Dopamine antagonist modulation of amphetamine response as detected using pharmacological MRI
Introduction
The neurotransmitter dopamine is involved in many aspects of normal brain function, including control of movement, emotion and motivation, and its dysfunction has been implicated in neurological and psychiatric disorders, notably Parkinson's disease (Ehringer and Hornykiewicz, 1960) and schizophrenia (Carlsson and Lindqvist, 1963). In addition dopamine has been implicated in mechanisms controlling reward and has been linked to a possible role in addiction (Di Chiara and Imperato, 1988).
Five main subtypes of dopamine receptor have been identified (Seeman et al., 1996), they can be broadly categorised into two types – D1-like (D1, D5), which have an excitatory action via stimulation of adenylate cyclase and D2-like (D2, D3, D4) which are inhibitory through inhibition of adenylate cyclase (Andersen et al., 1990). The anatomical distributions of these two receptor types overlap in the CNS, although their quantitative ratios differ significantly in certain anatomical areas (Mansour et al., 1990).
Evidence now suggests that D1 receptors may be particularly important in the manifestation and progression of Parkinson's disease (Blanchet et al., 1998) and in the action of l-Dopa on basal ganglia circuits in its treatment (Black et al., 2000), while D2 receptors are well-established as targets of antipsychotic drugs to treat neuropsychiatric disorders such as schizophrenia (Carlsson and Lindqvist, 1963). D2-type receptor dysfunction is also involved the etiology of hyperprolactinaemia (Sarapura and Schlaff, 1993) and drug and alcohol abuse (Wise and Bozarth, 1987).
The psychostimulant, amphetamine causes increases in extracellular dopamine, through actions on uptake mechanisms (Lau and Slotkin, 1976) and on monoamine oxidase (Mantle et al., 1976) therefore increasing dopamine availability to local dopamine receptors. Amphetamine administration is a popular model for studying schizophrenia (Robinson and Becker, 1986), behaviour (Kelly and Iversen, 1976) and reward systems (Kuczenski and Segal, 1992a). The region specific metabolic activation resulting from amphetamine stimulation can be imaged using many methods, including 2-deoxyglucose uptake (Wechsler et al., 1979), PET (Drevets et al., 1999) and SPECT (Dresel et al., 1998). However, these techniques all require administration of exogenous substances and may only allow a single time-point to be investigated (Wechsler et al., 1979).
Functional magnetic resonance imaging (fMRI) based on blood oxygen level dependant (BOLD) contrast (Ogawa et al., 1990), offers an approach to localise functional changes and map these changes sequentially over time in the same subject. Signal change observed in BOLD imaging results from a change in the ratio of oxygenated to deoxygenated haemoglobin. Thus, haemodynamic responses to increased neuronal activity such as increased cerebral blood flow and volume, result in an increase in the above ratio (hyperaemia), observed as changes in signal contrast (Ogawa et al., 1990). In experimental animals, fMRI has been used to measure signal changes following somatosensory stimulation (Hyder et al., 1994) and direct cortical stimulation (Austin et al., 2003). Pharmacolocical MRI (phMRI) uses the same technology, but measures the responses to drug administration: the dopamine system in particular lends itself to this type of study because of its regional specificity, and because reproducible animal models exist for dopamine receptor binding (Trugman and James, 1993). Amphetamine administration has been previously investigated using phMRI (Chen et al., 1997); where only particular regions of interest were examined. In the following experiment the nature of the functional response to amphetamine administration is investigated with regards to spatial and temporal response profiles, in the entire brain (30×1 mm) and also the relative contributions of different dopamine receptor activity in the response.
We used rapid acquisition with relaxation enhancement (RARE, Hennig et al., 1986), a fast imaging technique, to acquire time resolved, multiple slice datasets (volumes) in individual subjects, to image drug-induced changes. Experimental studies that can follow the effects of psychoactive compounds on cerebral function over time provide a greater insight into the time course of drug effects, as well as the anatomical loci of drug action; since different loci may be associated with therapeutically desirable actions as well as unwanted side-effects such information will providing greater insight into the properties of psychotropic agents.
In this study, an acute amphetamine administration model (Chen et al., 1997) was modified in order to investigate changes in functional dopaminergic activity during amphetamine administration, in the whole rat brain using phMRI. In addition, in order to assess the role of different receptor types in the action of amphetamine, separate groups of animals were pretreated with the dopamine D1 receptor antagonist, SCH23390, or the D2 receptor antagonist, sulpiride, prior to amphetamine administration. The concentration of antagonists were chosen on the basis of their previously reported blockade of both behavioural and pharmacological effects of amphetamine (Trugman and James, 1993, Marota et al., 2000, Jaworski et al., 2001).
Section snippets
Methods and materials
All procedures were performed in accordance with the Animals (Scientific Procedures) Act, 1986, under appropriate project and personal licence authority. Forty male Sprague–Dawley rats (250–300 g) (Harlan UK, Ltd, Bicester, UK), housed three per cage with food and water ad libitum, were assigned randomly into five groups: three drug administration groups and two control groups, in each group. The experimental groups were administered: (1) amphetamine (3 mg/kg, i.v), (2) pretreatment with
Vehicle control infusions (n=8)
Control infusions of either vehicle (saline or propylene glycol) did not cause any statistically significant changes in BOLD signal in any part of the brain (data not shown).
Experiment 1: amphetamine challenge (3 mg/kg, i.v, n=8)
Bonferroni corrected data showed that acute intravenous infusion of amphetamine had significant () effect on the BOLD signal in many areas throughout the brain. Four brain slices are shown in the statistical parametric maps of regions which represent statistically significant relative increases in BOLD (+veBOLD)
Discussion
The results show a widespread BOLD response to acute amphetamine challenge, extending from the olfactory cortex through to the cerebellum (Fig. 1b). Incidences of +veBOLD contrast were evident in many structures, and although largely subcortical, the increased contrast did extend up to the lower layers of the cortex, in particular the motor and somatosensory cortices. The anatomical pattern of amphetamine induced +veBOLD contrast detected in this study correlate with dopamine receptors
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