CaM Kinases: From Memories to Addiction

Abstract

Drug addiction is a major psychiatric disorder with a neurobiological base that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca 2+ /calmodulin-dependent protein kinases (CaMKs) are important Ca 2+ -sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drugrelated behaviours in animal models and in humans. Converging evidence shows now that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity; they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. Keywords: Ca 2+/calmodulin-dependent protein kinase, drug dependence, addiction, psychostimulants, alcohol, opioids 3 Drug Use and AddictionDrug addiction is a major psychiatric disorder for which only limited therapies are currently available [1,2]. A striking criterion for drug abuse and addiction is that it severely threatens one's own and others well-being and health. As such, there is a persistent need to treat drug addiction effectively, and ideally reverse the behavioural repertoire of an affected individual back to normal.An important feature of drug addiction is that it develops from a behavioural repertoire, which is considered to be normal in many societies of the world: the controlled consumption and instrumentalization of psychoactive drugs [3,4].Establishing and maintaining controlled drug consumption is based on systematic learning and memory retrieval of distinct behaviours, related to drug seeking, preparation, and consumption in a specific context [5,6]. Thereby, information is encoded within different behavioural systems, which can be summarized as "drug memories" [5,[7][8][9] (Box 1). It is believed that an intensification of these memories together with a loss of impulse control (compulsivity) is responsible for the transition from controlled drug use to addiction [10][11][12]. Understanding how these drug memories are established and how they may take control over a normal behavioural repertoire should, therefore, allow to improve the prevention of addiction and to develop new and more effective treatments [13]. From Memories to Drug MemoriesIt was suggested that anatomical pathways, micro-morphological adaptations, as well as molecular mechanisms in the brain, overlap between normal learning and memory and drug memories [14][15][16]. A crucial player for memory formation in the brain is the glutamatergic system and its plasticity based on experience [17]. Addiction research considered glu...

Brain molecular changes and behavioral alterations induced by propofol anesthesia exposure in peripubertal rats

“…Our findings are also consistent with previous reporting characteristic profile of behavioral sensitization in periadolescent rodents, ie, increased hyperactivity but not stereotypy . It is our belief that increased expression of pCaMKIIα within the striatum of propofol exposed rats contributed to observed increase in d‐AMPH‐induced locomotion, as CaMKIIα interacts with the dopamine transporter, favors AMPH‐induced dopamine efflux, and is important for locomotor sensitization . However, findings observed 4 hour after propofol exposure (augmented pCaMKIIα level without significant behavioral changes) indicate that pCaMKIIα is rather necessary than sufficient for increase in d‐AMPH‐induced locomotion in the propofol exposed peripubertal animals.…”

“…Unchanged pCaMKIIα/CaMKIIα ratio in the prefrontal cortex and the striatum suggests that observed increases in pCaMKIIα expression were accompanied by increased expression of CaMKIIα (although it was not assessed as significant per se ). Nevertheless, this is in line with the literature reporting that many addictive drugs increase CaMKIIα activity by increased expression, increased phosphorylation, or both …”

“…In light of that, our previous results were among the first that accentuated apoptotic neurodegeneration as well as disturbances in activity‐dependent processes/synaptic adjustment in neonatal rat brain immediately after propofol exposure, and altered response to psychotropic stimulation, hyperactivity, and cognitive difficulties later, during the periadolescence . Findings of the present study accentuate that in peripubertal rats, propofol exposure (i) affects expression/phosphorylation of critical brain signaling molecules that are already recognized in the action of addictive drugs, at time‐ and brain region‐specific manner; (ii) does not influence motor activity in basal conditions; (iii) increases locomotor response to d‐AMPH, an indication that these two drugs influence similar neural systems despite their different primary mechanisms of action; and (iv) decreases behavioral inhibition in aversive environment. In the absence of additional pharmacological manipulation, all detected effects receded within 48 hour after propofol exposure.…”

“…The increase was especially evident in the midline (with the accent on PVT) and the MD region of the thalamus, areas already recognized as a dopaminoceptive inside the rat thalamus . Contrary to the thalamus, the striatum and mPFC showed a significant increase in pCaMKIIα expression, a biochemical sensor of synaptic activity that plays an important role in drug memories, 4‐24 hour of postanesthesia period. However, the involvement of dopamine neurotransmission in the observed phenomenon should not be excluded as D1DR/PKA‐regulated signaling can result in increased CaMKIIα phosphorylation .…”

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

“…We also found that increased pain avoidance was associated with decreased phosphorylation of CaMKII Thr286 the VS. Tyrosine hydroxylase is the rate-limiting enzyme involved in dopamine biosynthesis, activated via serine 40 phosphorylation in a negative feedback fashion when there is a deficit of dopamine (Molinoff & Axelrod, 1971). In addition, CaMKII regulates dopaminergic activity in the striatum by regulating dopamine biosynthesis and dopamine transport (Sutoo et al, 2002; Fog et al, 2006; Steinkellner et al, 2012; Kawaai et al, 2015; Muller et al, 2016). Accordingly, our findings indicate that regulation of striatal dopamine signaling is closely associated with pain avoidance-like behavior.…”