Biomedical subjects

Peter W Kalivas

Publications and source records attributed to Peter W Kalivas.

57 records · Page 4Linked to original sources

PubMed2002

Neuroadaptive changes in NMDAR1 gene expression after extinction of cocaine self-administration.

The aim of the present work was to study the time course effects in levels of mRNA encoding N-methyl-d-aspartate receptor subunit 1 (NMDAR1) after long-term cocaine self-administration (1 mg/kg/ injection) and its extinction using a yoked-box procedure. NMDAR1 content was measured by quantitative in situ hybridization histochemistry in prefrontal cortex, caudate-putamen, nucleus accumbens, olfactory tubercle, and piriform cortex immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5, and 10 days after the extinction period. The results show that long-term cocaine self-administration and its extinction alter NMDAR1 gene expression in these forebrain regions, and that the changes depend upon the brain region examined and the type of cocaine administration (contingent, noncontingent, and saline). Compared to saline and noncontingent cocaine administration, contingent cocaine produced an up-regulation in NMDAR1 gene expression on Day 0 in all the brain regions analyzed. NMDAR1 levels of contingent animals decreased progressively in the absence of cocaine, and the decrement persisted 10 days after the extinction of cocaine self-administration behavior in all the forebrain areas, with the exception of olfactory tubercle. In contrast, noncontingent cocaine administration did not produce any change in NMDAR1 gene expression on Day 0, and extinction resulted in an increase of NMDAR1 mRNA content on Days 1 and 5 and returned to control (saline) values on Day 10. These results suggest that an interaction between environmental stimuli and the pharmacological action of cocaine during drug self-administration and its extinction may represent an important factor in the regulation of cocaine effects on NMDAR1 gene expression.

Analysis of Variance↗

PubMed2002

Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine.

Repeated cocaine produces enduring neuroadaptations in glutamate transmission in the nucleus accumbens that are thought to contribute to addiction. Group II metabotropic glutamate autoreceptors (mGluR2/3) regulate glutamate release, and this study investigates whether repeated cocaine injection produces long-lasting alterations in mGluR2/3 content, phosphorylation, and physiology. Rats were administered cocaine daily for 1 week, and 3 weeks after the last injection, mGluR2/3 protein levels were altered in the accumbens and prefrontal cortex (PFC) but not in the dorsal striatum or ventral tegmental area. The level of mGluR2/3 dimer was elevated in the accumbens and PFC and the monomer was reduced in the PFC only. Furthermore, the relative Ser phosphorylation state of the monomer was elevated in both the accumbens and PFC of cocaine-pretreated subjects, whereas the dimer demonstrated negligible phosphorylation in either treatment group. These changes in mGluR2/3 level and phosphorylation state were associated with reduced mGluR2/3 agonist-induced guanosine 5'-3-O -(thio)triphosphate binding in the accumbens and PFC, but not in the dorsal striatum. Stimulation of mGluR2/3 reduces extracellular glutamate by inhibiting Ca(2+)-dependent and cystine/glutamate antiporter-mediated glutamate release. The capacity of the mGluR2/3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit [(35)S]cystine uptake via cystine/glutamate antiporter in accumbens tissue slices was reduced by repeated cocaine. Also, the capacity of APDC to reduce the basal and potassium-stimulated extrasynaptic glutamate was significantly blunted in the accumbens of cocaine-pretreated subjects. Together, these data demonstrate that repeated cocaine produces an enduring reduction in mGluR2/3 function in the nucleus accumbens.

Animals↗

PubMed2002

Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens.

The regulation of extracellular glutamate in the nucleus accumbens by group II metabotropic glutamate receptors (mGluR2/3) was examined in vivo. Stimulation of mGluR2/3 with 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or N-acetylaspartylglutamate reduced extracellular glutamate levels. Conversely, blockade of mGluR2/3 by LY143495 or (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate, an effect antagonized by the coadministration of APDC. These effects likely involve both vesicular and nonvesicular glutamate, because the increase in glutamate by APICA or the decrease by APDC was prevented by blocking N-type calcium channels and the release of glutamate after potassium-induced membrane depolarization was antagonized by APDC. In addition, blockade of the cystine-glutamate exchange, a major nonvesicular source of extracellular glutamate, by (S)-4-carboxyphenylglycine blocked the effects induced by either APDC or APICA. However, blockade of Na(+) channels by tetrodotoxin or Na(+)-dependent glutamate transporters by DL-threo-beta-benzyloxyaspartate failed to affect the alterations in extracellular glutamate by APICA or APDC, respectively. Group II mGluRs are G(i)-coupled and coperfusion with the cAMP-dependent protein kinase (PKA) activator Sp-cAMPS blocked the reduction in glutamate by APDC and the PKA inhibitor Rp-cAMPS prevented the elevation in glutamate by APICA. Taken together, these data support three conclusions: 1) group II mGluRs regulate both vesicular and nonvesicular release of glutamate in the nucleus accumbens, 2) there is tonic in vivo stimulation of mGluR2/3 by endogenous glutamate, and 3) modulation of group II mGluRs of extracellular glutamate is Ca(2+)- and PKA-dependent.

Amino Acid Transport System X-AG↗