Actions of Lithium on the Cyclic AMP Signalling System in Various Regions of the Brain ‐ Possible Relations to its Psychotropic Actions ‐: A Study on the Adenylate Cyclase in Rat Cerebral Cortex, Corpus Striatum and Hippocampus

Abstract

It has been estimated that in most industrialized countries 1 person out of every 1000 in the population is undergoing lithium treatment to stabilize their episodic mood disturbances due to manic-depressive illness. Lithium may stabilize mood swings by altering the action of certain neurotransmitters at the synaptic level in the brain. Recent research suggests that lithium alters neurotransmission by affecting neurotransmitter-coupled second messenger systems. A major second messenger system is the adenylate cyclase, which generates intracellular cAMP from ATP. The adenylate cyclases (type I-IV) are regulated by stimulatory and inhibitory receptors, which either stimulate or inhibit the adenylate cyclase activity. The stimulatory and inhibitory neurotransmitter-receptor signals are transferred to the catalytic unit of the adenylate cyclase by Gs and Gi, respectively. The activated receptor induces GTP stimulation of the heterotrimeric G protein, leading to a dissociation of the protein into the active alpha*GTP and the beta gamma complex. The former stimulates the catalytic unit of adenylate cyclase. The stimulation is terminated by a GTPase located on the alpha subunit that converts GTP to inactive GDP. At present, G proteins are known to play a central role in coupling receptors to effector proteins. In addition to extracellular regulation due to neurotransmitters, some adenylate cyclases (type I, III) are regulated by CaM as a consequence of enhanced intracellular concentrations of free Ca2+. The Ca(2+)-dependent stimulation of adenylate cyclase by CaM is assumed to occur by a direct effect on the catalytic unit. The catalytic units sensitive to Ca(2+)-CaM are also subjected to regulation by stimulatory and inhibitory neurotransmitter stimuli. Magnesium is essential for adenylate cyclase activity, since MgATP2- is the enzyme substrate. Furthermore, one Mg2+ site located on the G protein regulates both the receptor agonist affinity and the dissociation of the G protein during the activation cycle. A second Mg2+ site on the catalytic unit is responsible for Mg2+ regulation of the catalytic activity. The present work aimed at investigating the mechanisms by which lithium in vitro and after chronic treatment (ex vivo) affects adenylate cyclase activities in various regions of the rat brain. Lithium in vitro and ex vivo inhibited the selective stimulation of adenylate cyclase by Ca(2+)-CaM in the cerebral cortex. Furthermore, lithium in vitro interacted directly with the catalytic unit of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 α and AP-2 β in Frontal Cortex of Rats Treated with Lithium for 6 Weeks

“…Another reason for delayed gene expression during lithium feeding to intact animals is the approximately 1-week half-life for lithium to reach a steady-state brain concentration, due to its slow penetration across the blood-brain barrier (Bosetti et al, 2002b). In this regard, lithium has been reported to target G-proteins (Li et al, 1993;Miki et al, 2001;Wang and Friedman, 1999), cyclic adenosine monophosphate (cAMP) (Mork, 1993;Mork and Geisler, 1995), protein kinase A (Mori et al, 1998), protein kinase C (PKC) (Manji et al, 1993(Manji et al, , 1996Soares et al, 2000) and its substrate MARCKS (Lenox et al, 1992;Watson and Lenox, 1996), glycogen synthase kinase-3 beta (GSK-3 b) (De Sarno et al, 2002), and activating protein 1 (AP-1) transcription factor (Ozaki and Chuang, 1997;Yuan et al, 1999). We reported that 6 weeks of lithium administration to rats, so as to produce therapeutically relevant plasma and brain lithium concentrations, resulted in reduced arachidonic acid (AA) turnover in brain phospholipids (Chang et al, 1996).…”

Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis

“…There are multiple studies suggesting its involvement in BP disorder, both because of alterations in its levels and activity [39][40][41][42] and because it is a target for lithium and other mood stabilizing agents. 43,44 In summary, we present evidence that, taken together with independent findings by other investigators, strongly suggests the presence of a gene for BP disorder on chromosome 8q24. Furthermore, we make an argument for more appropriate models in multipoint linkage of complex disorders that consider the likelihood of the existence of common variants with low penetrance in these diseases.…”

Acute and Long‐Term Treatments with the Selective Serotonin Reuptake Inhibitor Citalopram Modulate the HPA Axis Activity at Different Levels in Male Rats

“…The adenylyl cyclase activity was measured as described by Mørk ( 23). In brief, whole pituitaries were homogenized in 50 vol.…”