Abstract: Neuromolecular Imaging (NMI) with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/ voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc); dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) and Ltryptophan (L-TP) are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a) is an antihypertensive and cocaine and caffeine produce hypertension and (b) acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a) the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b) ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in NAc and open-field behaviors and (c) ketanserin inhibits 5-HT release in NAc and open-field behaviors produced by caffeine, but, surprisingly, acts to increase DA release in NAc. Importantly, the latter effect may be a possible adverse effect of the moderate dose of caffeine in hypertensive patients. Thus, an antihypertensive medication is shown here to play a role in inhibiting brain reward possibly via antihypertensive mechanisms at DA and 5-HT receptor subtypes within DA motor neurons. An explanatory note for the results obtained, is the role likely played by the G Protein Receptor Complex (GPRC) family of proteins. Empirical evidence shows that GPRC dimers, heteromers and heterotrimers may cause cross-talk between distinct signalling cascade pathways in the actions of cocaine and caffeine. Ligand-directed functional selectivity, particularly for ketanserin, in addition to GPRCs, may also cause differential responses. The results promise new therapeutic strategies for drug addiction, brain reward and cardiovascular medicine.
Keywords: anxiety; brain; caffeine; cocaine; dopamine; electrochemistry; G-protein receptor complexes (GPRC); homovanillic acid; hypertension; ketanserin; L-tryptophan; mesolimbic; motor tracts; neuromolecular imaging; nucleus accumbens; open-field behaviors; psychostimulants; serotonin; ventral tegmental area.
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Broderick, P.A.; Ho, H.; Wat, K.; Murthy, V. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior? Sensors 2008, 8, 4033-4061.
Broderick PA, Ho H, Wat K, Murthy V. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior? Sensors. 2008; 8(7):4033-4061.
Broderick, Patricia A.; Ho, Helen; Wat, Karyn; Murthy, Vivek. 2008. "Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?" Sensors 8, no. 7: 4033-4061.