Search PubMed⌕ Search

Biomedical subjects

Michael T Bardo

Publications and source records attributed to Michael T Bardo.

At least 19 recordsLinked to original sources
PubMed2006

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens.

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.

Amphetamine↗
PubMed2006

Environmental enrichment decreases responding for visual novelty.

Previous research has demonstrated that rats reared in an enriched condition (EC) with novel objects and social partners self-administer less amphetamine compared to rats raised in an isolated condition (IC). However, it is unclear if the enrichment-induced decrease in stimulant self-administration generalizes to non-drug rewards such as those provided by novel environmental stimuli. In the current study, EC, IC, and social condition (SC) rats were raised from 21 to 51 days of age before being tested in a two-lever operant conditioning chamber in which responding on one lever (active lever) resulted in illumination of a cue light. In Experiment 1, rats were initially assessed for baseline responding (no contingency) and then the contingent light was introduced. EC rats responded less than IC rats for the contingent light stimulus; however, EC rats also displayed a lower rate of baseline responding. In Experiment 2, rats were trained initially to lever press for a sucrose reward to decrease differences in baseline responding. While sucrose pretraining decreased baseline response differences between groups, EC rats still responded less for the contingent light stimulus than IC or SC rats. These results suggest that environmental enrichment decreases the incentive value of visual novelty.

Analysis of Variance↗
PubMed2006

Individual differences in the effect of novel environmental stimuli prior to amphetamine self-administration in rats (Rattus norvegicus).

These experiments determined whether individual differences in response to novelty subsequently predict the ability of novel stimuli, presented prior to the session, to decrease amphetamine self-administration. Using an inescapable locomotor test, the authors found that high-responder rats (Rattus norvegicus) showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-responder rats. This effect was dose dependent and generalized to sucrose-reinforced responding. Using a free-choice place preference test, the authors found that high-novelty-seeking rats also showed a greater novelty-induced decrease in the acquisition of self-administration compared with low-novelty- seeking rats. Regardless of individual differences, novelty had little effect on amphetamine self-administration during the maintenance phase. These results suggest that exposure to novel environmental stimuli may reduce acquisition of drug-taking behavior, especially among high-novelty-seeking individuals.

Amphetamines↗
PubMed2006

Monoamine-depleting doses of methamphetamine in enriched and isolated rats: consequences for subsequent methamphetamine-induced hyperactivity and reward.

The current study examined whether environmental enrichment alters the effects of monoamine-depleting doses of methamphetamine on subsequent methamphetamine-induced hyperactivity and conditioned place preference. Rats were raised in either an enriched or isolated condition from 21 to 55 days of age and then were treated with monoamine-depleting doses of methamphetamine (10 mg/kg, four injections at 2 h intervals) or saline. Eight days later, rats were assessed for methamphetamine-induced (0.3 or 1.0 mg/kg) hyperactivity and conditioned place preference. Results indicated that the monoamine-depleting dose regimen produced a similar hyperthermic response in enriched and isolated rats. Enriched and isolated rats also displayed a similar depletion of dopamine in the striatum and serotonin in nucleus accumbens. The monoamine-depleting dose regimen, however, enhanced methamphetamine hyperactivity across repeated conditioning sessions in enriched rats, but not in isolated rats. In contrast to isolated rats, enriched rats failed to display significant conditioned place preference to the low dose of methamphetamine (0.3 mg/kg) following the monoamine-depleting dose regimen, suggesting that the rewarding effect of methamphetamine was blunted by the combined effect of enrichment and methamphetamine treatment. Thus, environmental enrichment may exacerbate the behavioral consequences of monoamine-depleting doses of methamphetamine.

Animals↗
PubMed2006

Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding.

The current experiments aimed to determine whether differential rearing alters extinction and/or reinstatement of amphetamine self-administration or sucrose-maintained responding. Male Sprague-Dawley rats were raised in either an enriched condition or an isolated condition. Rats were then trained to lever press on a continuous reinforcement schedule across either 15 daily amphetamine self-administration sessions or 15 sucrose-reinforced sessions, followed by 10 sessions of extinction. After the extinction sessions, priming doses of amphetamine (0, 0.25 or 1.0 mg/kg) were administered 15 min before the session, or sucrose (one or 10 pellets) was delivered non-contingently at the beginning of the session. Enriched condition rats showed greater extinction for amphetamine and sucrose-maintained responding than isolated condition rats. When primed with amphetamine, isolated condition rats reinstated responding following 0.25 mg/kg of amphetamine, whereas enriched condition rats only reinstated responding after 1.0 mg/kg of amphetamine. Isolated condition rats failed to reinstate responding following sucrose delivery, while enriched condition rats reinstated responding following the delivery of 10 sucrose pellets. These results indicate that environmental enrichment enhanced the extinction of both amphetamine and sucrose-maintained responding. Environmental enrichment also raised the reinstatement threshold specific to the amphetamine prime, suggesting a reduction in the incentive motivational effect of amphetamine.

