Biomedical subjects

Brett C Ginsburg

Publications and source records attributed to Brett C Ginsburg.

9 recordsLinked to original sources

PubMed2006

Effects of chronic fluvoxamine on ethanol- and food-maintained behaviors.

Acute treatment with fluvoxamine reduces responding for ethanol more than responding for food. However, pharmacotherapy for alcoholism is likely to require chronic treatment. These experiments were performed to assess the effects of chronic fluvoxamine on ethanol- and food-maintained behaviors. Effects of chronic fluvoxamine (10 and 17.8 mg/kg/dayx30 days) on ethanol- and food-maintained responding were compared to responding during saline treatment in four Sprague-Dawley rats responding for ethanol and food under a multiple fixed-ratio 5, fixed-ratio 5 schedule. In two subjects, chronic fluvoxamine reduced ethanol-maintained responding more than food-maintained responding; however this effect was transient. In another subject, treatment persistently decreased food-maintained responding relative to ethanol-maintained responding. Finally, in one subject, fluvoxamine nonspecifically disrupted responding for food and ethanol. Similar to results in humans, outbred Sprague-Dawley rats had differential responses to chronic fluvoxamine. The effect was transient in rats that responded favorably (greater reduction of ethanol relative to food responding), while response reductions persisted throughout treatment in rats that responded unfavorably (greater reduction of food relative to ethanol or nonspecific reductions).

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PubMed2006

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors.

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30 min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends on the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration.

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PubMed2006

Cannabinoid effects on behaviors maintained by ethanol or food: a within-subjects comparison.

The cannabinoid CB1 antagonist rimonabant (SR141716A) has been proposed as a therapeutic agent for several addictive disorders, including alcoholism. Rimonabant may selectively reduce responding for an ethanol solution compared with an alternative. While this could represent a specific effect of CB1 inhibition on ethanol reinforcement, this could also result from differences in the baseline rates of behavior or experiences between comparison groups. We developed a procedure in rats that allows a within-subject comparison of ethanol and food-maintained responding and provides well matched baseline response rates. We determined the effects of acute doses of rimonabant (0.3-5.6 mg/kg, intraperitoneal) and the CB1 agonist Delta-9-tetrahydrocannabinol (1.0-5.6 mg/kg, intraperitoneal) on responding for food and ethanol under a multiple fixed-ratio schedule. To confirm that rimonabant blocked cannabinoid receptors, the ability of rimonabant to antagonize Delta-9-tetrahydrocannabinol effects in the same subjects under the same reinforcement schedule was also determined. In contrast with previous reports, rimonabant did not significantly alter responding for ethanol or food. The effects of Delta-9-tetrahydrocannabinol on responding for food were completely antagonized by rimonabant, whereas Delta-9-tetrahydrocannabinol effects on responding for ethanol were not. These results suggest that there may be neuroadaptation of the cannabinoid system following aging or chronic self-administration of ethanol.

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PubMed2005

Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys.

Environmental cues are thought to play a role in drug craving, leading to the high relapse rate observed in cocaine abusers. Cocaine-paired cues can reinstate cocaine-maintained behavior in rodents and nonhuman primates and can induce changes in dopamine levels in the rodent striatum. In the present study, squirrel monkeys were trained to self-administer cocaine under a second-order schedule, and then were implanted with guide cannulae targeted at the caudate nucleus. Caudate dopamine levels were measured while the animals performed the behavioral task, self-administering cocaine or saline under extinction conditions. In addition, animals received noncontingent (passive) cocaine infusions yoked to the drug self-administration sessions. Cocaine administration increased dopamine levels 2-fold, but a leftward shift was seen in the peak effect in animals self-administering cocaine as compared to animals passively receiving cocaine. Moreover, dopamine levels began to decline during the experimental session when animals were self-administering cocaine, even though they continued to receive cocaine injections. In contrast, dopamine levels declined below baseline during the session when animals were given access to saline. The results suggest that the environmental context associated with drug self-administration can modulate cocaine-induced elevations in extracellular dopamine.

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PubMed2005

Effects of fluvoxamine on a multiple schedule of ethanol- and food-maintained behavior in two rat strains.

