on the ethanol discrimination, but several 5-HT agonists (quipazine, 5-MeODMT [5-Methoxy-Nn-Dimethyltryptamine], buspirone, and 8-OH-DPAT [8-Hydroxy-2-di-n-propylamino-tetralin]) engendered intermediate ethanol-like responding, and the 5-HT1B-receptor agonist TFMPP (1-(3-trifluoromethylphenyl) piperazine) completely substituted for ethanol. In experiments designed to further explore the role of 5-HT receptors in the ethanol stimulus [23], the researchers used four 5-HT agonists with different selectivity for 5-HT1A, 5-HT1B, and 5-HT2C receptors to determine their ability to generalize to ethanol. The most selective 5-HT1B agonist tested (CGS 12066B [7-trifluoromethyl-4(4-methyl-1-piperazinyl) pyrnol [1,2-a]-quinoxaline dimaleate]) completely substituted for 1.0 g/kg ethanol, but not for higher training doses. The 5-HT1B/2C agonist mCPP (M-Chlorophenylpiperazine) also substituted for the 1.0-g/kg training dose but not for higher training doses. The 5-HT1A/1B agonist RU-24969 substituted for all training doses of ethanol (although not to as great a degree for the highest training dose of 2.0 g/kg), and the 5-HT1A agonist 8-OH-DPAT did not substitute for any training dose of ethanol. The upshot of these studies is that agonists with 5-HT1B activity produce effects similar to those of relatively low (1.0 g/kg) and intermediate (1.5 g/kg) training doses of ethanol but not higher doses.

In studies to explore the role of 5-HT3 receptors in the mediation of the interoceptive stimulus of ethanol in rats, Stefanski et al. [24] administered the 5-HT3 antagonists tropisetron and ondansetron, but they were unable to antagonize the ethanol cue. In addition, the 5-HT3-receptor agonist 1-(m-chlorophenyl)-biguanide did not generalize to ethanol. These data argue against a strong role for the 5-HT3 receptor in subserving the stimulus properties of ethanol.

Gamma-Aminobutyric Acid (GABA)

In mice trained to discriminate ethanol from saline, the inhalants toluene, halothane, and TCE (1,1,1,-trichloroethylene) and the benzodiazepine oxazepam all substituted for ethanol [25]. Thus, a gaseous anesthetic, some abused solvents, and an anxiolytic share behavioral effects with ethanol, and all of these compounds have been shown to produce pentobarbital-like discriminative stimulus effects, suggesting that these agents have a common mechanism of action at GABA receptors [26]. In later studies [27], it was further demonstrated that the volatile anesthetics desflurane, enflurane, isoflurane, and ether all produce ethanol-like discriminative stimuli in mice, furthering the tenet that these agents are all ethanol-like in their effects. In rats trained to discriminate either pentobarbital, ethanol, diazepam, or lorazepam from the no-drug condition, substitution experiments indicated that two pregnanolone-derived neuroactive steroids generalized completely to pentobarbital, ethanol, and diazepam but not lorazepam. These data indicated that endogenous steroids exhibit properties that are consistent with sedative/anxiolytic activities and that these effects are likely mediated through a nonbenzodiazepine GABA-A site [28].

In rats trained to discriminate ethanol or gamma-hydroxybutyrate (GHB) from water, both compounds were found to substitute completely for the other, albeit only over a narrow dose range [29]. Thus, at least under circumscribed doses, the mechanisms subserving the discriminative stimuli for each compound appear to be shared extensively.

In studies in monkeys trained to discriminate pentobarbital from saline, ethanol was found to generalize to pentobarbital, demonstrating that the ethanol and barbiturate internal cues are similar in the primate. In addition, it was shown via isobolographic analyses that the effects of pentobarbital and ethanol were dose additive, not synergistic [30], suggesting that the same receptor was involved in the effects of both agents. In rats trained to discriminate ethanol, dizocilpine (MK-801, a noncompetitive inhibitor of the N-methyl-D-aspartate [NMDA] subtype of glutamate receptor), and water in a three-choice drug-discrimination paradigm, it was demonstrated that the GABA-A mimetics (modulators) allopregnanolone, diazepam, and pentobarbital all substituted completely for ethanol, whereas phencyclidine (PCP, a noncompetitive inhibitor of the NMDA-receptor complex) substituted completely for dizocilpine. Neither RU-24969 (a 5-HT1A/1B agonist) nor TFMPP (a 5-HT1B agonist) completely substituted for either ethanol or dizocilpine. RU 24969 partially (≈60%) substituted for ethanol. Thus, these data showed that it is possible to tease out the involvement of the NMDA system in ethanol’s discriminative stimuli even while GABA-A receptor mechanisms remained involved [31].