Amphetamine↗
PubMed2006

Translation in tobacco and drug abuse prevention research.

The purpose of this article is to describe the translation of research on tobacco and drug abuse prevention from basic science to program development to large-scale program dissemination, and from animal to human studies. Where relevant, continuity of translation is discussed by referring to two variables that have been studied for their potential relationship to drug use risk in both animals and humans: sensation and novelty seeking and low impulse control. Review of the research indicates relatively slow translation until the early 1990s. The authors recommend several mechanisms to promote more rapid translation across types of research that encourage reciprocal rather than unidirectional transmission of knowledge to expedite the development and diffusion of more timely, targeted drug abuse prevention programs.

Animals↗
PubMed2005

Novelty seeking and drug use: contribution of an animal model.

Although sensation seeking or novelty seeking is a reliable predictor of drug use in humans, individual differences in free-choice novelty seeking in animal models have generally failed to predict drug use. In the current article, hierarchical multiple regression analyses were used on data collected from a large sample of rats. Rats were screened on measures of inescapable and free-choice novelty tests and then were trained to lever press for sucrose or intravenous amphetamine. Although scores from the inescapable novelty test weakly predicted responding for amphetamine, the addition of free-choice novelty preference scores into the regression analyses significantly improved the predictive models. These results indicate that, similar to evidence in humans, individual differences in novelty seeking may be able to predict drug use in rats.

Amphetamine↗
PubMed2005

Tolerance does not develop to the decrease in nicotine self-administration produced by repeated bupropion administration.

The atypical antidepressant bupropion has been shown to be an efficacious smoking cessation agent; however, its therapeutic mechanism of action is unknown. To further understand the mechanism by which bupropion reduces smoking, the present study determined the effect of repeated bupropion pretreatment on nicotine self-administration or sucrose-maintained responding. Rats were trained to self-administer intravenous nicotine (0.02 mg/kg/infusion; Experiment 1) or to respond for sucrose pellets (45 mg each; Experiment 2) on a fixed-ratio 5 schedule. Once rats reached stable responding, bupropion (70 mg/kg, subcutaneously) or vehicle was injected 15 min before the session for 14 consecutive sessions. Bupropion acutely decreased both nicotine self-administration and sucrose-maintained responding by approximately 60%-70%. With repeated bupropion pretreatment, however, responding for nicotine decreased completely. In contrast, the bupropion-induced decrease in responding for sucrose following acute administration did not change significantly with repeated bupropion administration. These results suggest that bupropion acquired some specificity with repeated use, decreasing the intake of nicotine and producing an extinction-like pattern in nicotine self-administration. Thus the present results parallel human clinical studies with bupropion demonstrating its smoking cessation properties following repeated treatment. These results indicate that the rat nicotine self-administration paradigm is a useful animal model for assessing smoking cessation pharmacotherapies.

Analysis of Variance↗
PubMed2005

Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex.

Rats raised in an enriched environmental condition (EC) exhibit a decreased (35%) maximal velocity (V(max)) of [3H]dopamine (DA) uptake in medial prefrontal cortex (mPFC) compared with rats raised in an impoverished condition (IC); however, no differences between EC and IC groups in V(max) for [3H]DA uptake were found in nucleus accumbens and striatum. Using biotinylation and immunoblotting techniques, the present study examined whether the brain region-specific decrease in DA transporter (DAT) function is the result of a reduction in DAT cell surface expression. In mPFC, nucleus accumbens and striatum, total DAT immunoreactivity was not different between EC and IC groups. Whereas no differences in cell surface expression of DAT were found in nucleus accumbens and striatum, DAT immunoreactivity in the biotinylated cell surface fraction of mPFC was decreased (39%) in EC compared with IC rats, consistent with the magnitude of the previously observed decrease in V(max) for [3H]DA uptake in mPFC in EC rats. These results suggest that the decrease in DAT cell surface expression in the mPFC may be responsible for decreased DAT function in the mPFC of EC compared with IC rats, and that there is plasticity in the regulatory mechanisms mediating DAT trafficking and function.

Animals↗
PubMed2004

The effect of novelty on amphetamine self-administration in rats classified as high and low responders.

