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.

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.

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).

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.

State-dependent stimulus control: cueing attributes of ethanol "hangover" in rats.

In Experiment 1, twelve 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. Rats were injected with either 4 g/kg ETOH or equivalent volumes of saline (SAL) 18 hr before the sessions. Each rat was injected with an additional 1 ml/kg injection of SAL 15 min before the sessions. EDE training sessions were always followed by a "day off." SAL sessions were conducted between 36-96 hr after an EDE training session. Rats demonstrated > 90% discriminative accuracy. Test sessions showed a time-dependent, cyclic, return from the experimental "hangover" state to the "normal" state, by 48 hr. The acute (immediate) effects of ETOH and chlordiazepoxide (0.75 g/kg or 0.18 mg/kg, respectively; @15 min) did not cross-generalize with the "hangover" state. Both these low-dose ETOH and chlordiazepoxide pretreatments blocked the stimulus attributes of "hangover." All subjects responded on the EDE-appropriate lever at 5.6 mg/kg pentylenetetrazole and exhibited an increase in susceptibility to clonic seizures. In Experiment 2 blood alcohol concentration kinetics functions were quantified in three groups (n = 8/group) of age-matched cohorts to Experiment 1 subjects (2, 3, and 4 g/kg ETOH) using a head-space gas chromatographic technique. The training stimulus state associated with 4 g/kg, at 18 hr postinjection intervals, in Experiment 1, did not produce any chromatogram peaks for ETOH or any its active metabolite (acetaldehyde, acetone, nor methanol).(ABSTRACT TRUNCATED AT 250 WORDS)