Differential development of behavioral tolerance and the subsequent hedonic effects of alcohol in AA and ANA rats.

RATIONALE: There at least two ways in which tolerance development to alcohol's behavioral effects could interact with its subsequent intake: 1) tolerance to alcohol's reward or reinforcing effects per se could lead to increased consumption, and 2) tolerance to alcohol's aversive effects could unmask alcohol's rewarding effects. These two mechanisms may differentially interact with preexisting genetic traits underlying alcoholism. OBJECTIVES: Alcohol's subjective attributes were assessed in selectively bred AA and ANA rats after the development of tolerance to alcohol's behaviorally disruptive effects on lever-press performance. METHODS: Rats were trained to press a lever under an FR30 schedule of food presentations. Group-dependent differential access to intoxicated practice, using a typical pre-post drug administration design, was utilized to promote the development of alcohol tolerance in only the group receiving intoxicated practice sessions. Subsequently, rats were trained to associate alcohol with unique place and taste stimuli in order to assess the relative changes in the approach towards, or avoidance of alcohol-related cues in each group. RESULTS: Groups of AA and ANA rats given access to intoxicated practice demonstrated tolerance development. These groups subsequently conditioned place preferences and failed to develop conditioned taste aversions to alcohol. Passive alcohol exposure in the ANA rats set the occasion for the development of a place preference and delayed taste conditioning. AA rats exposed to passive alcohol exposure failed to condition place preferences and developed rapid taste aversions. Saline control rats failed to develop tolerance or place preferences but did condition a robust alcohol-induced taste aversion. CONCLUSIONS: AA and ANA rats differ in their behavioral and pharmacokinetic response to chronic alcohol exposure. Compensatory responses interacting with approach-avoidance behaviors appear to be learned during intoxicated practice in the AA rats and during both intoxicated practice and passive exposure in the ANA rat line.

Cocaine-induced cardiovascular responses in rats during acute ethanol withdrawal.

The effects of cocaine administration during acute ethanol withdrawal on both the cardiovascular system and cocaine pharmacokinetics are unclear. This study demonstrated differences in the cardiovascular effects of i.v.-administered cocaine during acute ethanol withdrawal in awake, freely moving rats. The altered responses to cocaine while in acute ethanol withdrawal compared to control animals included: enhanced increases in mean arterial pressure and systemic vascular resistance, attenuated heart rate decreases, and enhanced cardiac index and stroke volume decreases. These results may suggest that acute ethanol withdrawal disrupts myocardial contractility when the myocardium is subjected to a large increase in blood pressure. Serial arterial blood sampling in additional groups of rats were done to assess plasma cocaine concentrations and to confirm the absence of ethanol in the blood. Plasma cocaine concentrations were not effected by acute ethanol withdrawal. These results indicate that the altered cardiovascular responses to cocaine during acute ethanol withdrawal were not a result of differences in cocaine plasma concentrations.

Discriminative effects of compound drug stimuli: a focus on attention.

Discrimination research has increasingly used compound stimuli emerging from drugs acting through multiple neurotransmitter systems or from injections of drug mixtures that approximate "street-wise" drug-taking behaviors. Accompanying this trend has been an interest in the role of cognitive factors in drug discrimination learning. Accounts of multidimensional drug stimuli have focused mainly on specific neuronal mechanisms, and have largely ignored the contribution of stimulus information to the perception of internal events or to the selection processes, heretofore called attention mechanisms, which may underlie the observer's idiosyncratic response to drug administration. It is argued here that research in drug discrimination may benefit from a more detailed consideration of the processes by which an observer interacts with the emergent stimulus properties of drug administration. Therapeutic intervention initiatives may critically depend on knowing the interactions between the specific attributes of the drug experience that capture the attention of the individual and that may later acquire stimulus control over complex drug-taking behaviors.

Effects of ethanol hangover on the operant self-administration of cocaine in rats.

To assess the interaction of experimentally induced ethanol hangover and cocaine self-administration, rats maintained to self-administer cocaine (0.5 mg/kg/inj) were given either saline or 2 or 4 g/kg ethanol (10% w/v, IP) 15 h prior to cocaine access (dose range tested 0.03-1.0 mg/kg/inj). Cocaine was shown to be dose-dependently self-administered in a significant inverted U-shaped function. EtOH hangover had a significant effect on the dose-dependent effects of cocaine, resulting in a general flattening of the inverted U-shaped function with increasing intensity of hangover. A significant dose-dependent reduction in the number of reinforcer deliveries occurred at the peak of the cocaine dose-response function (0.06 mg/kg/inj) following the 2 and 4 g/kg EtOH pretreatment doses when compared to saline pretreatment. These data suggest that hangover may alter the ability for moderate doses of cocaine to "prime" and maintain stable self-administration behavior.