RATIONALE: Rats categorized as high responders (HR) based on their activity in an inescapable novel environment self-administer more amphetamine than low responder (LR) rats. Previous research has also demonstrated that novel stimuli presented during the amphetamine self-administration session decreases the number of infusions earned. OBJECTIVES: This study determined whether individual differences in response to inescapable or free-choice novelty differentially predict the ability of novel stimuli to decrease amphetamine self-administration. Further, this study determined whether novel stimuli maintained the ability to reduce self-administration with repeated presentations, and whether the effect of novel stimuli varied as a function of the unit dose of amphetamine tested. METHODS: Male rats were screened for their response in inescapable and free-choice novelty tests. Following initial training using a high unit dose of amphetamine (0.1 mg/kg per infusion), the dose was reduced (0.03 mg/kg per infusion), and novel stimuli were presented in the operant conditioning chamber on four separate sessions. In experiment 2, novel stimuli were presented during several sessions at a variety of amphetamine doses (0.003, 0.01, 0.03, and 0.056 mg/kg per infusion). RESULTS: Four repeated presentations of novel stimuli reduced amphetamine self-administration with no significant loss in the effect of novel stimuli across repeated presentations. In experiment 2, novel stimuli reduced amphetamine self-administration at low unit doses (0.003 mg/kg and 0.01 mg/kg per infusion), and rats classified as HR based on their activity in inescapable novel stimuli were more disrupted by novel stimuli than LR rats. CONCLUSIONS: These results suggest that repeated presentation of novel stimuli can reduce amphetamine self-administration at low unit doses and that HR rats are more sensitive than LR rats to non-drug stimuli that compete with responding for amphetamine.

Amphetamine↗
PubMed2004

Environmental enrichment enhances sensitization to GBR 12935-induced activity and decreases dopamine transporter function in the medial prefrontal cortex.

Rats raised in an enriched condition (EC) during development display increased hyperactivity to the effect of acute amphetamine compared to rats raised in an impoverished condition (IC). The present study determined whether environmental enrichment differentially alters the effects of GBR 12935 administration, a selective dopamine transporter (DAT) inhibitor. Acutely, EC rats showed a greater, dose-dependent GBR 12935-induced increase in activity compared to IC rats; however, basal activity for EC rats was lower than for IC rats. After repeated GBR 12935, only EC rats exhibited behavioral sensitization. Kinetic analysis of DAT function in medial prefrontal cortex (mPFC) revealed that the maximal velocity of [3H]dopamine ([3H]DA) uptake in EC rats was less than in IC rats (4.9 +/- 0.6 and 7.7 +/- 0.6 pmol/min/mg, respectively), but not in striatum or nucleus accumbens. Furthermore, GBR 12935-induced inhibition of DAT function, [3H]GBR 12935 binding density and DA content in mPFC, striatum and nucleus accumbens were not different between EC and IC rats. However, dihydroxyphenylacetic acid content in mPFC was lower in EC than IC rats, whereas no differences were found in striatum and nucleus accumbens. These results suggest that EC-induced changes in activity may be due to decreased DAT function and decreased DA metabolism in the mPFC.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

On the nature of the intra-administration unconditioned stimulus: comment on McDonald and Siegel (2004).

R. V. McDonald and S. Siegel (see record 2004-10475-001) present convincing evidence that a small dose of morphine (5 mg/kg) may elicit withdrawal signs in rats previously injected on a number of occasions with a large dose of morphine (50 mg/kg), thus suggesting that intra-administration associations may be involved in drug withdrawal. This finding is important for basic and applied researchers studying drug reward mechanisms. Although R. V. McDonald and S. Siegel point out that the morphine conditional stimulus (CS) and unconditioned stimulus (US) making up the intra-administration association differ in onset and magnitude, the author of this comment argues that the CS and US may also differ in terms of pharmacologic activity.

Animals↗
PubMed2004

Impoverished rearing environment alters metabotropic glutamate receptor expression and function in the prefrontal cortex.

Rearing rats in impoverished (IC) and enriched (EC) environmental conditions alters synaptic plasticity and cognitive processes. Metabotropic glutamate receptors (mGluRs) are known to play a key role in synaptic and behavioral plasticity. In the present study, the effect of rearing conditions on the expression of mGluR proteins in the prefrontal cortex (PFC) was assessed by immunoblotting. A significant difference in the content of prefrontal mGluR1 and mGluR5 (ie group I) and mGluR2/3 (ie group II) was observed between IC and EC rats. To functionally characterize this difference, in vivo microdialysis was used to verify differences in mGluR regulation of extracellular glutamate in the PFC. The results indicate that the capacity of group I and II mGluRs to elevate extracellular glutamate levels was significantly blunted in the PFC of IC rats compared to either EC subjects, or rats reared in normal environmental conditions (ie NIH standards). Group II mGluR receptors regulate performance in a forced T-maze spatial memory task that involves the PFC, and IC rats demonstrated deficits in this task relative to EC rats. These data suggest that reduced mGluR transmission in the PFC produced by impoverished, relative to enriched, rearing environments may contribute to cognitive deficits.

