Kathy L. Carl

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.

Attenuation of the amphetamine discriminative cue in rats with the atypical antipsychotic olanzapine

Sixteen male Sprague-Dawley rats were trained to discriminate between saline and amphetamine injections (1.0 mg/kg ip) using a standard two-lever (FR10) drug discrimination paradigm. A baseline dose-effect curve was generated for amphetamine administration alone, using doses both above and below the training dose (0.0-2.2 mg/kg ip). Once completed, a single dose of olanzapine (OLZ; 1.5 mg/kg sc) was tested for its ability to attenuate the amphetamine cue. OLZ pretreatment (60 min) successfully interfered with an animals ability to discriminate amphetamine injections across various doses. The percentage of correct responding on the amphetamine lever and rate of responding were both significantly decreased across some but not all of the amphetamine doses. Therefore, we believe that this preliminary investigation has successfully shown that an OLZ dose of 1.5 mg/kg sc at 60 min can interfere with an animals ability to detect some subjective cue(s) associated with amphetamine administration.

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.

Opiate delta-2-receptor antagonist naltriben does not alter discriminative stimulus effects of ethanol

The ability of a selective 2-opiate receptor antagonist, naltriben, to modulate ethanol discrimination was investigated in a rat model using a drug discrimination procedure. Rats were trained to discriminate ethanol (1.25 g/kg, IP) from saline on a fixed-ratio schedule, FR10. Once rats had acquired the ethanol-saline discrimination, ethanol dose-response tests were conducted with 15-min pretest injections. Following the characterization of the ethanol dose-response curve, the effect of naltriben on ethanols discriminative stimulus was assessed by administering naltriben (0. 032-5.6 mg/kg, IP) 15 min before the ethanol administration. In the present study, naltriben did not have any modulatory effect on ethanol discrimination, suggesting that either Delta(2)-opiate receptors are not involved in the formation of ethanols discriminative stimulus or the antagonism of Delta(2)-opiate receptors is not sufficient to alter ethanols compound discriminative stimulus.

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.