The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl(-/-)arg(-/-) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.
Background Intermittent access to drugs of abuse, as opposed to continuous access, is hypothesized to induce a kindling-type transition from moderate to escalated use, leading to dependence. Intermittent 24-hour cycles of ethanol access and deprivation can generate high levels of voluntary ethanol drinking in rats. Methods The current study uses C57BL/6J mice (B6) in an intermittent access to 20% ethanol protocol to escalate ethanol drinking levels. Adult male and female B6 mice were given intermittent access to 20% ethanol on alternating days of the week with water available ad libitum. Ethanol consumption during the initial 2 hours of access was compared to a short term, limited access “binge” drinking procedure, similar to drinking-in-the-dark (DID). B6 mice were also assessed for ethanol dependence with handling-induced convulsion (HIC), a reliable measure of withdrawal severity. Results After 3 weeks, male mice given intermittent access to ethanol achieved high stable levels of ethanol drinking in excess of 20 g/kg/24h, reaching above 100 mg/dl BEC, and showed a significantly higher ethanol preference than mice given continuous access to ethanol. Also, mice given intermittent access drank about twice as much as DID mice in the initial 2-hour access period. B6 mice that underwent the intermittent access protocol for longer periods of time displayed more severe signs of alcohol withdrawal. Additionally, female B6 mice were given intermittent access to ethanol and drank significantly more than males (ca. 30 g/kg/24h). Discussion The intermittent access method in B6 mice is advantageous because it induces escalated, voluntary, and preferential per os ethanol intake, behavior that may mimic a cardinal feature of human alcohol dependence, though the exact nature and site of ethanol acting in the brain and blood as a result of intermittent access has yet to be determined.
(1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D(2) receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABA(A) receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.
The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA–accumbens–PFC–amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe–PFC–hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.
Dopamine (DA) and serotonin have been implicated in the regulation of aggressive behavior, but it has remained challenging to assess the dynamic changes in these neurotransmitters while aggressive behavior is in progress. The objective of this study was to learn about ongoing monoamine activity in corticolimbic areas during aggressive confrontations in rats. Male Long-Evans rats were implanted with a microdialysis probe aimed at the nucleus accumbens (NAC) or medial prefrontal cortex (PFC); next, 10 min samples were collected before, during, and after a 10 min confrontation. Rats continued to display aggressive behavior while being sampled, and they performed two to six attack bites as well as 140 sec of aggressive acts and postures. Dopamine levels in NAC were significantly increased up to 60 min after the confrontation. Peak levels of 140% were achieved ϳ20-30 min after the confrontation. No concurrent changes in accumbal serotonin levels were seen during or after the confrontation. Dopamine and serotonin levels in PFC changed in the opposite direction, with a sustained decrease in serotonin to 80% of baseline levels during and after the confrontation and an increase in dopamine to 120% after the confrontation. The temporal pattern of monoamine changes, which followed rather than preceded the confrontation, points to a significant role of accumbal and cortical DA and 5-hydroxytryptamine in the consequences as opposed to the triggering of aggressive acts. The increase in accumbal DA in aggressive animals supports the hypothesis that this neural system is linked to the execution of biologically salient and demanding behavior. Key words: aggression; dopamine; serotonin; nucleus accumbens; prefrontal cortex; rats; microdialysis; behaviorThe proposal of a deficit in brain serotonin [5-hydroxytryptamine (5-HT)] as a trait marker for violence-prone individuals is based on measurements that are divorced from the actual behavioral event (Mann et al., 1995;Mann, 1999). In such individuals, low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in CSF compared with nonviolent controls (Brown et al., 1982;Linnoila et al., 1983;Kruesi et al., 1990;Coccaro, 1992;Virkkunen et al., 1996;Kavoussi et al., 1997). In juvenile monkeys, low levels of 5-HIAA are correlated with increased risk-taking and impulsivity (Higley et al., 1992(Higley et al., , 1996Mehlman et al., 1994). If 5-HT undergoes dynamic state changes (Jacobs and Fornal, 1999) then in vivo measures would indicate whether altered serotonin actually is linked to the occurrence of episodes of aggression.In rodents, aggressive behavior is effectively reduced by treatment with 5-HT 1A and 5-HT 1B receptor agonists (Olivier and Mos, 1986;Olivier et al., 1987;De Almeida and Lucion, 1997;Simon et al., 1998;de Boer et al., 1999;Ferris et al., 1999;Fish et al., 1999). Furthermore, aggression is increased in 5-HT 1B receptor knock-out mice (Saudou et al., 1994). 5-HT modulates aggressive behavior in interaction with other neurotransmitters, of...
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