Animals↗
PubMed2004

High-risk behavior during adolescence: comments on part I.

Cardinal and Steinberg provide evidence from both laboratory animal and human studies indicating that behavior is controlled by two distinct brain systems, one activational and the other inhibitory. This conceptual framework continues to be a useful integrative framework in developmental neurobiology and psychology. Despite the conceptual framework that posits a two-system control of high-risk behavior, it is notable that the bulk of research related to this topic has focused on one system in isolation from the other. Since the activational and inhibitory systems are constructs that are amenable to investigation using both laboratory animals and human subjects, it seems that a fruitful avenue for future interdisciplinary research would be to ascertain the interactive effect of these systems across the periadolescent period.

Adolescent↗
PubMed2003

Environmental enrichment decreases nicotine-induced hyperactivity in rats.

RATIONALE: Previous research has determined that rats reared in an enriched condition (EC) are more sensitive to the effects of acute systemic amphetamine than rats raised in an impoverished condition (IC). OBJECTIVES: The present experiments examined the effect of environmental enrichment on locomotor activity following repeated injections of nicotine. Experiment 1 assessed differences in locomotor activity in EC and IC rats and experiment 2 assessed differences between EC rats and rats housed in pairs without novel objects or daily handling (social condition; SC) to determine whether enrichment causes changes beyond that of social contact alone. METHODS: In experiment 1, EC and IC rats were treated with saline, 0.2 mg/kg or 0.8 mg/kg nicotine, and locomotor activity was assessed for 60 min. Nicotine-induced activity was measured every 48 h for a total of eight sessions. All rats were challenged with 0.8 mg/kg nicotine on session 9. In experiment 2, EC and SC rats were treated with saline or 0.2 mg/kg nicotine, and locomotor activity was assessed using the same regimen as in experiment 1. RESULTS: In experiment 1, EC rats exhibited less sensitivity than IC rats to the psychostimulant effect of nicotine upon both acute and repeated administration. On the nicotine challenge session (session 9), EC rats were again less sensitive to the hyperactive effects of nicotine. In experiment 2, EC rats were also less sensitive than SC rats to nicotine-induced hyperactivity across repeated injections. CONCLUSIONS: These results suggest that environmental enrichment during development reduces the stimulant effect of nicotine.

Analysis of Variance↗
PubMed2003

Effect of bupropion on nicotine self-administration in rats.

RATIONALE AND OBJECTIVE: The mechanisms underlying the therapeutic efficacy of bupropion as a smoking cessation agent are unknown. Bupropion inhibits monoamine uptake as well as neuronal nicotinic receptor (nAChR) function. The present study compared effects of bupropion on nicotine self-administration to those of other stimulant drugs (methamphetamine and apomorphine) that lack nAChR activity in order to determine its mechanism of action. To determine the specificity of bupropion-induced changes in nicotine self-administration, the ability of bupropion to alter sucrose-maintained responding or amphetamine self-administration was determined. METHODS: In nicotine and amphetamine self-administration and sucrose-maintained responding experiments, rats responded for nicotine (0.01 or 0.02 mg/kg per infusion, IV), amphetamine (0.2 mg/kg per infusion, IV) and sucrose pellets (45 mg), respectively, on a fixed ratio 5 schedule. Once responding stabilized, rats were pretreated 15 min before the session with bupropion (1-78 mg/kg) or vehicle. The ability of methamphetamine (0.3-3 mg/kg) or apomorphine (0.01-0.2 mg/kg) to alter responding for nicotine (0.02 mg/kg per infusion, IV) was determined. RESULTS: Bupropion produced a biphasic dose-response pattern at both nicotine infusion doses, increasing infusions at low bupropion doses and decreasing infusions at high bupropion doses. Methamphetamine produced a similar biphasic pattern, whereas apomorphine only decreased nicotine infusions at high doses. Bupropion dose-dependently decreased responding for sucrose and amphetamine. CONCLUSIONS: These results suggest that high bupropion doses decrease responding nonspecifically; whereas low bupropion doses selectively increase responding for nicotine. The increase in nicotine self-administration is likely due to inhibition of dopamine and norepinephrine transporters, combined with inhibition of nAChRs.

Animals↗