The a-Ca 2 þ /calmodulin-dependent protein kinase II (aCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of aCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of aCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in aCaMKII autophosphorylation-deficient aCaMKII T286A mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in aCaMKII T286A mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that aCaMKII T286A mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in aCaMKII T286A mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest aCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.
There is evidence that both cholinergic and GABAergic systems are involved in the neurobiology of anxiety. In the present study, we investigated the effects and interaction of nicotinic and GABAergic systems in the central amygdala of rats, using the elevated plus maze test of anxiety. Bilateral administration of nicotine (1 and 2 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) into the central amygdala (intra-CeA) induced an anxiogenic-like effect, shown by specific decreases in the percentage of open-arm time (%OAT) and percentage of open arm entries (%OAE). Intra-CeA injection of mecamylamine, a selective nicotine acetylcholine receptor antagonist (20, 30 and 50 ng/rat; 1 µl/rat; 0.5 µl/rat in each side) produced significant anxiolytic-like behaviour. The intra-CeA injection of the GABAA receptor agonist muscimol (0.25, 0.5 and 0.75 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) decreased %OAT and %OAE, indicating anxiogenic-like behaviour. However, intra-CeA administration of the GABAA receptor antagonist bicuculline (0.25, 0.5 and 1 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) produced significant anxiolytic-like behaviour. Nicotine in a subeffective dose (0.25 µg/rat) when co-administered with muscimol did not significantly increase the anxiety behaviour. An effective dose of nicotine (2 µg/rat) in combination with bicuculline (0.25, 0.5 and 1 µg/rat) had no interaction on %OAT, %OAE and locomotor activity. It can be concluded that in the central amygdala, the GABAergic system is not involved in the anxiogenic response to nicotine.
Aims:In the present study, we investigated the possible influence of the opioidergic system of the dorsal hippocampus on anxiety-like behaviors.Methods: Elevated plus-maze, which is one of the methods used for testing anxiety, was used in the present study. Rats were anesthetized with ketamine and xylazine and special cannulas were inserted stereotaxically into the CA1 region of the dorsal hippocampus. After 1 week of recovery, the effects of intra-CA1 administration of morphine (0.25, 0.5, 1 and 2 mg/rat; 1 ml/rat; 0.5 ml/in each side), naloxone (2, 4, 6 and 8 mg/rat), enkephalin (1, 2, 5 and 10 mg/rat) and naltrindole (0.25, 0. ]-enkephalin acetate hydrate into the CA1, induced an anxiolytic-like effect. Furthermore, intra-CA1 injection of d-opioid receptor antagonist, naltrindole hydrochloride, increased anxiety-related behaviors. Conclusions:The results of the present study demonstrate that activation of m-opioid receptors in this area produce an anxiogenic response while activation of d-opioid receptors produces an anxiolytic response.
Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca2+/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKIIT286A mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg−1, intraperitoneal). In vivo microdialysis revealed that αCaMKIIT286A mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg−1, intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKIIT286A mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine's reinforcing effects.
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