Biomedical subjects

F A Holloway

Publications and source records attributed to F A Holloway.

At least 19 recordsLinked to original sources

PubMed2001

5-HT 3 receptor antagonist ICS 205-930 alters the discriminative effects of ethanol.

The ability of a selective 5-hydroxytryptamine (5-HT(3)) receptor antagonist, ICS 205-930 (3-tropanyl-indole-1-carboxylate, tropisetron), to block the discriminative stimulus effects of ethanol was investigated in rats that were trained to discriminate ethanol (1.25 g/kg ip) from saline with food as the reinforcement. Prior administration of ICS 205-930, at the dose of 0.01 mg/kg, significantly decreased ethanol's discriminative stimulus effect at ED(75) dose of ethanol, while higher doses of ICS 205-930 (10 and 17 mg/kg) showed enhancement of ethanol's discriminative effects at ED(0), ED(25), and ED(50) doses of ethanol. Under conditions where ICS 205-930 (10, 17 mg/kg) was tested alone, rats responded exclusively on the saline-appropriate lever. These effects occurred without significantly altering response rates or blood ethanol concentrations. The results suggest that the 5-HT(3) antagonist ICS 205-930 at lower concentration decreases, and at higher concentration enhances the discriminative stimulus effects associated with a lower to moderate dose of ethanol.

Animals↗

PubMed2001

Alcohol's interactions with circadian rhythms. A focus on body temperature.

The complex interaction between alcohol and the body's circadian rhythm has become a rapidly expanding area in chronopharmacology. This area has key implications for the field of alcohol research, because understanding alcohol's effects on the body's internal clock will aid scientists in designing medications and behavioral interventions for treating alcohol abuse and dependence. A number of studies provide evidence that alcohol sensitivity and preference vary with circadian timing. However, only a few studies support alcohol's ability to influence the circadian phase directly. This review focuses on studies examining how alcohol and the body's circadian rhythm interact, using body temperature as an index of circadian rhythm function. Though the research is limited, findings indicate that alcohol sensitivity and preference for drinking to indeed appear to vary with circadian timing and that alcohol may act directly on the central pacemaker to alter circadian functioning.

Alcohol Drinking↗

PubMed2000

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 ethanol's 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 ethanol's discriminative stimulus or the antagonism of Delta(2)-opiate receptors is not sufficient to alter ethanol's compound discriminative stimulus.

Animals↗

PubMed2000

Conditioned place aversion to the "hangover" phase of acute ethanol administration in the rat.

The purpose of this study was to examine ethanol's delayed effects (termed hangover) using conditioned place testing. Four groups of rats received a single pairing of a distinctive environment (tactile and visual) 10 h after injection with ethanol (0, 2, 3, 4 g/kg, i.p. ) or saline in a counterbalanced design. Rats receiving 3 and 4 g/kg ethanol showed a conditioned place aversion to ethanol hangover. Conditioning 10 h after 0 or 2 g/kg ethanol did not produce a significant place preference or aversion. The results suggest that the hangover following an acute injection of high doses of ethanol (3-4 g/kg) produces a significant and dose-related conditioned place aversion in the rat.

Animals↗

PubMed1998

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.

Animals↗

PubMed1998

Cocaine and caffeine: conditioned place preference, locomotor activity, and additivity.

Conditioned place preference (CPP) was employed to clarify the reinforcing and locomotor stimulating effects of several doses of cocaine and caffeine (0.32, 1.0, 3.2, 5.6, and 10.0 mg/kg) and to explore the possibility of additive effects between the two drugs. Additionally, the hypothesis that the reinforcing effects of psychostimulants are mediated by the same systems that control psychostimulant-induced locomotor activity was examined by conducting correlational studies between drug-induced locomotor activity and time spent in the drug-conditioned compartments. Several doses of cocaine (1.0, 3.0, 5.6, 10.0 mg/kg), and caffeine (0.32, 1.0, 3.2, 5.6, 10.0) were found to condition place preference and stimulate locomotor activity. A combination of low doses (0.32 mg/kg) of each drug appeared to be additive. A positive relationship between locomotor activity observed during conditioning and time spent in the conditioned compartment during testing was found for cocaine but not caffeine or the low-dose combination of cocaine and caffeine.

Animals↗

PubMed1998

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.

Acute-Phase Reaction↗

PubMed1998

Methylnaltrexone attenuates taste aversion conditioned by low-dose ethanol.

