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.

Keywords: amphetamine sensitization
animal models
mice behavioral analysis
schizophrenia
drug addiction
Advisor: Bannerman, D
Murphy, R