Glutamate

MK-801 was shown to have ethanol-like stimulus properties in rats [32, 33], confirming similar observations in pigeons and bolstering the premise that part of the ethanol interoceptive cue is mediated by blockade of the NMDA-receptor complex. In rats trained to an NMDA discrimination, ethanol failed to antagonize the NMDA cue and did not substitute fully for either the competitive NMDA antagonist NPC 12626 or the noncompetitive antagonist phencyclidine (PCP); a maximum of about 50% PCP-appropriate responding indicated partial substitution [34]. It was concluded that ethanol’s effects on NMDA discrimination were distinct from competitive antagonists but similar to those of noncompetitive antagonists.

Further support for the involvement of the NMDA receptor in mediating the interoceptive ethanol cue comes from generalization studies in rats whereby MRZ 2/579, a novel uncompetitive NMDA-receptor antagonist [35], dose dependently generalized to the ethanol cue. Bienkowski et al. [36] showed that in rats trained to discriminate 1.0 g/kg ethanol from saline, dizocilpine and CGP 37849 (another competitive NMDA-receptor antagonist) substituted partially, and CGP 40116 (a competitive NMDA-receptor antagonist) and the active D-stereoisomer of CGP 37849 completely substituted for ethanol. These same authors [37] assessed the ability of N-methyl-D-aspartate and D-cyloserine (a partial agonist at the glutamate binding site) to antagonize the discriminative stimulus of ethanol. Neither compound antagonized the ethanol interoceptive cue in the rat, indicating that at least some agonists at the NMDA receptor do not block ethanol’s discriminative stimulus.

Ethanol is known to be a potent inhibitor of the NMDA receptor in a variety of brain areas. Patch-clamp recordings from cells in culture have shown that ethanol does not appear to interact with NMDA at either the glutamate recognition site of the receptor or at any of the known modulatory sites such as the polyamine or glycine site [38]. Ethanol does not cause blockade of open ion channels and does not interact with magnesium ions at the site where Mg²⁺ causes open channel block. Molecular biological techniques have shown that the ability of ethanol to inhibit responses to NMDA is dependent on the subunit makeup of the NMDA receptor, with the NR1/NR2A and NR1/NR2B combinations being preferentially sensitive to inhibition by ethanol [38]. Chronic exposure to ethanol increases the number of NMDA receptors and facilitates the receptor function, which is thought to cause withdrawal-related seizures after cessation of exposure [38].

In further studies on the pharmacology of the ethanol-discriminative stimulus in rats, Bienkowski et al. [39] assessed the effects of compounds from another class of NMDA-receptor antagonists: glycine-, strychnine-insensitive receptor (glycine B site) antagonists. The generalization of the selective glycine B site antagonists, L-701,324 and MRZ 2/576, and memantine (a noncompetitive antagonist at the NMDA-receptor ion-channel site) were assessed in animals trained to discriminate ethanol from saline. Memantine and L-701,324 substituted for ethanol, whereas MRZ 2/576 produced only half-maximal (≈50%) ethanol-appropriate responding. Glycine did not antagonize the ethanol stimulus. Thus, it appeared that glycine-, strychnine-insensitive site antagonists may induce some ethanol-like stimuli in rats. However additional studies indicated that neither the glycine antagonists L-701,324 or MRZ 2/502, the polyamine-site antagonist arcaine, nor the polyamine-site ligand spermidine substituted for ethanol [40]. These authors also demonstrated dose-dependent generalization of the NMDA-receptor ion-channel blockers dizocilpine, memantine, and phencyclidine (PCP) as well as the sigma1-receptor antagonists (+)–pentazocine and (+)–N-allyl-normetazocine (NANM) to ethanol. Thus it appears that some of the acute effects of ethanol are mediated via both NMDA receptors and sigma1-binding sites.

