David V. Gauvin

Historical factors in the development of ETOH-conditioned place preference.

Three groups of male Sprague-Dawley rats were conditioned with ethanol (ETOH) and water in a Conditioned Place Preference task. To assess the contribution of prior drug/behavioral history on the relative hedonic valence of ETOH, the three groups differed in the task demands and degree of prior ETOH exposure. One group was trained to self-administer 20% w/v ETOH in a home-cage self-administration task using a Samson sucrose-fading procedure prior to place conditioning trials (Group SA/CPP). A second group was initially trained in a two-choice ETOH-Saline drug discrimination (DD) task and subsequently conditioned in the place preference paradigm (Group DD/CPP). The third group of rats had no history of drug exposure and were experimentally naive prior to the place learning task (Group NH/CPP). Group SA/CPP developed a significant conditioned place preference; Group DD/CPP failed to demonstrate either a preference or aversion, whereas the Group NH/CPP demonstrated a significant place aversion. Data suggest that both present and past contingencies contribute to the algebraic summation of ETOHs hedonic valences.

Behavioral interaction between cocaine and caffeine: A drug discrimination analysis in rats

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine greater than cocaine greater than caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeines effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as supra-additive, in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.

Do Rat Strain Differences in Ethanol Consumption Reflect Differences in Ethanol Sensitivity or the Preparedness to Learn

Three strains of rats (Wistar, Sprague-Dawley, Long-Evans; n = 10/strain) were trained to drink various concentrations of ethanol (ETOH) in the rats home cage in daily 30-min drinking sessions using a modified Samson sucrose-fading procedure. Wistar and Sprague-Dawley rats were similar in their voluntary intake of a wide range of ETOH concentrations and both of these strains drank considerably more ETOH than the Long-Evans strain. For comparison purposes only, pharmacological pretreatment tests were later conducted with the Sprague-Dawley strain of rats using a maintenance concentration of 20% w/v ETOH. Low-dose ETOH pretreatments increased (125% of control), and high-dose ETOH pretreatments decreased the subsequent voluntary consumption of ETOH. Low-dose nicotine pretreatments increased ETOH consumption to 148% of control intake, and high doses of nicotine decreased ETOH consumption. Both opiate antagonists, naloxone and naltrexone, produced dose-dependent decreases in ETOH consumption. The dopamine antagonist, haloperidol, produced dose- and time-dependent increases in voluntary ETOH consumption. The strain differences in voluntary ETOH consumption described in the present study differ from those previously described by other labs. We suggest that this strain-dependent disparity between laboratories, with respect to ETOH consumption/preference tasks, may reflect genetic differences in the preparedness to condition (learn) voluntary ETOH consumption rather than genetic differences in ETOHs reward/reinforcement attributes.

Potentiation of cocaine's discriminative effects by caffeine: A time-effect analysis

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 male Sprague-Dawley rats were trained to discriminate between 10 mg/kg cocaine and saline. Time-effect analysis of the training dose resulted in a median effective time interval (the duration of the discriminable effects of cocaine in producing 50% cocaine-appropriate responding), of 60.5 minutes postinjection. Caffeine partially generalized to the cocaine stimulus and, when administered with cocaine, produced a dose- and time-dependent increase in the percentage of drug-appropriate responding. Data are discussed with reference to our previous results with cocaine-caffeine interactions.

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.

Role of context in ethanol tolerance and subsequent hedonic effects

Two groups of male Sprague-Dawley rats received ethanol dose-effect tests for FR30, food-reinforced operant performance, in each of two environmental contexts, before and after a period of daily presession ethanol or saline injections. During the latter period, context alternated daily. The ethanol group received ethanol prior to sessions for one context and saline, prior to sessions for the other context. The saline group always received presession saline. The ethanol, but not the saline, group displayed robust tolerance to ethanols rate-decreasing effects, with no difference between tests in each context. Both groups then received training and testing in an ethanol-conditioned place preference task. The saline group displayed significant avoidance of the compartment paired with ethanol. The ethanol group displayed no initial aversion for the ethanol compartment and, with extended conditioning, showed a significant increase in time spent in the ethanol compartment. We suggest that this tolerance represents context-independent, learning to compensate for ethanol-induced effects, and that this tolerance subsequently blocked the conditioned place aversion evident in nontolerant controls, thereby enhancing the estimates of ethanols reward properties.

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.

The discriminative stimulus properties of legal, over-the-counter stimulants administered singly and in binary and ternary combinations

Ninety-six male Sprague-Dawley rats were trained in one of seven drug versus saline (SAL) discrimination (DD) tasks under a variable-ratio 5–15 schedule of food-motivated lever press responding. Three groups of rats (n=12/group) were trained to discriminate between one of the legal over-the-counter (OTC) stimulants — caffeine (CAF), ephedrine (EPHED), phenylpropanolamine (PPA), and SAL. Three other groups (n=2/group) were trained to discriminate between one of three binary stimulant combinations — CAF + EPHED, CAF + PPA, EPHED + PPA, and SAL. The seventh group of rats (n=24) was trained to discriminate between SAL and a ternary combination of the OCT stimulants, CAF + EPHED + PPA. Generalization tests were conducted with each of the OTC stimulants and the controlled stimulants — amphetamine (AMPHET) and cocaine (COC). The data suggest: 1) there is cross-generalization between some OTC combinations and controlled stimulants; 2) full generalization between the OTC and controlled stimulants were demonstrated in rats trained to discriminate two of the binary stimulant combinations from SAL; 3) drug mixtures are not perceived as new entities distinct from their component elements; 4) training dose-ratio may influence the characteristics of mixture discriminations; 5) stimulus overshadowing may be a factor determining drug mixture cues, and 6) the DD properties of aggregate drug compounds may function within a euclidean metric space. We propose that some binary OTC stimulant combinations may effectively function as a methadone-like replacement therapy in cocaine dependence.

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.

The discriminative stimulus properties of ethanol and acute ethanol withdrawal states in rats

Twelve male Sprague-Dawley rats were trained in a standard two-choice Drug 1-Drug 2 discrimination task utilizing 3.0 mg/kg chlordiazepoxide (CDP, an anxiolytic drug) and 20 mg/kg pentylenetetrazol (PTZ, an anxiogenic drug) as discriminative stimuli under a VR 5-15 schedule of food reinforcement. Saline tests conducted at specific time points after acute high doses of ethanol (3.0 and 4.0 g/kg) indicated a delayed rebound effect, evidenced by a shift to PTZ-appropriate responding. Insofar as such a shift in lever selection indexes a delayed anxiety-like state, this acute withdrawal reaction can be said to induce an affective state similar to that seen with chronic ethanol withdrawal states. Ethanol generalization tests: (1) resulted in a dose- and time-dependent biphasic generalization to CDP, (2) failed to block the PTZ stimulus and (3) failed to block the time- and dose-dependent elicitation of an ethanol-rebound effect. These data suggest that ethanols anxiolytic effects are tenuous.