Biomedical subjects

K Brebner

Publications and source records attributed to K Brebner.

11 recordsLinked to original sources

PubMed2005

Distinct proteomic profiles of amphetamine self-administration transitional states.

In the rat, continuous access to d-amphetamine (d-AMPH) leads to lengthy bouts of self-administration, voluntary abstinence, and relapse to self-administration. Previous studies have revealed that the progression from psychostimulant self-administration to abstinence to relapse is mediated in part by the ventral hippocampus. Stimulation of the ventral subiculum (vSub) during voluntary abstinence from d-AMPH self-administration reinstates self-administration and increases nucleus accumbens (NAc) dopamine efflux. Quantitative proteomic examination of the hippocampus from rats naive to amphetamine, during a self-administration session 'Binge', during voluntarily abstinence 'Abstinent', and after reinstatement of self-administration 'Relapse', revealed a differential proteomic state during abstinence. Actin- and cytoskeletal-related proteins were over-represented in the changes occurring during abstinence and suggest a decrease in actin filament polymerization. These changes may underlie alterations in neuronal tone during abstinence that could affect both neurotransmission and behavior. These data provide the first classification of addiction-related behaviors based on clustering of quantitative proteomic measurements. .

Actins↗

PubMed2002

Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement.

In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.

Animals↗

PubMed2001

Cocaine-responsive gene expression changes in rat hippocampus.

Chronic cocaine use is known to elicit changes in the pattern of gene expression within the brain. The hippocampus plays a critical role in learning and memory and may also play a role in mediating behaviors associated with cocaine abuse. To profile the gene expression response of the hippocampus to chronic cocaine treatment, cDNA hybridization arrays were used to illuminate cocaine-regulated genes in rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days. Validation of mRNA changes illuminated by hybridization array analysis was accomplished by measuring immunoreactive protein (via specific immunoblots). The induction of protein kinase Calpha, potassium channel 1.1, and metabotropic glutamate receptor 5 seen by hybridization arrays was confirmed at the level of protein. Immunoblot screening of previously described cocaine-responsive genes demonstrated increased levels of protein tyrosine kinase 2, beta-catenin, and protein kinase Cepsilon. While some of these changes exist in previously described cocaine-responsive models, others are novel to any model of cocaine use. The inductions of potassium channel 1.1, protein tyrosine kinase 2 and metabotropic glutamate receptor 5 are novel findings to hippocampal cocaine-responsive gene expression. These proteins have been shown to subserve learning and memory and/or long-term potentiation functions within the hippocampus. Additionally, these genes are known to interact with one another, forming a more complex pattern of gene expression changes. The findings suggest altered expression of genes with a number of different functions in the rat hippocampus after a 'binge' style of non-contingent cocaine administration. These changes in gene expression may play roles in neuronal plasticity and the behavioral phenomena associated with cocaine abuse.

Animals↗

PubMed2000

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules.

RATIONALE: Recent reports have indicated that the gamma-aminobutyric acid (GABA)B agonist baclofen attenuates the reinforcing effects of cocaine. OBJECTIVES: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. METHODS: In the first series of experiments, three dose-response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FRI schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 microg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. RESULTS: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine-reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. CONCLUSION: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule.

Animals↗

PubMed2000

Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement.

The effect of microinjections of baclofen into the ventral tegmental area (VTA), nucleus accumbens, or striatum on cocaine self-administration reinforced on a progressive ratio schedule was investigated. Intra-VTA baclofen produced the most potent modulation of cocaine intake, causing a significant reduction in cocaine-reinforced break points at a dose (56 ng/side) that was substantially lower than doses necessary to produce comparable reductions in the nucleus accumbens or striatum. During the time that cocaine-reinforced responding was suppressed, rats demonstrated the capacity to complete several hundred responses on a concurrently available food-reinforced lever, indicating that the effect of baclofen on cocaine intake was not due to a generalized disruption in operant responding. The results indicate that GABA(B) receptors in the VTA may have the potential to modulate reward processes associated with cocaine use.

Animals↗

PubMed2000

Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations.

The proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) influence neuroendocrine activity, promote central neurotransmitter alterations, and induce a constellation of symptoms collectively referred to as sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological disturbances in humans. In the present investigation, systemic IL-1beta and TNF-alpha dose-dependently and synergistically disrupted consumption of a highly palatable food source (chocolate milk), possibly reflecting anorexia or anhedonia engendered by the treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1beta and TNF-alpha provoked variations of amine turnover in the hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this respect. Nevertheless, in view of the central amine variations induced by the cytokines, it is suggested that immune activation may come to influence complex behavioral processes, as well as affective state.

Animals↗

PubMed2000

GABA modulation of cocaine self-administration.

Recent experiments suggest that GABA compounds produce a clinically relevant modulation of cocaine reinforcement. This review summarizes the results of a number of studies that examined the effect of the GABAB agonist baclofen on cocaine self-administration using a variety of schedules of reinforcement. The results demonstrate that baclofen causes a dramatic reduction in cocaine self-administration which does not appear to be accounted for by a general disruption of behavior. However, the effect is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. These results predict that in a clinical setting any potential therapeutic effect of baclofen will interact with the cost and availability of cocaine.

Animals↗

PubMed1999

Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations.

Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

The GABA(B) agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure.

Previous self-administration experiments have shown that baclofen, the prototypical GABA(B) agonist, produces an apparent attenuation in the reinforcing effects of cocaine in rats. The present experiments examined the effects of CPG 44532, a novel and highly specific GABA(B) agonist, on cocaine self-administration using two distinctly different procedures. CGP 44532 (0.063-0.5 mg/kg) produced a dose dependent decrease in break point on a progressive-ratio (PR) schedule. A low dose of CGP 44532 (0.125 mg/kg) produced an apparent shift of the cocaine dose-response curve to the right. In contrast there was comparatively little effect on food-reinforced responding on the same PR schedule. Using a discrete-trials procedure that engendered a circadian pattern of self-administration, CPG 44532 (0.063-0.5 mg/kg) produced a dose-dependent suppression of cocaine intake in the 4 h period following treatment. When a concurrently available food reinforced lever was added to the discrete trials paradigm CGP 44532 failed to disrupt responding for food at any of the doses tested. Data from the PR and discrete-trials procedures taken together indicate that CGP 44532 produced a specific decrease in the motivation to self-administer cocaine.

Animals↗

PubMed1985

Characterization of the messenger RNA population coding for components of viperid snake venom.

Total polyadenylated messenger RNA was prepared from the milked venom glands of the South African puff adder (Bitis arietans) and translated in an in vitro translation system. The products of cell free synthesis were immunoprecipitable with puff adder venom antiserum. Treatment of these cell free products with a dog pancreas microsomal membrane preparation demonstrated the presence of signal peptides. Northern blot hybridization of total puff adder venom gland mRNA to its complementary single stranded copy DNA revealed two discrete mRNA populations coding for the major components of puff adder venom. The relative amounts of these polyadenylated mRNA sequences changed during the onset of venom synthesis, suggesting mRNA deadenylation, general endonucleolytic RNA degradation and selective degradation of high molecular weight message components.

Animals↗

PubMed1984

Blot hybridisation analysis of genomic DNA.

Restriction endonuclease analysis of specific gene sequences is proving to be a valuable technique for characterisation and diagnosis of inherited disorders. This paper describes detailed protocols for isolation, restriction, and blot hybridisation of genomic DNA. Problems and alternatives in the procedure are discussed and a troubleshooting guide has been provided to help rectify faults.

Autoradiography↗