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Peter W Kalivas

Publications and source records attributed to Peter W Kalivas.

At least 55 records · Page 3Linked to original sources
PubMed2003

Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration.

Astrocytes actively participate in synaptic plasticity and respond to insult or metabotropic glutamate receptor activation with increased expression of the intermediate filament glial fibrillary acidic protein (GFAP). Extended withdrawal from repeated cocaine administration induces many forms of neuroplasticity. The present study with rats utilized a 3-week withdrawal period from daily cocaine administration (i.p.; 7 days) to investigate whether astrocytes participate in cocaine-mediated plasticity observed in brain nuclei associated with addiction. Following the 3-week withdrawal period, immunoblotting revealed increased GFAP expression in the prefrontal cortex (PFC) and in the shell and core compartments of the nucleus accumbens (NAshell and NAcore). Upregulation of GFAP did not occur in the striatum or in any brain region tested following shorter withdrawal times from repeated cocaine (24 h or 1 week) or following 2-h withdrawal from an acute cocaine injection (30 mg/kg i.p.). However, GFAP expression increased following a 3-week withdrawal from a single cocaine injection selectively in the NAshell. Cell counts revealed that astrocyte cell number increased only in the NAcore while immunoblots of a marker for immature or reactive astrocytes, vimentin, showed an increase only in the PFC following the 3-week withdrawal. Taken together, these results suggest that altered intermediate filament expression within forebrain astrocytes may be a significant part of the plasticity occurring during withdrawal from repeated cocaine. Furthermore, the increase in GFAP may arise from regionally distinct mechanisms, with the NAcore relying more on cell proliferation while the PFC relies on a larger reactive astrocyte population.

Animals↗
PubMed2003

Homer1 proteins and AMPA receptors modulate cocaine-induced behavioural plasticity.

Homer proteins form functional assemblies in the excitatory postsynaptic density, and withdrawal from repeated cocaine administration reduces the expression of Homer1b/c in the nucleus accumbens. To determine if the reduction in Homer1b/c may be contributing to cocaine-induced behavioural sensitization, antisense oligonucleotides were infused over two weeks into the nucleus accumbens of rats to reduce Homer1 gene expression by approximately 35%. Infusion of antisense sequences (AS1 and AS2) caused a sensitization-like augmentation in the motor response to acute cocaine administration in naive rats. One of the sequences (AS1) also prevented the development of sensitization to repeated cocaine treatment, while AS2 was without effect. A panel of immunoblots for other proteins in the excitatory postsynaptic density revealed that AS1, but not AS2 reduced the level of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 protein. This posed the possibility that altered AMPA signalling may mediate the inhibitory effect of AS1 on the development of sensitization. To examine this possibility, rats were pretreated in the accumbens with drugs to block AMPA/kainate, N-methyl-d-aspartate, group 1 metabotropic glutamate or dopamine receptors prior to each daily injection of cocaine. Only AMPA/kainate receptor blockade prevented the development of behavioural sensitization to cocaine. These data indicate that the expression of behavioural sensitization arises in part from a reduction in Homer1 gene products in the accumbens, while the development of sensitization requires stimulation of AMPA/kainate receptors.

Animals↗
PubMed2003

Inhibition of non-vesicular glutamate release by group III metabotropic glutamate receptors in the nucleus accumbens.

Previous in vitro studies have shown that group III metabotropic glutamate receptors (mGluRs) regulate synaptic glutamate release. The present study used microdialysis to characterize this regulation in vivo in rat nucleus accumbens. Reverse dialysis of the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (L-AP4) decreased, whereas the antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP) increased the extracellular level of glutamate. The decrease by L-AP4 or the increase by MSOP was antagonized by co-administration of MSOP or L-AP4, respectively. Activation of mGluR4a by (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid or mGluR6 by 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid had no effect on extracellular glutamate. (R,S)-4-Phosphonophenylglycine (PPG), another group III agonist with high affinity for mGluR4/6/8, reduced extracellular glutamate only at high concentrations capable of binding to mGluR7. The increase in extracellular glutamate by MSOP was tetrodotoxin-independent, and resistant to both the L-type and N-type Ca2+ channel blockers. L-AP4 failed to block 30 mm K+-induced vesicular glutamate release. Blockade of glutamate uptake by d,l-threo-beta-benzyloxyaspartate caused a Ca2+-independent elevation in extracellular glutamate that was reversed by L-AP4. Finally, (S)-4-carboxyphenylglycine, an inhibitor of cystine-glutamate antiporters, attenuated the L-AP4-induced reduction in extracellular glutamate. Together, these data indicate that group III mGluRs regulate in vivo extracellular glutamate in the nucleus accumbens by inhibiting non-vesicular glutamate release.