RATIONALE: Previous studies show that selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, have a greater effect on ethanol-maintained responding compared with an alternative reinforcer. However, none of these studies matched baseline responding for reinforcers. Because behavioral effects of many drugs depend on the baseline response rate, the preferential effects of SSRIs may be due to different baseline response rates. OBJECTIVES: Fluvoxamine effects on ethanol- and food-maintained responding were compared using a multiple schedule of behavior, providing matched baseline responding and allowing within-subject analysis in two strains of rats. METHODS: The multiple schedule consisted of three consecutive 5-min, fixed-ratio five components (Food1, Ethanol, Food2). Fluvoxamine (3-30 mg/kg, i.p.) was administered 30 min presession. In Lewis rats, fluvoxamine effects were determined at several available ethanol concentrations [8, 16, 32, and 8% (w/v) redetermination]. In Sprague-Dawley rats, fluvoxamine effects were determined when the available ethanol concentration was 8% (w/v). RESULTS: Baseline responding was stable and well matched under all conditions except 32% ethanol, when responding for ethanol was lower than for food. After the administration of 17.8 mg/kg fluvoxamine, ethanol-maintained responding was 15-33% lower than food-maintained responding in four of the five conditions tested. Breath ethanol assessments indicated that rats had blood ethanol levels of 33 mg/dl following responding for 8% ethanol. CONCLUSIONS: These results are in agreement with previous findings that SSRIs preferentially reduce ethanol-maintained responding and suggest this is not likely due to different baseline levels of responding between the comparison conditions. Further, these results support the hypothesis that alteration of synaptic serotonin can modulate ethanol reinforcement.

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PubMed2005

Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys.

Drugs that target the dopamine transporter (DAT) have been proposed as pharmacotherapies to treat cocaine abuse. Accordingly, it is paramount to understand pharmacological interactions between cocaine and DAT inhibitors. The present study characterized acute interactions between cocaine and several DAT inhibitors (RTI-177, FECNT, RTI-112) that differed in selectivity for monoamine transporters on operant behavior and in vivo neurochemistry in squirrel monkeys. RTI-177 and FECNT, two DAT inhibitors with low affinity at norepinephrine transporters (NET), produced dose-dependent stimulant effects on behavior maintained by a fixed-interval schedule of stimulus termination. Compared to cocaine, RTI-177 and FECNT had a slower onset and longer duration of action. In vivo microdialysis in the caudate nucleus of awake monkeys confirmed dose-dependent increases in extracellular dopamine that corresponded to behavioral effects. Among the drugs characterized, RTI-112 is reportedly the least selective for binding to DAT, NET, and serotonin transporters (SERT). Interestingly, RTI-112 failed to produce significant behavioral-stimulant effects, and its effects on extracellular dopamine were highly variable across subjects. The results indicate that the pharmacological profile of DAT inhibitors may be influenced by actions at multiple monoamine transporters. Importantly, there was little evidence of additivity on behavioral or neurochemical measures when cocaine was administered in combination with behavioral-stimulant doses of the DAT inhibitors.

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PubMed2005

Alphaxalone and epiallopregnanolone in rats trained to discriminate ethanol.