Phase-response curve for ethanol: alterations in circadian rhythms of temperature and activity in rats.

Circadian rhythms of core body temperature and general activity in Sprague-Dawley rats were monitored for 21 days using remote radiotelemetry to examine acute and sustained effects of 0 (saline) 1.0, and 2.0 g/kg ethanol injections administered at four different times of day. Ethanol produced dose-dependent and statistically significant hypothermia and hypoactivity when injected at 0100, 0700, 1300, and 1900 h; however, the magnitude of the hypothermic effect was greatest at the 1900-h injection time. Cosinor analyses revealed persistent alterations in both activity and temperature rhythms, which lasted for at least 48 h postinjection. Ethanol significantly shortened the period of activity rhythms when injected in either 1.0 or 2.0 g/kg doses at 0700 and 1300 h, and produced similar period-shortening effects on temperature rhythms at 1300 and 1900 h. The acrophase of the activity rhythm was significantly phase delayed by 1.0 g/kg ethanol at 0700 h, while the acrophase of temperature was significantly phase advanced by 2.0 g/kg ethanol at 0100 h, but significantly phase delayed by the same dose administered at 1300 h. A statistically significant and dose-dependent reduction in the amplitude of the body temperature rhythm was observed at the 1900-h administration time. There were no differences in the MESOR (Midline Estimating Statistic of Rhythm; i.e., rhythm-adjusted mean value) of either temperature or activity circadian rhythms as a function of ethanol treatment at any dose.

State-dependent stimulus control: cuing attributes of acute cocaine rebound in rats.

Sprague-Dawley (Rattus norvegicus) rats were trained in a drug discrimination task using the state-dependent interoceptive stimulus attributes of cocaine's delayed or rebound effects (CDE) versus "normal" basal homeostasis. Rats were injected with either 32 mg/kg cocaine or equivalent volumes of saline (SAL), subcutaneously, 13 hr before the sessions. Rats demonstrated > 90% discriminative accuracy. Test sessions showed a time-dependent acute cocaine isodirectional rebound state that engendered a shift from predominantly SAL- to CDE-appropriate responding approximately 7 hr after the high training dose injection and lasted for approximately 10 hr (17 hr postinjection). The delayed or rebound state was dose dependent and engendered only a biphasic partial generalization with acute cocaine injections. There were no detectable levels of cocaine or any of its behaviorally active metabolites at the 13-hr postinjection interval. Tests conducted with various doses of lidocaine, chlordiazepoxide, N-methyl-d-aspartic acid, ketamine, and buspirone engendered SAL- or default-appropriate responding. The anxiogenic drug, pentylenetetrazole, produced partial generalization to the cocaine rebound cue.

Reinforcing effects of caffeine, ephedrine, and their binary combination in rats.

The reinforcing effects of caffeine, ephedrine, and caffeine + ephedrine combinations were tested in rats maintained to self-administer 0.5 mg/kg/injection of cocaine in daily 4 h limited access periods. The dose-response relationship for cocaine demonstrated a a typical inverted U-shaped function. The dose-dependent administration of cocaine was stable over the 3-day substitution epochs. Similar to earlier reports, neither caffeine nor ephedrine engendered stable patterns of self-injections. Combinations of caffeine + ephedrine produced biphasic patterns of administration only on the first day of substitution. Days 2 and 3 of the caffeine-ephedrine substitution periods engendered variable and inconsistent reinforcer deliveries that did not significantly differ from saline substitution tests. These reduced patterns of self-administered caffeine-ephedrine combinations were not attributed to behavioral toxicity. Progressive-ratio tests demonstrated rank ordered break points of: food > cocaine > caffeine ephedrine combination = caffeine = ephedrine = saline. Caffeine-ephedrine pretreatments failed to show any significant change in the administration of the maintenance dose of cocaine except at the highest combination dose tested. Although previous data from this laboratory demonstrated symmetrical crossgeneralization between the discriminative effects of caffeine-ephedrine combinations and cocaine, the present data suggest limited reinforcing effects of these combinations in rats.

Moderate, long-term, alcohol consumption potentiates normal, age-related spatial memory deficits in rats.