Using compounds thought to inhibit the release of glutamate (lamotrigine and riluzole), it was demonstrated that lamotrigine but not riluzole substituted for the ethanol discriminative stimulus in rats [41]. The authors suggested that the noted difference between these two compounds to generalize to ethanol was likely due to the ability of lamotrigine, but not riluzole, to inhibit voltage-gated calcium channels.

Calcium Channels

In rats trained to discriminate ethanol from water, the L-type calcium channel antagonist isradipine was found to block ethanol discrimination in a dose-dependent manner [42]. It was also demonstrated that isradipine completely and dose-dependently inhibited the ethanol cue in a two-choice maze procedure, whereas the dopaminergic antagonist haloperidol did not [42]. Thus, these data argue for a role of L-type calcium channels in the ethanol interoceptive cue.

Acetylcholine

It has been shown in rats that neither nicotine nor the nicotinic acetylcholinergic-receptor antagonist, mecamylamine, substituted for ethanol and that mecamylamine did not antagonize the ethanol stimulus [43]. Therefore it seems unlikely that the neurotransmitter acetylcholine plays a significant role in the ethanol-discriminative stimulus.

System Interactions

Given that a preponderance of the literature suggests an involvement of both GABA-A and NMDA receptors in the ethanol discriminative stimulus, subjects were trained to discriminate a combination of the GABA-A agonist, diazepam, and the NMDA antagonist, ketamine, from vehicle [44]. In animals so trained, diazepam and ketamine both generalized completely to the mixture, and ethanol was almost completely substituted. These findings were taken to indicate that simultaneous GABA-A agonism and NDMA antagonism produce a greater ethanol-specific discriminative stimulus than activation of either component individually.

Recently, it has been demonstrated that several neuroactive steroids are potent modulators of a number of membrane receptors, including GABA-A, NMDA, 5-HT3, and sigma1 receptors. To further explore the pharmacology of these compounds, drug-discrimination procedures in rats were used to assess the generalization of pregnanolone to a variety of other agents [45]. Neither the opiate agonist morphine nor the negative GABA-A modulator, dehydroepiandrosterone, substituted for the pregnanolone cue, whereas all of the tested GABA-A-positive modulators did; these included allopregnanolone, epipregnanolone, androsterone, pentobarbital, midazolam, and zolpidem. Direct GABA-A-site agonists, including muscimol, did not generalize to pregnanolone, but ethanol and the sigma1-receptor agonist SKF-10047 generalized completely. The NMDA-receptor antagonist MK-801 partially substituted, but the 5-HT3 antagonist tropisetron did not. The 5-HT3 agonist SR 57227A completely substituted for pregnanolone, but another 5-HT3 agonist (m-chlorophenylbiguanide) produced only partial substitution. These observations suggest that (a) positive GABA-A modulation, but not direct agonism, confers a discriminative stimulus effect similar to that of pregnanolone and (b) antagonism of NMDA receptors and activation of 5-HT3 and sigma1 receptors modulate stimulus effects similar to the pregnanolone cue. Here, the observation that ethanol generalized completely to pregnanolone provided further evidence that the interoceptive cue of ethanol likely involves both the GABA-A- and NMDA-receptor systems.

It was shown that for rats self-administering ethanol, the interoceptive cue was mediated by both the GABA-A- and NMDA-receptor systems, as evidenced by the ability of both pentobarbital (GABA-A-receptor modulator) and MK-801 or dizocilpine (a noncompetitive NMDA-receptor antagonist) to completely substitute for ethanol in rats trained to discriminate ethanol from saline [46].

Anatomy

The involvement of specific brain areas in the discriminative stimulus properties of ethanol has also been explored to some degree with direct application of the non-competitive NMDA antagonist MK-801 into the nucleus accumbens core (AcbC) or the CA1 region of the hippocampus, resulting in complete dose-related substitution for the ethanol discriminative stimulus in rats [47]. Infusion of MK-801 into either the amygdala or the prelimbic cortex (PrLC) did not substitute for ethanol, and neither did injection of the competitive NMDA antagonist CPP into the AcbC. The direct GABA-A agonist muscimol resulted in full ethanol substitution in a dose-related manner when injected into either the AcbC or the amygdala but not the PrLC. The findings from these studies support the notion that ethanol’s discriminative stimulus properties are mediated centrally by NMDA and GABA-A receptors in specific limbic brain regions and point to a strong role for the interplay between ionotropic GABA-A and NMDA receptors in the nucleus accumbens [47].

