Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA.
Psychopharmacology (Impact Factor: 3.88). 09/2010; 212(1):59-72. DOI: 10.1007/s00213-010-1924-6
Source: PubMed


Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry.
We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry.
We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography.
D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques.
MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum.

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    • "The D2-like family includes D2, D3 and D4 receptors that interact with G i or G 0 proteins (Neve et al., 2004). DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas (Choi et al., 2010) that have been found to be critically involved in reward-related learning induced by drugs of abuse (Di Chiara and Imperato, 1988; Nestler, 2005; Stuber et al., 2005; Hyman et al., 2006; Schultz, 2010). This expression pattern has sparked numerous studies on the role of this receptor in drug-induced behaviors and motivated intense efforts in drug discovery (Parsons et al., 1996; Pilla et al., 1999; Heidbreder et al., 2005; Micheli and Heidbreder, 2008; Heidbreder and Newman, 2010; Spanagel and Vengeliene, 2013). "
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    ABSTRACT: Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-minute (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least one week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings.
    Full-text · Article · Mar 2013 · Neuroscience
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    • "It has been shown that hemodynamic regulation is heterogeneous and that functionally induced microvascular changes can occur at small spatial scales, i.e., at the level of columns and layers (Chaigneau et al., 2003; Erinjeri and Woolsey, 2002). Laminar differences in blood volume and flow have been observed in baseline conditions as well as after stimulation, showing that blood flow regulation differs between layers and between superficial vessels and parenchyma (Choi et al., 2010; Moskalenko et al., 1998; Zaharchuk et al., 1999). Baseline blood flow and vascularization are highest in the center of the cortex (Duvernoy et al., 1981; Gerrits et al., 2000; Moskalenko et al., 1998; Weber et al., 2008). "
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    ABSTRACT: The six cortical layers have distinct anatomical and physiological properties, like different energy use and different feedforward and feedback connectivity. It is not known if and how layer-specific neural processes are reflected in the fMRI signal. To address this question we used high-resolution fMRI to measure BOLD, CBV, and CBF responses to stimuli that elicit positive and negative BOLD signals in macaque primary visual cortex. We found that regions with positive BOLD responses had parallel increases in CBV and CBF, whereas areas with negative BOLD responses showed a decrease in CBF but an increase in CBV. For positive BOLD responses, CBF and CBV increased in the center of the cortex, but for negative BOLD responses, CBF decreased superficially while CBV increased in the center. Our findings suggest different mechanisms for neurovascular coupling for BOLD increases and decreases, as well as laminar differences in neurovascular coupling.
    Preview · Article · Nov 2012 · Neuron
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    • "Indeed, the time course for the CBV change induced with cocaine in the hypothalamus matches well with the time course produced by administration of the D3 agonist 7-OHDPAT (compare time courses in Fig. 6 with Fig. 9) and both responses are larger in the saline-yoked animals than in the cocaine SA animals. We recently showed that 7-OHDPAT produces negative CBV changes in hypothalamus whereas the D3 selective antagonist PG-01037 produces positive changes in the hypothalamus (Choi et al., 2010). Therefore, these data suggest that measurement of cocaine-induced signal changes in hypothalamus may produce a readout on the status of D3 receptors, although this concept requires further proof. "
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    ABSTRACT: Chronic use of cocaine is associated with lasting alterations in brain metabolism, circuitry, and receptor properties. We used neuroimaging with pharmacological magnetic resonance imaging to assess alterations in response to cocaine (0.5 mg/kg) in animals trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement, as well as saline-yoked controls, after 28 days of cocaine abstinence. We fitted the cerebral blood volume (CBV) curves for full-width half-maximum (FWHM) as well as peak CBV response. There were significant increases in the FWHM of the response curves in the cocaine self-administering (SA) animals as compared with saline-yoked controls in the medial prefrontal cortex (mPFC) and the caudate/putamen (CPu), and increases in peak CBV in the M1 motor cortex, CPu, and pedunculopontine tegmental nucleus. Functional connectivity analysis showed increased correlations in the cocaine SA rats upon acute cocaine challenge, especially in the S1, mPFC, and thalamus. As D3 receptor expression is postulated to increase following chronic cocaine administration, we also examined the response to 0.2 mg/kg of the D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT). Cocaine SA animals showed a decreased overall CBV response to this drug, except in the globus pallidus. The hypothalamus showed a negative CBV change in response to cocaine challenge, similar to that noted with the D3 agonist, and showed a smaller response in the cocaine SA animals than in the controls. Given the good coupling of cerebral hemodynamics with dopamine dynamics previously observed with pharmacological magnetic resonance imaging, these data suggest that increased persistence of dopamine in the prefrontal cortex may be responsible for some of the behavioral alterations observed subsequent to chronic cocaine use.
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