Amphetamine sensitization animal model for schizophrenia and drug addiction: study of learning, memory and spontaneous behaviours

Amphetamine sensitization induces neuro-adaptations in the cortico-limbic-striatal circuit. Consequently, it disrupts reward processing and incentive salience attribution to behavioural stimuli. It is used as a model for aspects of drug addiction and positive symptoms in schizophrenia. However, it is unclear whether it models cognitive impairment and negative symptoms, which often represent an unmet medical need. Amphetamine sensitization was confirmed by testing the mice used on locomotor response to a 2.5mg/kg amphetamine challenge 4 or 9 months post withdrawal from a repeated saline or amphetamine (2.5 mg/kg or 5 mg/kg) regimen. Our first aim was to expand previous findings showing attenuated cue but spared spatial learning for rewards in amphetamine sensitized mice dependent on basolateral amygdala and hippocampus respectively (Ito and Canseliet, 2010). The same dual learning paradigm in the t-maze used in that study was used here but we regularly rotated the maze in order to prevent mice from relying selectively on intra-maze cues to solve the task. Spatial learning was not acquired by mice. Cue learning was spared in amphetamine sensitized mice, showing that the latter can proceed normally under conditions that spatial learning is not acquired. Our second aim was to study appetitive spatial reference memory acquisition (acquisition phase), performance as well as spatial working memory (testing phase) and spatial pattern separation (both phases) in a within subjects, within trials radial maze task. No group differences were found. This is consistent with unaffected spatial learning shown by Ito and Canseliet (2010). Latency to acquire all rewards in the acquisition phase was reduced in the combined amphetamine sensitized group. Our third aim was to study spontaneous behaviours. This is the first study that shows impaired social interaction of freely interacting pairs of mice 2 months post d-amphetamine withdrawal. No elevated anxiety was found on elevated plus maze or open field test. Social approach in the non-reciprocal sociability test as well as novel object recognition were unaffected. There was a non-significant trend for a reduced discrimination ratio for the novel conspecific in amphetamine sensitized mice with 5mg/kg in the social recognition test. Finally, an object-in-place test was used but didn’t work for control mice. Overall amphetamine sensitization does not seem to impair familiarity recognition or novelty preference. Thus, it does not model short term habituation deficit in schizophrenia. Also, it does not seem to impair learning and memory under conditions that the task does not involve simultaneous cue and spatial learning acquisition. Amphetamine sensitization might model social withdrawal selectively under conditions that involve reciprocal social interaction, but not cognitive impairment or anxiety in schizophrenia. This adds to previous evidence that amphetamine sensitization has poor validity as a model for cognitive impairment in schizophrenia. Also, it shows that it may have some validity as a model for social behaviour. Further research is required to clarify these findings

The involvement of substance P in the induction of aggressive behavior

Aggression is a complex social behavior that involves a similarly complex neurochemical background. The involvement of substance P (SP) and its potent tachykinin receptor (NK1) in the induction of both defensive rage and predatory attack appears to be a consistent finding. However, an overall understanding of the nature of the SP involvement in the induction of aggressive behavior has not yet been fully achieved. The aim of this review is to summarize and present the current knowledge with regards to the role of SP in the induction of aggressive behavior and to synopsize: (a) its biochemical profile, and (b) the exact anatomical circuits through which it mediates all types of aggressive behavior. Future studies should seriously consider the potential use of this knowledge in their quest for the treatment of mood and anxiety disorders

Experimentally-induced Wernicke's encephalopathy modifies crucial rat brain parameters: the importance of Na+,K+-ATPase and a potentially neuroprotective role for antioxidant supplementation

Wernicke's encephalopathy (WE) is a serious neuropsychiatric syndrome caused by chronic alcoholism and thiamine (T) deficiency. Our aim was to shed more light on the pathophysiology of WE, by introducing a modified in vivo experimental model of WE and by focusing on changes provoked in the total antioxidant status (TAS) and three crucial brain enzyme activities in adult rats. Rats were placed on ethanol (EtOH) consumption (20 % v/v) for a total of 5 weeks. By the end of the third week, rats were fed a T-deficient diet (TDD) and were treated with pyrithiamine (PT; 0.25 mg/kg) for the remaining 2 weeks. Following the induction of WE symptomatology, rats were treated with three consecutive (every 8 h) injections of saline or T (100 mg/kg) and were sacrificed. Brain homogenates were generated and used for spectrophotometrical evaluation of TAS and enzymatic activities. Additionally, in vitro experiments were conducted on brain homogenates or pure enzymes incubated with T or neuromodulatory antioxidants. Pre-exposure to EtOH provided a successful protocol modification that did not affect the expected time of WE symptomatology onset. Administration of T ameliorated this symptomatology. WE provoked oxidative stress that was partially limited by T administration, while T itself also caused oxidative stress to a smaller extent. Brain acetylcholinesterase (AChE) was found inhibited by WE and was further inhibited by T administration. In vitro experiments demonstrated a potential neuroprotective role for L-carnitine (Carn). Brain sodium-potassium adenosine triphosphatase (Na(+),K(+)-ATPase) activity was found increased in WE and was reduced to control levels by in vivo T administration; this increase was also evident in groups exposed to PT or to TDD, but not to EtOH. In vitro experiments demonstrated a potential neuroprotective role for this Na(+),K(+)-ATPase stimulation through T or L-cysteine (Cys) administration. Brain magnesium adenosine triphosphatase (Mg(2+)-ATPase) activity was found decreased by prolonged exposure to EtOH, but was not affected by the experimental induction of WE. Our data suggest that T administration inhibits AChE, which is also found inhibited in WE. Moreover, increased brain Na(+),K(+)-ATPase activity could be a marker of T deficiency in WE, while combined T and antioxidant co-supplementation of Cys and/or Carn could be neuroprotective in terms of restoring the examined crucial brain enzyme activities to control levels

Inform, conform, reform and do not deform: a four axons' framework for the Hellenic academic institutions facing the Greek crisis challenge

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