In rats, stimulation of GABA-A receptors in the nucleus accumbens (by local infusion of muscimol) results in full substitution for the ethanol discriminative stimulus. Blockade of GABA-A receptors in the amygdala (by local infusion of bicuculline) attenuates the ability of GABA-A agonism in the nucleus accumbens to substitute for the ethanol cue [48]. Thus, it would appear that the ethanol-like stimulus effects of GABA-A agonism in the nucleus accumbens are modulated by GABA-A-receptor activity in the amygdala.

Summary of the Discriminative Stimulus Properties of Ethanol

Some authors have postulated that the effects of lower doses of ethanol (≤0.5 g/kg in rats) are mediated via GABAergic systems; that at intermediate doses (0.75 to 2.0 g/kg) several other neurotransmitter systems are affected; and that at high doses nonspecific effects emerge, probably involving even more neurotransmitter systems [49]. A nice summary of the dose dependence of the ethanol interoceptive cue and its interaction with the GABA-A, 5-HT1, and NMDA systems can be found in Grant and Colombo [50], who suggest that at a lower ethanol dose of 1.0 g/kg, the discriminative stimulus is primarily subserved by GABA-A interaction, which decreases with dose such that at 2.0 g/kg, the stimulus is primarily subserved by the NMDA system. The 5-HT1 contribution appears to be present to about the same degree at several doses: 1.0, 1.5, and 2.0 g/kg [50]. Thus, the 5-HT1 mechanisms appear to occur at most doses, whereas GABA-A involvement appears greatest at lower doses and NMDA involvement appears greatest at higher doses. A review of ethanol’s interactions with a host of neurotransmitter gated ion channels [51] describes potential molecular mechanisms that may be relevant to its effects on the neurotransmitter systems identified via drug-discrimination studies.

Effects of Ethanol on Other Aspects of Cognition: Attention, Learning, and Memory

Attention/Impulsivity

Assessments of attention are often made using some form of continuous performance test (CPT; see Rosvold et al. [52]). This type of test is thought to provide metrics of attentional capacity (or vigilance) and requires subjects to respond in a selective fashion to a series of stimuli (usually visual in the form of shapes, colors, or lights for animals, and numbers or letters for humans) presented rapidly and for very short durations (e.g., 500 msec). Generally, subjects must attend to specific stimuli and respond accordingly when one is detected. In human tests, subjects might be asked to push a response key every time they see an X appear on a monitor. More difficult versions might require a response to an X only if it occurs immediately after an O. For the rat equivalent, subjects might be required to respond to one of several locations every time they detect illumination of a stimulus light at that location. The usual measures for this type of task include omission errors (misses), commission errors (false alarms), and latencies. Omission errors are thought to indicate deficits in attention or vigilance; commission errors are interpreted by many to represent aspects of impulsivity, since they are thought to result from anticipatory or incomplete processing of stimuli [53]; and response latencies are thought to provide metrics of processing requirements, psychomotor speed, or the level of difficulty of the discrimination. The application of signal detection analyses to CPT data can also provide measures of target stimulus discriminability and other measures such as response bias and strategy [53].

While research on the effects of ethanol on CPT performance in animals is scarce, Rezvani and Levin employed a similar operant visual-signal-detection task to examine the acute effects of ethanol in rats [54]. In that study, ethanol impaired performance by decreasing percent correct rejections and percent hits, suggesting an effect to impair sustained attention. Data from human CPT studies suggest that if the task is of sufficient difficulty, even small doses (≈0.035% breath alcohol concentration) can produce measurable alterations in task performance. These effects include decreased target stimulus discrimination, increased commission errors, and changes in response strategies. Such effects have even been noted in the absence of significant effects on percent correct detections or response latencies [53]. The observed effect of ethanol to increase errors of commission could be interpreted to mean that ethanol increases aspects of impulsivity. Along those lines, performance under differential reinforcement of low response rate (DRL) schedules has also been interpreted by some to yield metrics of impulsivity [55]. For DRL tasks, subjects are required to withhold a response — say a lever press for food — for a specific duration (e.g., 10 sec). Responding too early resets the time clock so that the possibility of reinforcement is delayed by another 10 sec. Treatments that are thought to increase “impulsive” behavior would be predicted to cause an increase in the number of early responses in this task. Thus, based on the interpretation that ethanol increased impulsivity in the 1999 study by Dougherty et al. [53], one might predict that ethanol should increase premature responses in DRL tasks. However, Popke et al. [56] reported that ethanol, over a wide range of doses, did not increase early responses in rats performing a DRL 10- to 14-sec task, and thus the prediction did not hold. On the other hand, nicotine did significantly increase premature responding in rats performing the exact same DRL task [57], and ethanol significantly enhanced this effect. Whether DRL responding can provide insight into aspects of behavior that somehow inform mechanisms underlying human impulsivity remains to be determined, but the findings for nicotine and nicotine plus ethanol are intriguing.

