Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.

Monitoring tissue elimination of fluorescein with the perfusion fluorometer: a new method to assess capillary blood flow.

Visual assessment of tissue staining after intravenous fluorescein is a common technique for predicting viability of questionably perfused tissue. The development of the perfusion fluorometer has permitted quantification of tissue fluorescein, providing increased precision. This study employed this instrument to calculate fluorescein elimination from rats with and without raised dorsal pedicle flaps. Control animals exhibited homogeneous patterns of fluorescein elimination consistent with first-order kinetics. Elimination in experimental animals was assessed after the animals received full back skin flaps with the cephalad pedicle remaining intact. Three distinct patterns of elimination were noted in each flap. In the cephalad portion, elimination was similar to control. At the caudad end, no elimination was noted. Midflap, fluorescein was eliminated slowly. These elimination patterns predicted ultimate viability 14 days postoperatively, as they correspond to viable, dystrophic, and transitional sections, respectively (P less than 0.001). We conclude that perfusion fluorometry can assess capillary flow in healthy and ischemic tissue by documenting elimination as well as delivery of fluorescein.

Quantification of tissue fluorescein delivery and prediction of flap viability with the fiberoptic dermofluorometer.

Quantitative fluorescence assessment with the fiberoptic dermofluorometer has been introduced to overcome the inadequacies of ultraviolet inspection following intravenous administration of fluorescein. Initial applications in the pedicle flap of the rat have indicated that this method can predict flap viability with reproducible precision and accuracy. This minimally invasive technique should be of considerable assistance to the evaluation of hypoperfused states in laboratory and clinical situations.