A modified "Samson" sucrose fading procedure was used to establish voluntary consumption of a 20% ethanol (EtOH) solution in male Sprague-Dawley rats for 18 consecutive months. Intakes were stable over the life span, and corresponded to the moderate to high levels of intake typically observed in human "social" drinkers and alcoholics. The Morris Water Maze (WM), Olton Radial Arm Maze (RM), and a "balance beam" test were used to assess the effects of alcohol and aging on spatial memory and motor function. Aged EtOH-consuming rats (AGED/ALC) demonstrated impaired task acquisition, relative to aged controls (AGED), not reaching criterion performance in either spatial memory task even when given four additional days of training. AGED/ALC rats scored significantly lower on percent correct out of the first eight arm entries, and committed more perseverative errors in the RM. There were no significant performance differences between AGED and AGED/ALC rats on a balance beam test of fine motor coordination and equilibrium, suggesting that deficits observed in the RM and WM were not related to differential motor functioning. These results demonstrated that long-term, moderate, oral self-administration of EtOH, within the range typically consumed by humans, had adverse effects on spatial memory in rats, and that such a pattern of EtOH consumption seemed to exacerbate the decline in cognitive functioning associated with normal aging.

The stimulus properties of two common over-the-counter drug mixtures: dextromethorphan + ephedrine and dextromethorphan + diphenhydramine.

Two groups of rats were trained in a two-choice drug discrimination procedure under a fixed-ratio 10 schedule of food reinforcement. One group of rats (n=12) was trained to discriminate the presence and absence of a drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg diphenhydramine. The other group of rats (n=12) was trained to discriminate the presence and absence of another drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg ephedrine. Cross-generalization tests conducted with each of the stimulus elements demonstrated that (1) the drug mixtures were not perceived as new entities distinct from their component elements and (2) the stimulus element saliency may be a factor determining the nature of discriminative control by drug mixtures. Cross-generalization tests conducted with the psychomotor stimulants, cocaine and amphetamine, engendered complete generalization to the training cues in both groups, whereas, pentobarbital engendered predominantly saline- or default-lever responding. These data suggest a potential abuse liability for both of these common over-the-counter drug mixtures and cautions against the use of such combinations in pediatric patients.

Genetic selection of alcohol preference can be countered by conditioning processes.

Twenty-four P rats and 24 NP rats were conditioned to consume 10% w/v alcohol in daily 0.5-h limited access periods using a modified version of Samson's sucrose fading procedure. Both P and NP rats demonstrated a strikingly similar day-to-day pattern of alcohol intakes. For the most part, P rats drank more than NP rats, but by the middle of the fourth month of drinking, P and NP rats were drinking equivalent amounts of alcohol. Both P and NP rats consumed alcohol in amounts similar to two outbred strains of rats (Wistar and Sprague-Dawley) previously conditioned to drink alcohol in this laboratory.

Physiological and subjective effects of acute cocaine withdrawal (crash) in rats.

The physiological and subjective effects of high acute doses of cocaine and the subsequent homeostatic acute withdrawal syndrome were measured in rats. Radiotelemetry recordings of body temperature and activity were monitored in rats for 48 h after 32 mg/kg cocaine (COC) and saline (SAL) were administered by both intraperitoneal and subcutaneous (s.c.) routes. COC initially produced hypothermia and hyperactivity, followed by a prolonged hyperthermic and hypoactive rebound that seemed to peak around 12 h after injections. The s.c. route of administration produced the greatest rebound effect. Eight additional rats were monitored for EEG activity by telemetry for 48 h after SC administration of SAL or 32 mg/kg COC. COC produced an initial decrease in alpha and beta wavelength bands, with a trend toward increases in alpha and beta power demonstrated from the 10th through 14th h after injections. Using a three-choice haloperidol (HDL), saline, and COC drug discrimination task, we demonstrated a COC-like subjective state produced during the 10th through 12th h after a 32-mg/kg s.c. COC injection with no HDL-like responding engendered during any tested period of the acute or rebound effects of COC. These data provide evidence for an acute COC withdrawal syndrome (crash) in rats occurring 10-14 h after a high-dose COC treatment.

Effects of time-of-day and photoperiod phase shifts on voluntary ethanol consumption in rats.