Conditioning

In adult rats, acute ethanol administration at 2.0 g/kg disrupts conditioning of a visual but not an olfactory discrimination, suggesting that the olfactory system in the rat might be much more resistant to chemical effects in this species. In addition, the 5-HT3-receptor antagonist MDL 72222 was not able to prevent the disruptive effects of ethanol on the conditioning of the visual discrimination, although it did ameliorate ethanol-induced hyperlocomotion [58]. Thus, while the effects of ethanol to increase locomotor activity appeared to be mediated by serotonergic involvement at the 5-HT3 receptor, its effects on visual discrimination (much like its ability to produce discriminative interoceptive stimuli, as noted previously) do not appear to involve those receptors.

In a similar study in preweanling (gestational day [GD] 21) rats, it was demonstrated that ethanol (1.5 g/kg) disrupted visual (brightness) but not olfactory conditioning [59]. These findings in young animals also support the proposition that the olfactory system is more resistant to perturbation than the visual system in the rat. Because the olfactory system becomes functional at birth, while the visual system does not become functional until approximately 15 days of age [59], it is possible that the differences in sensitivity noted in these younger animals are simply a reflection of the maturity of the two systems, with the more immature visual system being more susceptible to disruption at this age. Alternatively, it could be that because the olfactory system is likely so much more important to the rat than the visual system, it may be that the olfactory system is much more protected from perturbation than is the visual system.

Learning and Memory

Learning — the acquisition of new information — is critically important to the survival of organisms. A popular learning assessment procedure, the repeated acquisition (RA) of response sequences or behavioral chains [60], has been used in both human subjects [61] and animals [14, 15, 62] to repeatedly study learning in the same subjects, often for long periods of time. In these procedures, subjects are required to learn a new sequence of responses during each test session. Typically, a panel containing several response manipulanda (levers, press plates, response keys, etc.) is presented to the subject, and the subject must acquire (learn) a specific sequence of responses to obtain reinforcers (typically food for animals; money, credits, or other secondary reinforcers for humans). The correct sequence of responses changes such that subjects must learn new response sequences during every test session. In many RA studies, performance components alternate with acquisition components within the same test session. In the performance component, the correct response sequence is invariant (does not change from session to session), and responding in this component serves as a control for the motoric and motivational requirements of the acquisition component, in which the correct response sequence changes during each session. Ethanol significantly impairs accuracy (increases errors) in the learning component at doses that do not affect responding in the performance component [61, 63], suggesting a relatively selective effect of ethanol to disrupt active learning or new acquisition while leaving motoric function, motivation, and long-term procedural memory intact.

Working/Short-Term Memory

Working memory can be considered to be a type of short-term memory that can be described as the moment-to-moment maintenance, monitoring, and processing of information [64]. In the laboratory setting, working memory generally refers to the capacity to retain information across trials within a test session [65, 66]. Thus, the ability of subjects to perform spatial-alternation tasks (i.e., if a left choice was correct on one trial, then the right choice will be correct on the next trial) is an indication of working-memory integrity. In studies in rats, it has been shown that ethanol disrupts accuracy of performance in such tasks at plasma levels that would be within the legal limits for people driving cars [67]. It is interesting in this context that these authors also found that caffeine potentiated many of the adverse effects of ethanol (decreased accuracy) while normalizing other aspects of performance (intertrial intervals, length of pausing).

