Richard J. Briscoe

Aversive attributes of ethanol can be attenuated by dyadic social interaction in the rat

Forty-eight male Sprague-Dawley rats were conditioned with either water or 4 g/kg ethanol in a standard drug place-learning task. In addition to the drug treatment, the opportunity for social interaction with either a sober or intoxicated conspecific was varied across groups (N = 8 rats/group). Ethanol produced a robust conditioned place aversion. The opportunity for dyadic social interaction with either a sober or intoxicated cohort attenuated the aversive attributes of ethanol. However, the initial preference scores did not significantly shift in water-conditioned rats in isolation or given access to either a sober or intoxicated cohort. These data are similar to clinical reports and suggest that social factors can influence the aversive affective properties of ethanol.

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.

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.

A catalytic antibody against cocaine attenuates cocaine's cardiovascular effects in mice: a dose and time course analysis

The murine monoclonal antibody 15A10 (mAb 15A10), elicited by a transition-state analog for cocaine hydrolysis, has previously been shown to metabolize cocaine in vitro and in vivo. The present experiments were designed to evaluate further the in vivo effectiveness of mAb 15A10 in blocking cardiovascular effects of acute cocaine administration. Balb/c mice were implanted with a femoral artery catheter utilized for mean arterial pressure (MAP) monitoring, and administered intravenous (i.v.) pretreatments of either mAb 15A10 (10, 32, 100 and 300 mg/kg) or vehicle prior to cocaine injection (100 mg/kg, i.p.). A time course analysis for mAb 15A10s effect was also conducted, for which either vehicle or 100 mg/kg mAb 15A10 was infused 1, 3, 10 and 30 days prior to cocaine treatment. During the cardiovascular recording sessions, mice were awake and freely moving within a limited area. Increases in MAP (approximately 25 mm Hg) following cocaine injection were dose-dependently attenuated by mAb 15A10. The antibody-attenuated cocaine-induced increases in MAP at 1- and 3-day pretreatment times, and reduced mortality at some of the time points studied. With 100 mg/kg antibody, plasma cocaine levels were significantly decreased early in the recording session, whereas levels of ecgonine methyl ester increased significantly. Although 10-fold greater quantities of antibody are required to observe significant effects in mouse, compared to our previous studies in rats, the present mouse model provides a convenient paradigm for investigating catalytic and non-catalytic antibodies.

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.

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.

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

Abstract.Rationale: There at least two ways in which tolerance development to alcohols behavioral effects could interact with its subsequent intake: 1) tolerance to alcohols reward or reinforcing effects per se could lead to increased consumption, and 2) tolerance to alcohols aversive effects could unmask alcohols rewarding effects. These two mechanisms may differentially interact with preexisting genetic traits underlying alcoholism. Objectives: Alcohols subjective attributes were assessed in selectively bred AA and ANA rats after the development of tolerance to alcohols 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.

Neurosteroid modulation of [3H]flunitrazepam binding in the medulla: an autoradiographic study

Neurosteroids bind to unique sites on the GABA(A) receptor complex and modulate receptor function. The effects of neurosteroids on GABA(A) receptors have been well characterized in forebrain regions. However, little is known about their effects on GABA(A) receptors in the medulla, especially those areas involved in autonomic reflex pathways. Stimulation of [3H]flunitrazepam binding to the GABA(A) receptor by two progesterone metabolites, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) and 3beta-hydroxy-5alpha-pregnan-20-one (3beta-OH-DHP), was studied using autoradiographic methods in the medulla and cerebellum of female rats at estrus. [3H]Flunitrazepam binding was enhanced by 3alpha-OH-DHP in every nucleus examined in the medulla and cerebellum. This effect was stereoselective since 3beta-OH-DHP had no effect on binding in any region. No differences were observed in the degree of stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP among medullary brain regions. However, in the cerebellum, the stimulation of binding was significantly greater in the granular layer than in the molecular layer. Stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP in nuclei involved in the baroreflex pathways supports previous studies which report that neurosteroids modulate autonomic regulation of blood pressure. These actions may also underlie alterations in autonomic function during pregnancy.