Two experiments were conducted to examine the circadian fluctuations in voluntary ethanol (ETOH) consumption in male Sprague-Dawley rats conditioned to consume ETOH in their homecage and exposed to photoperiod phase shifts equivalent to those experienced by humans. Using a maintenance concentration of 20% w/v ETOH, changes in homecage drinking in 42 rats were assessed after photoperiod phase shifts similar to those inducing "jet lag" in humans and after experimenter-induced "hangover." A single 8-hr photoperiod phase advance significantly increased ETOH intake for three consecutive days, and a single photoperiod phase-delay increased intake only on the day of the phase shift. Acute ETOH withdrawal significantly reduced the voluntary consumption of ETOH for two consecutive days. In a second group of 30 rats maintained to consume a lower concentration of 10% w/v ETOH, the long-term effects of "shift lag" initiated by repeated photoperiod phase shifting similar to those experienced by humans working under a rotating work schedule were examined. Significant increases in intake occurred over the 2-month testing period. The significant alterations in voluntary intake initiated by the shift work schedule was related to the significant changes in blood alcohol concentrations.

Cross-generalization of an EtOH "hangover" cue to endogenously and exogenously induced stimuli.

Twenty male Sprague-Dawley rats were trained in a two-choice food-reinforced drug discrimination task (10 min sessions) using the state-dependent interoceptive stimulus attributes of ethanol's (EtOH) delayed or rebound effects (EDE) versus "normal" basal homeostasis. Cross-generalization tests were conducted with 0.18 mg/kg naloxone injected after three days of three injections per day of either SAL or 10 mg/kg morphine. Naloxone failed to generalize to the EDE-state after chronic saline; however, the precipitated morphine withdrawal state produced complete generalization to the EDE training cue. Daily tests were conducted after 8 h photoperiod phase-shifts. An 8 h phase-advance, equivalent to a west-to-east intercontinental night-time flight in humans, produced a biphasic, graded, increase in EDE-appropriate responding, which peaked on the second day after the phase-advance and recovered by the fourth day. The 8 h phase-delays failed to engender significant EDE-appropriate responding. These data provide evidence for the subjective similarity between EtOH hangover, opiate withdrawal states, and the physiological disruption induced by circadian phase-advances.

Cumulative vs. acute dose-response procedures produce differential BAC and behavioral functions for ethanol.

The discriminative stimulus attributes of ethanol (ETOH) were characterized in rats trained to discriminate between 1.25 g/kg ETOH and saline. The ETOH generalization functions were assessed using both acute and cumulative dosing procedures. The cumulative procedures differed in the individual incremented doses used to generate the functions. Acute dosing procedures produced discriminative functions that were significantly different from cumulative dose-response curves (DRCs). Similar cumulative DRC's were generated within each cumulative dosing procedure, whereas significant differences were produced between the two dosing incremented procedures. When blood alcohol concentrations (BACs) were quantified, a cumulative testing procedure produced significantly lower BACs than acute testing procedures at every dose above the initial or starting dose. Interestingly, response rate functions did not differ within or between cumulative and acute procedures. These data may suggest that differential ETOH dosing procedures may differentially influence the behavioral choice and BAC functions in rats, and cautions against the use of cumulative procedures to assess shifts in DRCs during chronic treatments without a concomitant assessment of BACs.

The paradoxical hedonic valence of acute ethanol withdrawal (hangover) states in rats: place and taste conditioning.

The hedonic valence of EtOH's delayed effects, usually referred to as "hangover," was assessed 18 h after a 4 g/kg injection using both place and taste learning tasks. In the place conditioning task two CS-,CS+ intervals were used (48 h and 144 h); within each treatment interval, experimentally induced "hangover" was paired with the initially nonpreferred conditioning compartment for half of the experimental group (N = 10 rats) and with the initially preferred conditioning compartment for the half (N = 10 rats). Saline injections were paired with placement in the alternate conditioning compartment. A third group (N = 10 rats) was conditioned with milliliter equivalent volumes of saline on both sides. A conditioned place preference was conditioned with the hangover state-induced interoceptive stimuli. Attempts were made to taste condition 24 rats with the interoceptive stimulus attributes of hangover. Experimentally induced hangover was associated with an adipsogenic state, defined as a significant decline in voluntary intake of both saccharin and water, which prevented taste conditioning.

Free radical production during ethanol intoxication, dependence, and withdrawal.