Aminobutyrates↗
PubMed2003

Repeated cocaine administration changes the function and subcellular distribution of adenosine A1 receptor in the rat nucleus accumbens.

Adenosine A1 receptor (A1) protein and mRNA is increased in the nucleus accumbens following repeated cocaine treatment. In spite of this protein up-regulation, A1 agonist-stimulated [35S]GTPgammaS binding was attenuated in accumbens homogenates of rats withdrawn for 3 weeks from 1 week of daily cocaine injections. Cellular subfractionation revealed that the discrepancy between total A1 protein and G protein coupling resulted from a smaller proportion of receptors in the plasma membrane. The decrease in functional receptor in the plasma membrane was further indicated by diminished formation of heteromeric receptor complex consisting of A1 and dopamine D1A receptors. To explore the functional significance of the altered distribution of A1 receptors, at 3 weeks after discontinuing repeated cocaine or saline, animals were injected with cocaine and 45 min later the subcellular distribution of A1 receptors quantified. Whereas a cocaine challenge in repeated saline-treated animals induced a marked increase in membrane localization of the A1 receptor, the relative distribution of receptors in repeated cocaine rats was not affected by acute cocaine. These data suggest that the sorting and recycling of A1 receptors is dysregulated in the nucleus accumbens as the consequence of repeated cocaine administration.

Animals↗
PubMed2003

Chronic ethanol consumption by C57BL/6 mice promotes tolerance to its interoceptive cues and increases extracellular dopamine, an effect blocked by naltrexone.

BACKGROUND: C57BL/6 (B6) mice voluntarily consume ethanol. Although preingestive factors might be accountable, the fact that B6 mice voluntarily consume sufficient ethanol to set the conditions for an ethanol-deprivation effect suggest that post-ingestive pharmacological induced changes also occur. In this study, we determined the amounts of ethanol voluntarily consumed by B6 mice and associated blood ethanol levels (BEL), the effects of this consumption on extracellular dopamine (DA) and how this was altered by naltrexone, as well as on its interoceptive discriminative cues. METHODS: In experiment 1, the amounts of 12% ethanol consumed at 2, 4, and 6 hr into the active phase of the circadian cycle and associated BEL were determined. In experiment 2, dialysate samples were collected for 1 hr to establish basal DA levels. Mice were then injected with saline or naltrexone (6 mg/kg) and given access to water and 12% ethanol or to water only, and samples were collected at 20-min intervals for the next 2 hr. In experiment 3, mice were trained to discriminate ethanol's interoceptive cues via operant techniques, and half were given 3 weeks access to ethanol and water, the other half water only. Ethanol-consuming and water control mice were again tested for their ability to discriminate the drug's interoceptive cues. RESULTS: Mice ingested nearly 6 g/kg of ethanol and attained BEL near 100 mg/100 mL by 6 hr into the active phase. Ethanol intake at 2-hr into the dark phase was approximately 2.5 g/kg, and increased DA to approximately 100% above basal levels. Naltrexone reduced ethanol consumption and blocked the DA increase. Ethanol consumption for 3 weeks attenuated its discriminative cues. CONCLUSIONS: B6 mice voluntarily consume sufficient ethanol (1) to produce intoxicating BEL; (2) to increase DA levels in nucleus accumbens, an effect blocked by naltrexone; and (3) to attenuate its discriminative cues.

Alcoholism↗
PubMed2003

Glutamate transmission and addiction to cocaine.

