In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but

not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired Histone Methyltransferase inhibitor cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for

the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.”
“Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (Ca(V)3) calcium channels in thalamocortical physiology, the direct involvement of these calcium channels in cocaine-mediated effects needs to be further explored.

The objective of this study was to investigate the effect of T-type calcium channel blockers on acute and repetitive Pexidartinib cocaine administration that mediates thalamocortical alterations in mice using three different T-type blockers: 2-octanol, nickel, and mibefradil.

During in vitro experiments, whole-cell patch-clamp recordings were conducted in ventrobasal (VB) thalamic neurons from mice treated with acute repetitive cocaine administration (3 x 15 mg/kg, i.p., 1 h apart), under bath application of mibefradil (10 mu M), 2-octanol (50 mu M), or nickel (200 mu M). After systemic administration of T-type calcium channel blockers, we evaluated locomotor activity and also recorded GABAergic neurotransmission onto VB neurons in vitro.

Bath-applied mibefradil, 2-octanol, or nickel significantly reduced both GABAergic neurotransmission and T-type currents of VB neurons in cocaine-treated

mice. In vivo Tobramycin i.p. pre-administration of either mibefradil (20 mg/kg and 5 mg/kg) or 2-octanol (0.5 mg/kg and 0.07 mg/kg) significantly reduced GABAergic mini frequencies onto VB neurons. Moreover, both mibefradil and 2-octanol were able to decrease cocaine-induced hyperlocomotion.

The results shown in this study strongly suggest that T-type calcium channels play a key role in cocaine-mediated GABAergic thalamocortical alterations, and further propose T-type channel blockers as potential targets for future pharmacological strategies aimed at treating cocaine’s deleterious effects on physiology and behavior.”
“A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse.