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J Psychopharmacol. 2014 Sep;28(9):857-65. doi: 10.1177/0269881114527360. Epub 2014 Mar 26.

Amphetamine sensitisation and memory in healthy human volunteers: a functional magnetic resonance imaging study.

Author information

1
Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK Centre for Neuroimaging Sciences, King's College London, London, UK o.o'daly@kcl.ac.uk.
2
Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK.
3
Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK Oxleas NHS Foundation Trust, London, UK.
4
Department of Economics, University of Zürich, Zürich, Switzerland Wellcome Trust Centre for Neuroimaging, University College London, London, UK.
5
Department of Psychosis Studies, King's College London, London, UK.
6
Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK The National Psychosis Unit, South London and Maudsley NHS Foundation Trust, London, UK.

Abstract

Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.

KEYWORDS:

Amphetamine; dopamine; medial temporal lobe; midbrain; motor learning; sensitisation

PMID:
24671338
DOI:
10.1177/0269881114527360
[Indexed for MEDLINE]

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