Indices of free radical production and cell damage were examined in male Sprague-Dawley rats chronically exposed to either ethanol (ETOH) or water vapor. In experiment 1, rats experienced either 1 or 11 cycles of ETOH exposure and withdrawal. Brain tissue was harvested 12 hr after ETOH exposure, and 1 hr after being injected with sodium salicylate as a scavenger. Brain tissue was analyzed for the formation of salicylate hydroxylation products as a measure of .OH production during withdrawal. Significant group differences for .OH production were demonstrated for 2,3- and 2,5-dihydroxybenzoic acid in the single cycle ETOH exposed rats compared with their water cohorts. A significant between group difference for 2,5-dihydroxybenzoic acid, only, was demonstrated for the multiple cycles of ETOH exposure. Spontaneous seizures were shown to correlate with increased production of .OH in ETOH exposed rats. In experiment 2, brain tissue was harvested from different groups of rats after removal from the chambers, at 0, 2, 12, 24, 36, and 48 hr after a single exposure cycle. Tissue was analyzed for (1) salicylate hydroxylation (as above), (2) glutamine synthetase activity, (3) whole brain glutamate concentration, and (4) oxidized protein. A multiple regression analysis was conducted on the five dependent variables and found they could be predicted by specific behavioral and neurological ratings. These data suggest that cell damage during withdrawal may have multiple time-dependent components.

Cross-generalization between a cocaine cue and two antihistamines.

Rats were trained to discriminate between 10 mg/kg cocaine and saline injections under a fixed ratio 10 schedule of food-motivated lever press responding. Once stimulus control was achieved, reinforced test sessions were conducted to assess the degree of generalization of a wide range of cocaine doses and the cross-generalization between the cocaine training stimulus and two over-the-counter antihistaminic drugs, diphenhydramine and doxylamine, when administered with saline or in drug combinations. Cocaine produced a dose-dependent generalization to the 10 mg/kg training stimulus. Cocaine also produced mild rate-increasing effects at low test doses and response rate suppression at higher doses. Both diphenhydramine and doxylamine produced a partial generalization to the 10 mg/kg cocaine training stimulus. Drug mixtures produced complete cross-generalization with the training cue.

Influence of thiamine on the behavioral sensitivity to ethanol.

Changes in sensitivity to ethanol's rate-decreasing effects on operant performance were examined in control rats and cohorts that received diet-induced or diet+pyrithiamine-induced thiamine deficiency. Seven groups of male Sprague-Dawley rats (12 rats/group) were trained in a 5-cycle lever-press operant task under a fixed-ratio 30 schedule of food reinforcement. Once trained to maintain consistent operant performance across all 5 cycles, each rat was tested with various doses of ethanol injected at the beginning of each time-out cycle. Each group of rats demonstrated equivalent saline baseline operant performance and ED50 for ethanol's rate-suppressing effects. Training sessions were suspended and rats received either a short- (9 days) or long-term (5-week) exposure to regular rat chow diet or thiamine-deficient diet, and received either saline or pyrithiamine injections in a 2 x 2 design. Three additional control groups were maintained on a regular rat chow diet and received supplemental injections of either thiamine+pyrithiamine injections, thiamine+saline injections, or saline+pyrithiamine injections. The controlled diet phase continued until the development of overt signs of thiamine deficiency, at which time thiamine supplements were administered for 4 days. In phase 3, all rats were retrained in the operant task and a second ethanol dose-effect function was generated. A history of thiamine deficiency and recovery failed to shift the behavioral dose-effect functions significantly for ethanol and their associated blood alcohol curves. Most interestingly, significant behavioral sensitization to ethanol's rate suppressant effects was demonstrated in the two control groups of rats receiving regular rat chow diet in combination with supplemental injections of thiamine and either saline or pyrithiamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine-induced conditioned place approach in rats: the role of dose and route of administration.

The hedonic valence of the interoceptive stimuli associated with a wide range of cocaine doses administered by either SC or intraperitoneal injections was assessed in rats. Ninety-six male Sprague-Dawley rats were randomly assigned to different dose- and route-of-administration dependent groups (n = 8/group) and conditioned in a place learning task. During half of the conditioning trials, rats received either SC or intraperitoneal injections of saline or an individual dose of cocaine from 0.32 to 32 mg/kg (10 groups, 0.5 log common log unit increments), and were immediately placed in the initially nonpreferred compartment of a straight alley-way place-conditioning chamber. Prior to the other conditioning trials, rats received equivalent volumes of saline injections via the same routes of administration and were immediately placed in the initially preferred compartment. Two additional control groups received saline injections on both sides. Each rat received eight conditioning trials (four on each side). Significant conditioned place approach was produced by both SC- and IP-injected cocaine. However, the IP route of cocaine administration required a dose of 10 mg/kg cocaine to elicit a conditioned place approach, whereas a 0.32 mg/kg SC cocaine injection produced a CPP. Saline injections alone did not change the initial preference scores, and conditioned place aversions were not produced by any cocaine dose. The results of the present study demonstrate the relative safety of SC cocaine administration in the rat and a behavioral potency difference between these two routes of administration relative to the hedonic valence of the associated subjective states.