tacrolimus and adenosine-3--5--cyclic-phosphorothioate

The nucleus accumbens (NAc) plays a critical role in amphetamine-produced conditioned place preference (CPP). In previous studies inhibition or activation of cyclic adenosine monophosphate-dependent protein kinase (PKA) blocked NAc amphetamine-produced CPP. PKA activation unrelated to ongoing DA transmission may disrupt reward-related learning. Calcineurin (CN) down-regulates downstream PKA targets. Unlike PKA activation, CN inhibition may preserve and enhance reward-related learning. The PKA signalling cascade is negatively regulated by calcineurin (CN). We tested the hypothesis that post-training CN inhibition in NAc will enhance NAc amphetamine-produced CPP and that PKA activation will block CPP. Eight but not four or two 30-min conditioning sessions were sufficient to establish significant CPP. Immediate post-training, NAc injection of the calcineurin inhibitor FK506 (5.0 but not 1.0 microg in 0.5 microL per side) led to a significant amphetamine CPP in rats receiving four but not two training sessions; the 5.0-microg dose had no effect on rats trained with eight sessions. Injections of the PKA activator Sp-cAMPS (2.5 or 10.0 microg in 0.5 microL per side) failed to affect CPP following two or four training sessions and blocked CPP produced by a standard 8-day conditioning schedule. Results suggest that CN acts as a negative regulator in the establishment of NAc amphetamine-produced CPP, a form of reward-related learning.

Topics: Amphetamine; Analysis of Variance; Animals; Behavior, Animal; Calcineurin; Central Nervous System Stimulants; Conditioning, Operant; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Activation; Functional Laterality; Male; Motor Activity; Nucleus Accumbens; Protein Kinase Inhibitors; Rats; Rats, Wistar; Reaction Time; Tacrolimus; Thionucleotides; Time Factors

Treatment of small resting B cells with soluble F(ab')2 fragments of anti-IgM, an analogue of T-independent type 2 antigens, induced activation characterized by proliferation and the expression of surface CD5. In contrast, B cells induced to proliferate in response to thymus-dependent inductive signals provided by either fixed activated T-helper 2 cells or soluble CD40 ligand-CD8 (CD40L) recombinant protein displayed elevated levels of CD23 (Fc epsilon II receptor) and no surface CD5. Treatment with anti-IgM and CD40L induced higher levels of proliferation and generated a single population of B cells coexpressing minimal amounts of CD5 and only a slight elevation of CD23. Anti-IgM- but not CD40L-mediated activation was highly sensitive to inhibition by cyclosporin A and FK520. Sp-cAMPS, an analogue of cAMP, augmented CD40L and suppressed surface IgM-mediated activation. Taken together these results are interpreted to mean that there is a single population of small resting B cells that can respond to either T-independent type 2 (surface IgM)- or T-dependent (CD40)-mediated activation. In response to different intracellular signals these cells are induced to enter alternative differentiation pathways.

Topics: Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; B-Lymphocytes; CD40 Antigens; CD5 Antigens; Cells, Cultured; Cyclic AMP; Cyclosporine; Dose-Response Relationship, Drug; Flow Cytometry; Immunoglobulin M; Immunologic Capping; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Receptors, Antigen, B-Cell; Receptors, IgE; Signal Transduction; Spleen; Tacrolimus; Thionucleotides