Mary Vallett

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.

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.

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 Samsons 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.

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.

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.

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 DRCs 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.