Previous research has shown that activation of a subset of peripheral opioid receptors located in the gut produce aversive effects as measured in the place and taste conditioning (CTA) paradigms. Endogenous opioid activity and tetrahydroisoquinolines (TIQs) are stimulated or formed after ethanol (EtOH) administration and both are known to activate opioid receptors. We therefore examined the hypothesis that a portion of the aversive effects of EtOH may be mediated through peripheral opioid receptors, activated by EtOH-induced opioids or TIQs. EtOH CTAs were slightly attenuated when animals were pretreated with the putative peripheral opioid receptor antagonist methylnaltrexone. By itself MNTX did not condition a taste preference or aversion. However, blood EtOH levels (BELs) in animals pretreated with MNTX were lower than those of saline-pretreated subjects, an effect that just reached statistical significance and was not present at specific EtOH doses. The results indicate that a portion of the aversive conditioning effects of EtOH (using a two-bottle CTA paradigm) may be receptor-mediated effects, exerted by an action on peripheral opioid receptors, but the specific mechanism of attenuation is unclear.

Animals↗

PubMed1998

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.

Alcohol Drinking↗

PubMed1998

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.

Animals↗

PubMed1998

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.

Adrenergic Agents↗

PubMed1997

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.

Animals↗

PubMed1997

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.

Alcohol Drinking↗

PubMed1995

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.

Animals↗

PubMed1994

Perceptual masking of the chlordiazepoxide discriminative cue by both caffeine and buspirone.

Twelve male Sprague-Dawley rats were trained to discriminate between the interoceptive stimulus attributes of 5 mg/kg chlordiazepoxide (CDP) and saline in a two-lever operant task under a fixed-ratio 10 (FR-10) schedule of food reinforcement. Caffeine, buspirone, and Ro 15-1788 failed to engender complete generalization when tested in combination with saline. In drug interaction test sessions caffeine (56 mg/kg) blocked the discriminative stimulus properties of the training dose of CDP and shifted the CDP discriminative dose-response function to the right. This rightward shift in CDP discriminative function was paralleled by a concomitant downward shift in the rate-of-responding dose-response function. Drug interaction test sessions conducted with 3.2 mg/kg of buspirone in combination with various doses of CDP engendered a downward shift in both the discriminative and rate-of-responding dose-response functions. Because 3.2 mg/kg buspirone in combination with the training dose of CDP resulted in complete response rate suppression, additional combination tests were conducted with 3 mg/kg CDP, a dose which reliably engendered > 90% CDP-appropriate responding, and various doses of buspirone. Similar to the CDP-caffeine interactions, buspirone blocked the cueing properties of 3 mg/kg CDP with a parallel reduction in response rates. Interaction test sessions conducted with Ro 15-1788 and CDP resulted in rightward shifts in both the discriminative and rate functions of CDP. We suggest that the interactions between CDP and both caffeine and buspirone resulted from the perceptual masking of the interoceptive (subjective) effects of CDP, whereas the interaction between Ro 15-1788 and CDP reflect pharmacological antagonism.

Animals↗

PubMed1994

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.

Animals↗

PubMed1994

Technical report: the subcutaneous administration of cocaine in the rat.

Eight male Sprague-Dawley rats were treated with 32 mg/kg cocaine, twice daily, for 2 weeks using a SC route of administration. Using a cocaine stock solution of 1.2-1.6 mg of cocaine hydrochloride per ml of sterile saline, we demonstrate, for the first time, the relative safety of subcutaneously administered cocaine in the rat. There was absolutely no evidence for focal dermal necrosis, in any rat, after the 2-week chronic period.

Animals↗

PubMed1994

A three-choice haloperidol-saline-cocaine drug discrimination task in rats.

This study was conducted to test whether rats could be trained and successfully maintain a three-choice drug discrimination task using 0.1 mg/kg haloperidol (SC, 2-h pretreatment), saline (IP or SC, 2 h and 15 min pretreatment), and 10 mg/kg cocaine (IP, 15-min pretreatment) as training stimuli. Six male Sprague-Dawley rats achieved criterion performance for stimulus control by these training stimuli under a fixed-ratio-5 schedule of food reinforced lever-press responding in an average of 164 training sessions. Dose-response functions for cocaine and haloperidol demonstrated both quantitative and qualitative specificity of the training stimuli. The data also are presented along a single pharmacological continuum (agonist-antagonist) that we hypothesize to represent a parallel subjective or interoceptive stimulus continuum associated with the drug injections. Based on the previous multidimensional model of drug stimuli dimensionality (3), this specific stimulus dimension is characterized as an unidimensional bipolar continuum represented by the hypothetical states of hedonia or euphoria on one end (cocaine) and anhedonia or depression on the opponent end (haloperidol), with a neutral (saline) centroid region. We propose that this specific three-choice drug discrimination task in rats may function as an animal analog of the subjective states associated with cocaine abuse and the subsequent withdrawal or, crash, in humans (7,8,21).

Animals↗