Working/short-term memory function in animals is typically studied using delayed-recall tasks that require subjects to discriminate and “encode” specific stimuli and then use that information to make choice responses that occur later (usually over the seconds-to-minutes range). Such tasks often employ visual-discrimination tasks such as delayed matching-to-sample (DMTS) and delayed non-matching-to-sample (DNMTS) procedures or position-discrimination tasks such as delayed spatial alternation (DSA). In a typical DMTS task, subjects are shown an initial or “sample” stimulus, like a red dot. After some period of presentation, or when the subject indicates that the stimulus has been observed, the sample is removed and a “recall delay” intervenes prior to the presentation of two or more choice stimuli, one of which matches the sample stimulus for that trial. A response to the choice stimulus that “matches” the sample stimulus is correct. While visual forms of this task can be used in a variety of species with good visual acuity, spatial versions have been developed for rodent species (e.g., delayed matching or non-matching-to-position [68]).

Other types of tasks also used in the assessment of learning and memory include a variety of mazes (e.g., Morris and Cincinnati water mazes [69] and radial arm mazes [70], in which subjects are given repeated opportunities to learn how to navigate to a goal point or points).

The basic approach in all of these procedures is to present subjects with information (cues, stimuli) that is to be held in working memory and recalled a short time later. Efficient encoding of information is thought to be heavily dependent on the constructs of attention and vigilance: if subjects are not paying attention to a given stimulus, or if they are distracted during the encoding of that stimulus, then the likelihood that it will be efficiently encoded is diminished. Over the short term (seconds to minutes), generally within a given session, such retrieval is thought to be dependent on working memory, whereas recall over longer periods of several hours and beyond is thought to be dependent on consolidation of more-permanent or long-lasting memory. For the purposes of discussion here, we will be focusing more on the acute effects of ethanol on short-term rather than long-term-memory issues.

Correct choice responding at zero or very short recall delays (1 to 2 sec) is thought to be a good metric of processes associated with attention/encoding; if choice accuracy is good, then encoding obviously occurred with efficiency. As recall delays are increased, then processes associated with working memory or retrieval are thought to play increasingly important roles in performance. The slope of the percent-correct choice versus recall-delay curve is taken to represent a quantitative aspect of working memory or memory retrieval; the intercept of this line with the y-axis (zero recall delay) is thought to represent primarily attentional or encoding processes. Thus, it can be envisioned that a drug or chemical could change the intercept (affect encoding/attention) but not alter the slope of the line (have no effect on rate of memory decay). Alternatively, if the intercept is unaffected by treatment but the slope is altered, then it could be posited that attention/encoding processes remained unaffected but that working memory/retrieval processes were affected. If both the intercept and the slope are altered, then all processes might be affected.

To examine the effects of ethanol on working memory in rhesus monkeys, Mello [71] utilized a titrating delayed-matching-to-sample (TDMTS) task, in which the recall delay increased or decreased as a function of a subject’s prior performance accuracy. While it was noted that performance accuracy decreased with increasing ethanol doses, working memory did not appear to be selectively impaired. That is, error frequency did not increase as a function of recall delay interval; errors generally clustered at the shorter delays, with animals performing accurately at longer delays, even with blood alcohol levels of >200 mg/100 ml. These observations support the notion that ethanol affected attentional/encoding processes to a greater degree than working memory/retrieval. In further support of this possibility, the findings of Melia and Ehlers [72] in 1989, obtained from squirrel monkeys performing a conditional discrimination task (correctness of choice dependent on the presence or absence of a conditional stimulus [sphere]), showed that the primary effects of ethanol were to decrease the discriminability of the stimuli-controlling behavior. This conclusion was based on a signal-detection analysis of their data and the demonstration that ethanol caused dose-related decreases in choice accuracy that were accompanied by decreases in the sensitivity of subjects to discriminate the stimuli in the absence of any response bias [72]. These findings are also in accord with those reported for humans, where ethanol caused dose-dependent declines in sensitivity of subjects to stimuli in a recognition task, with no accompanying change in response bias [73].

In other studies in monkeys (Macaca mulatta), it has been demonstrated that accuracy of recall was affected at a dose of ethanol (0.5 g/kg) that was lower than that needed (1.0 g/kg) to affect reaction times [74]. These same authors demonstrated that several aspects of eye movement (frequency of saccades; fixation periods [durations]; saccade excursion, velocity, and duration) are affected in a dose-dependent fashion, with several measures showing effects at relatively low doses (0.25 g/kg). These results were interpreted to mean that ethanol selectively affects cerebral substrates associated with visual attention [75]. However, subsequent studies in rats performing a delayed spatial-matching task showed that low doses of ethanol (0.25 and 0.50 g/kg) actually decreased the rate of forgetting [76]. Thus, processes associated with working memory or recall were clearly not adversely affected by ethanol at doses that affected attention or encoding.