A variety of data point to the possibility that neuroadaptations in glutamate transmission are produced by repeated exposure to cocaine that result in the expression of behaviors characteristic of addiction, such as craving and relapse. Using the reinstatement model of relapse in rats, glutamate release in the projection from the prefrontal cortex to the nucleus accumbens has been shown to underlie cocaine- and stress-primed reinstatement. In this report, four adaptations produced by withdrawal from repeated cocaine are described that may regulate the release of glutamate underlying reinstatement of drug-seeking resulted. (1) Neurons in the prefrontal cortex have increased levels of activator of G protein signaling 3 (AGS3) that causes reduced signaling through Gi coupled receptors, and normalization of AGS3 blocked cocaine-primed reinstatement. (2) The activity of the cystine-glutamate exchanger is reduced resulting in decreased extracellular glutamate in the nucleus accumbens, and normalization of exchanger activity prevented cocaine-primed reinstatement. (3) Metobotropic glutamate receptor function is diminished after repeated cocaine administration that results in reduced regulation of glutamate release. (4) Homer1 protein is reduced in the nucleus accumbens, and Homer2 knockout mice show enhanced responsiveness to cocaine. Taken together, there appears to be both pre- and postsynaptic changes in glutamate transmission that dysregulates the glutamatergic projection from the prefrontal cortex to the nucleus accumbens. These adaptations are hypothesized to facilitate glutamate release in response to a cocaine injection or acute stress and lead to the reinstatement of drug-seeking behavior.

Animals↗
PubMed2002

Pretreatment with serotonin 5-HT(3) receptor antagonists produces no observable blockade of long-term motor sensitization to cocaine in rats.

RATIONALE: Serotonin 5-HT(3) receptor antagonists are proposed to serve as potential anti-addictive and anti-psychotic therapies. OBJECTIVE: The present study re-examined the hypothesis that the activation of 5-HT(3) receptors is required for the development of long-term motor sensitization to repeated cocaine (COC). METHODS: Rats were pretreated with vehicle (VEH) or one of three 5-HT(3) receptor antagonists, MDL 72222, Y-25130 or ondansetron, 30 min prior to seven daily COC or saline (SAL) injections. Three weeks later, animals were challenged with COC in a test for sensitization. For comparison, the effects of pretreatment with the dopamine (DA) receptor antagonist fluphenazine and a combination of fluphenazine and Y-25130 were assessed. RESULTS: Pretreatment with ondansetron, Y-25130, fluphenazine and their combination significantly attenuated COC-induced behaviors during repeated treatment but not on the test for sensitization. MDL 72222 pretreatment enhanced motor sensitization on the test day. In repeated SAL rats, pretreatment with ondansetron, Y-25130 and fluphenazine+Y-25130 enhanced COC-induced rearing on the test for sensitization. CONCLUSIONS: These data indicate the effects of 5-HT(3) receptor antagonists on both acute COC-induced motor behavior and COC-induced motor sensitization are compound-selective. As none of the 5-HT(3) receptor antagonists attenuated the magnitude of the sensitized motor response to COC in the long term, these data also indicate that like DA receptor activation, 5-HT(3) receptor activation is necessary for the full expression of acute COC-induced motor hyperactivity, but it is not required for the development of long-term motor sensitization.

Anesthetics, Local↗
PubMed2002

The origin and neuronal function of in vivo nonsynaptic glutamate.

Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ and Ca2+ channels produced relatively minimal changes (0-30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine-glutamate antiporter. By measuring [35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission.

Animals↗
PubMed2002

Repeated cocaine administration alters the expression of genes in corticolimbic circuitry after a 3-week withdrawal: a DNA macroarray study.

Addiction to psychostimulants elicits behavioral and biochemical changes that are assumed to be mediated by alterations of gene expression in the brain. The changes in gene expression after 3 weeks of withdrawal from chronic cocaine treatment were evaluated in the nucleus accumbens core and shell, dorsal prefrontal cortex and caudate using a complementary DNA (cDNA) array. The level of mRNA encoded by several genes was identified as being up- or down-regulated in repeated cocaine versus saline subjects. The results from the cDNA array were subsequently confirmed at the protein level with immunoblotting. Of particular interest, parallel up-regulation in protein and mRNA was found for the adenosine A1 receptor in the accumbens core, neuroglycan C in the accumbens shell, and the GluR5 glutamate receptor subtype in dorsal prefrontal cortex. However, there was an increase in TrkB protein in the nucleus accumbens core of cocaine-treated rats without a corresponding alteration in mRNA. These changes of gene expression in corticolimbic circuitry may contribute to the psychostimulant-induced behavioral changes associated with addiction.

Animals↗