Positron Emission Tomography of Cocaine Binding Sites on the Dopamine Transporter

Bk, Madras; Dr, Elmaleh; Pc, Meltzer; Ay, Liang; Gl, Brownell; Al, Brownell

doi:10.1037/e495902006-006

Cited by 6 publications

(8 citation statements)

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“…Furthermore, DAT inhibition is the mechanism of action for a number of pharmaceuticals designed to enhance DA neurotransmission as well as drugs of abuse, such as cocaine (Hitri et al, 1994; Madras et al, 1994). …”

Section: Dopamine At the Cellular Level: Gatekeeper Of Cognitionmentioning

confidence: 99%

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Bales

Wagner

Kline

et al. 2009

Neuroscience & Biobehavioral Reviews

222

190

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Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.

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Section: Dopamine At the Cellular Level: Gatekeeper Of Cognitionmentioning

confidence: 99%

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Bales

Wagner

Kline

et al. 2009

Neuroscience & Biobehavioral Reviews

222

190

View full text Add to dashboard Cite

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“…These results were sufficiently encouraging to propose the synthesis of N-[ 11 CH 3 ] WIN 35,428 for PET imaging and the synthesis of its 4-iodo analog as a gamma-emitting agent (3␤-carbomethoxy-4␤ [ 123 I]iodophenyltropane, currently designated RTI-55 or ␤-CIT) for SPECT imaging (Canfield et al, 1990;Madras et al, , 1990. Phenyltropanes are now the ligands of choice for imaging and quantifying dopamine neurons in vivo (Brownell et al, 1996;Halldin et al, 1996;Fischman et al, 1996Fischman et al, , 1998Frost et al, 1993;Hantraye et al, 1992;Innis et al, 1991;Madras et al, 1991Madras et al, , 1994Morris et al, 1996;Wong et al, 1993Wong et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

Altropane, a SPECT or PET imaging probe for dopamine neurons: I. dopamine transporter binding in primate brain

Meltzer

Liang

Elmaleh

et al. 1998

Synapse

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Increasing evidence suggests that the dopamine transporter is an important marker for physiological and pathological changes in dopamine neurons. Potent dopamine transport inhibitors of the phenyltropane series (e.g., WIN 35,428 or CFT) are particularly suitable for PET (positron emission tomography) or SPECT (single photon emission computed tomography) imaging of the dopamine transporter in living brain. We investigated whether altropane, an N-iodoallyl analog of WIN 35,428 (IACFT:E-N-iodoallyl-2 -carbomethoxy-3beta-(4-fluorophenyl)tropane), displayed in vitro properties suitable for evaluation as a SPECT imaging agent. In brain striatum of cynomolgus monkey (Macaca fascicularis), the unlabeled E-isomer (IC50: 6.62 +/- 0.78 nM) was more potent than the Z-isomer (IC50: 52.6 +/- 0.3 nM) and displayed a relatively high dopamine:serotonin transporter selectivity (28-fold). In radiolabeled form, [125I]altropane bound to sites in the striatum with a single high affinity (KD: 5.33 +/- 0.55 nM) and with a site density (BMAX: 301 pmol/g original wet tissue weight) that was within the density range reported previously for the dopamine transporter in striatum. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their potencies for inhibiting [3H]WIN 35,428 binding (r2: 0.99; P < 0.0001) to the blocking dopamine transport. The favorable binding properties of altropane, together with its rapid entry into primate brain and highly localized distribution in dopamine-rich brain regions, suggest it is a suitable iodinated probe for monitoring the dopamine transporter in vitro and in vivo by SPECT or PET imaging.

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“…Such information is needed to clarify whether brain dopamine neurons preferentially bind trace and high doses of cocaine, and whether the distribution of cocaine corresponds to its effects on regional brain metabolism and other physiological parameters (Porrino, 1993). Finally, information is needed to assess the suitability of novel cocaine congeners as probes for cocaine binding sites in brain regions (Boja et al, 1992;Canfield et al, 1990;Carroll et al, 1991;Cline et al, 1992;Madras et al, 1989aMadras et al, ,b, 2990Madras et al, ,1994aMeltzer et al, 1993Meltzer et al, ,1994.…”

Section: Introductionmentioning

confidence: 99%

Cocaine accumulates in dopamine‐rich regions of primate brain after I.V. Administration: Comparison with mazindol distribution

Madras

Kaufman

1994

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Pharmacological and neurochemical evidence suggest that brain dopamine systems, and the dopamine transporter in particular, contribute significantly to the behavioral effects and reinforcing properties of cocaine. The first objective of this study was to determine whether the brain distribution of cocaine supports these conclusions. A high resolution neuroanatomical map of cocaine disposition in brain after i.v. administration was developed. [3H]Cocaine ([3H](-)-cocaine) was administered to squirrel monkeys (Saimiri sciureus) at a trace dose (0.001 mg/kg) and at doses at or above the threshold for producing behavioral effects (0.1 mg/kg, 0.3 mg/kg). After 15 min, ex vivo autoradiography revealed the highest accumulation of [3H]cocaine in dopamine-rich brain regions, including the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle. The norepinephrine-rich locus coeruleus, the hippocampus, and amygdala also accumulated large quantities of [3H]cocaine. Moderately high levels were found in the stria terminalis, medial septum, substantia nigra, and other regions. Lowest levels were found in the cerebellum. A high and positive correlation was established for the brain distribution of [3H]cocaine administered at trace or at behaviorally relevant doses (r: 0.94; P < 0.001). To determine whether radioactivity represented [3H]cocaine or its metabolic products, tissue extracts from brain regions with high levels of cocaine were subjected to thin layer chromatography using two solvent systems. In caudate-putamen, nucleus accumbens, cortex, and hippocampus, radioactivity comigrated with standard [3H]cocaine. In substantia nigra, less than 70% of the radioactivity comigrated with [3H]cocaine, suggesting that cocaine metabolites are generated more rapidly in the substantia nigra than in other brain regions. The second objective was to determine the brain distribution of mazindol, a potent norepinephrine and dopamine transport inhibitor with low abuse liability in humans. The disposition of intravenously administered [3H]mazindol in brain (0.001 mg/kg, 0.007 mg/kg) was surveyed by ex vivo autoradiography. In sharp contrast to [3H]cocaine distribution, the highest accumulation of [3H]mazindol was localized in the norepinephrine-rich pineal gland, discrete regions of the hypothalamus (paraventricular nucleus, supraoptic nucleus), and the locus coeruleus. Moderately high levels were detected in the caudate-putamen, nucleus accumbens, and other regions. The following conclusions were drawn: (1) Although dopamine-rich brain regions are principal targets of cocaine after i.v. administration to the nonhuman primate, other prominent targets of cocaine (locus coeruleus, hippocampus, and amygdala) may contribute to the acute and chronic effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)

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Positron Emission Tomography of Cocaine Binding Sites on the Dopamine Transporter

Cited by 6 publications

References 0 publications

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Altropane, a SPECT or PET imaging probe for dopamine neurons: I. dopamine transporter binding in primate brain

Cocaine accumulates in dopamine‐rich regions of primate brain after I.V. Administration: Comparison with mazindol distribution

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