In studies focusing more on aspects of long-term memory and consolidation processes, it was found that rats given high doses of ethanol (3 g/kg) immediately after training in either a shuttle (active) avoidance procedure or an inhibitory (passive) avoidance procedure performed no differently than controls when tested days later [77]. These results suggest that ethanol does not interfere with consolidation of short-term memory into long-term memory.

In a nonspatial visual matching-to-sample procedure in rats [78], it was determined that ethanol decreased both the ability of subjects to detect or respond to “sample” visual stimuli (decreased vigilance, attention, or encoding) and to retain information over time (caused a working-memory deficit). In addition, it was found that local infusion of ethanol directly into the medial septal area caused a selective decrease in choice accuracy as a function of recall delay without a concomitant decrement in sustained attention [78]. Thus, in this case, the medial septum appears to play an important role in working memory.

In an eight-arm radial-maze delayed test of working/short-term memory, rats were treated with ethanol prior to beginning their daily sessions. After entry into four of the eight arms, they were provided either a 15-sec or a 1-h delay prior to entry into the fifth arm. Ethanol was found to significantly impair recall at the 1-h delay but not the 15-sec delay [79], suggesting a disruption of short-term memory but not working memory.

Comparative Sensitivities of Different Cognitive Functions to the Effects of Ethanol

In rodent studies in which subjects performed a battery of food-reinforced operant behavioral tasks designed to simultaneously model a variety of complex brain functions, it was shown that ethanol selectively impaired aspects of cognition at doses that did not affect the ability of subjects to respond. The battery of tasks [56] consisted of:

A temporal-response differentiation (TRD) task to assess time perception
A differential reinforcement of low response rate (DRL) task to assess time perception and response inhibition/impulsivity
An incremental repeated acquisition (IRA) task to monitor learning
A conditioned position responding (CPR) task to assess auditory, visual, and position discrimination
A progressive ratio (PR) task to assess appetitive motivation

For the TRD task, subjects had to hold a response lever down for a minimum of 10 sec but no more than 14 sec. For the DRL task, subjects had to withhold responding (lever press) for at least 10 sec but not more than 14 sec. For the IRA task, subjects had to learn a new sequence of lever presses during each session, where sequence lengths were incremented from easy (press the correct one out of three levers) to increasingly difficult (up to six correct lever presses required to complete the response chain) as subjects demonstrated mastery of the easier sequences. For the CPR task, subjects had to respond on a left lever after presentation of a low-frequency tone or a low-intensity visual stimulus and on a right lever after presentation of a high-frequency tone or a high-intensity visual stimulus. For the PR task, subjects had to increase the amount of work (number of lever presses) emitted for each subsequent reinforcer: the first food pellet “cost” one lever press, the second cost two, the third cost three, and so on.

The most alcohol-sensitive behaviors in the battery were the DRL (time perception and response inhibition/impulsivity), CPR (auditory and visual discrimination), and PR (motivation) tasks, all of which were significantly disrupted by the same dose of ethanol (1.5 g/kg). The TRD (time perception) task was significantly affected as the dose of ethanol was increased, but the IRA (learning) task was never significantly affected over the dose range tested (up to 3.0 g/kg). Thus, it appears that at doses of ethanol that affect motivation to respond for food, the ability to inhibit responding (i.e., to maintain “impulse” control) as well as sensory discrimination, time perception, and active learning capabilities remains unaffected, with learning function seemingly the most resilient to disruption by ethanol. Reports in human subjects have also indicated that time perception is not significantly affected by ethanol [80]. In an excellent summary of the ethanol sensitivity of a variety of tasks in a variety of species including humans, Newland [81] has shown that tremor- and response-duration measures in monkeys are some of the most sensitive, showing effects at blood concentrations as low as ≈0.3 mg/ml. In contrast, learning tasks, eye tracking, and driving simulations in humans require blood alcohol concentrations of ≈0.8 to 1.2 mg/ml.