BACKGROUND: Neurosteroids with a 3 alpha-hydroxy orientation share pharmacological effects with ethanol, increase in brain after ethanol administration, and may mediate ethanol effects. 3beta-hydroxy neurosteroids antagonize in vitro and some, but not all in vivo effects of ethanol and 3 alpha-hydroxy neurosteroids. METHODS: We assessed the discriminative stimulus and rate altering effects of alphaxalone, a 3 alpha-hydroxy neurosteroid, and epiallopregnanolone, a 3beta-hydroxy neurosteroid, in rats trained to discriminate either 0.8 g/kg or 1.2 g/kg ethanol. The ability of epiallopregnanolone to antagonize the discriminative stimulus or rate-altering effects of ethanol or alphaxalone was also assessed. RESULTS: Ethanol had similar discriminative ED50s (0.5 g/kg) in both groups; however rats trained with the lower ethanol dose were more sensitive to rate-decreasing effects of ethanol. Alphaxalone occasioned ethanol-appropriate responding in both training groups, although less effectively in rats trained on the lower ethanol dose (maximum 65% versus 80% ethanol-appropriate responding). No difference in sensitivity to the rate-decreasing effects of alphaxalone was present between groups. Epiallopregnanolone did not reliably occasion ethanol-appropriate responding in either training group, and rats trained on the lower ethanol dose were slightly more sensitive to epiallopregnanolone rate decreasing effects. Epiallopregnanolone did not alter any effects of ethanol or alphaxalone. CONCLUSIONS: Our results agree with previous reports that 3 alpha-hydroxy neurosteroids occasion ethanol-appropriate responding, while 3beta-hydroxy neurosteroids do not; as well as reports showing no antagonism of the discriminative stimulus or rate-suppressant effects of ethanol or 3 alpha-hydroxy neurosteroids by 3beta-hydroxy neurosteroids. Results of the present study demonstrate that ethanol and 3 alpha-hydroxy neurosteroids share discriminative stimulus effects. However, these results are inconsistent with the hypothesis that such neurosteroids mediate the discriminative stimulus of ethanol.

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PubMed2005

Rat breathalyzer.

BACKGROUND: The purpose of this study was to characterize the estimation of blood alcohol (ethanol) concentration (BAC) in laboratory rats by measuring ethanol concentration in breath (BrAC) using a specialized apparatus in combination with a gas chromatography system. METHODS: The apparatus consisted of a body chamber, a plastic cylinder, from which the head of the rat protruded, a head chamber, and a water-jacketed cylinder, in which the rat's head was placed while the breath sample was collected. The breath sample was withdrawn from the head chamber through a sample loop by a Minipuls pump and then injected directly into the gas chromatography system that was equipped with a flame ionization detector for the quantification of ethanol. For these experiments, Lewis rats were catheterized 1 week before the commencement of the experiments so that blood samples were collected at exactly the same time as the breath samples. RESULTS: Our results show that Lewis rats can be trained to enter and be secured in the body chamber and that they appear to be comfortable for periods as long as 150 min. The profiles of the pharmacokinetic curves for BrAC and BAC were essentially identical. Cmax for BrAC and BAC at 8 min after the intraperitoneal injection of ethanol was directly proportional to the doses of ethanol. The ratio of BrAC expressed as peak area to BAC (expressed as mM) was calculated to be 3282. This conversion factor can be used to directly estimate the BAC from the BrAC. CONCLUSIONS: The principal conclusion of this study was that the rat breathalyzer is an accurate and convenient laboratory method to estimate BAC in a noninvasive manner. This procedure will be particularly useful for studies requiring repeated assessment of alcohol levels.

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PubMed2002

Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys.

Preclinical studies have documented that serotonin (5-HT) can modulate the behavioral effects of cocaine. The present study examined the ability of 5-HT to attenuate the reinforcing and neurochemical effects of cocaine in nonhuman primates. In squirrel monkeys trained to self-administer cocaine (0.1 and 0.3 mg/injection) under a second-order schedule of i.v. drug delivery, the 5-HT uptake inhibitor alaproclate (3.0 and 10.0 mg/kg) and the 5-HT direct agonist quipazine (0.3-1.0 mg/kg) decreased response rates at doses that had no significant effect on behavior maintained by an identical schedule of stimulus termination. The neurochemical bases of the observed drug interactions on behavior were investigated further using in vivo microdialysis techniques in a separate group of awake monkeys to monitor drug-induced changes in extracellular dopamine (DA). Cocaine (1.0 mg/kg) elevated the concentration of DA in the caudate nucleus to approximately 300% of basal levels. Pretreatment with alaproclate or quipazine attenuated cocaine-induced increases in extracellular DA at the same pretreatment doses that decreased cocaine self-administration. The results obtained suggest that increasing brain 5-HT activity can attenuate the reinforcing effects of cocaine, ostensibly by decreasing the ability of cocaine to elevate extracellular DA in brain areas that mediate the behavioral effects. These findings extend those reported previously for the behavioral-stimulant effects of cocaine and identify a potential neurochemical mechanism underlying drug interactions on behavior.

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