Age-Related Differences in Sensitivity to Ethanol

Given that in vitro administration of ethanol inhibits synaptic activity and plasticity more potently in hippocampal slices from immature rats than in older rats, studies were conducted in whole animals (rats) to determine whether the effects of ethanol on the acquisition of spatial memory (using a Morris water maze) were also age dependent [82]. It was found that pretreatment with ethanol significantly impaired spatial-memory acquisition in adolescents but not adults. Interestingly, ethanol did not impair the acquisition of nonspatial memory in either adolescents or adults, demonstrating the increased sensitivity of spatial memory in younger animals [82]. In later studies it was also demonstrated that rats exposed to bingelike alcohol episodes as adolescents exhibited enhanced susceptibility (compared with animals exposed as adults to alcohol binges) to the memory-impairing effects of alcohol when tested as adults [83]. In studies in which ethanol was given after training sessions in an odor-discrimination task, it was found again that, relative to adults, memory in adolescent rats is more strongly disrupted than that of adults. Here, ethanol was given after training to avoid confounding the effects of ethanol on memory with those on sensory and motivational influences, which might manifest when ethanol is given during training. These findings are of interest because adolescent rats are actually less sensitive than adults to a variety of noncognitive effects of ethanol, including hypothermia, muscle relaxation, hypnosis, and lethality [84]. These and other observations reviewed in Smith [85] make it clear that the effects of ethanol in young or periadolescent animals are not the same as those seen in adults, suggesting that younger subjects are more susceptible to the disruptive effects of ethanol than adults.

In yet other studies examining the effects of ethanol on spatial and nonspatial memory in adolescent and adult rats — in this case using an appetitive, dry (sandbox) maze — it was shown that nonspatial acquisition was unaffected by ethanol at either age, but that spatial acquisition was disrupted in adults but not adolescents. The authors of this study postulated that “the adolescent-associated development of stress-sensitive regions involved in spatial learning may have contributed to the differences observed between” their study [86] and the earlier study [82].

Environmental and Other Influences on the Effects of Ethanol

It has been demonstrated under a variety of circumstances that the effects of ethanol are influenced by the environment and other factors. For example, under conditions where patterns and rates of lever pressing are strictly controlled by the scheduling of reinforcements around these responses, ethanol increases low rates of responding while decreasing high rates of responding in the same subjects [87, 88]. Others have demonstrated that the effects of ethanol can depend not only on the ongoing rate of a particular behavior, but also on the context in which the behavior occurs and the behavioral history of the subject [89, 90]. In addition, genetic differences can influence the effects of ethanol. For example, it is well known that ethanol can serve as a positive reinforcer in a variety of animal species and that it is self-administered by many [91]. Genetic differences, however, can be important with respect to the ability of ethanol to serve as a positive reinforcer, as evidenced by its ability to engender self-administration [90]. For example, studies in alcohol accepting (AA) and alcohol nonaccepting (ANA) mice have shown that ethanol readily serves as a reinforcer in AA mice but not in ANA mice. If genetic differences can influence the ability of ethanol to serve as a reinforcer, then it follows that genetic differences might also influence the effects of ethanol on other aspects of CNS function. These observations are critically important because, if they are not taken into consideration, interpretation of findings from seemingly easily interpretable behavioral studies can be easily confounded.

Overview

Ethanol clearly interacts with a variety of neurotransmitter systems, affecting different functional and anatomical systems to varying degrees. These effects depend on dose, time after administration, age, genetics, and a variety of other influences. Depending on the circumstances prevailing at the time of administration, ethanol can have seemingly opposite effects, e.g., stimulation versus sedation or performance enhancement versus disruption. The preponderance of the data support the proposition that ethanol acts to disrupt important aspects of cognitive function, primarily by degrading the discriminability of relevant stimuli. It is unclear at this time whether such effects result from or cause decreases in encoding or attentional properties. However, it does seem fairly clear that ethanol does not selectively disrupt working memory or learning at doses that adversely affect stimulus discriminability, attention, or encoding. The observation that important brain functions (such as learning and olfactory discrimination in rodents) are relatively insensitive to the adverse effects of ethanol suggests that the systems subserving these functions are greatly protected from chemical perturbation.

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Paule MG. Animal Models and the Cognitive Effects of Ethanol. In: Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press/Taylor & Francis; 2006. Chapter 5.

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