Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration.

Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1-3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1-3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1-1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse.

Comparison of short-term health and performance effects related to prophylactic administration of tulathromycin versus tilmicosin in long-hauled, highly stressed beef stocker calves.

Health and feed performance parameters of 293 beef stocker calves at risk for bovine respiratory disease were compared after metaphylactic administration of one of two antimicrobials (tulathromycin or tilmicosin) with different durations of activity; the antimicrobial was administered 1 day after arrival. Calves that received metaphylactic tulathromycin displayed significant improvement in morbidity, mortality, and first-treatment success rates (P<.05) compared with tilmicosin-treated calves. Tulathromycin-treated calves also showed a significantly improved average daily gain and feed:gain ratio (P<.05) compared with tilmicosin-treated calves. Under conditions of this study, calves receiving tulathromycin were healthier through a 43-day growing phase compared with calves receiving tilmicosin. This health difference likely accounted for the differences in feed performance between the treatment groups.

Age-related changes in the dynamics of potassium-evoked L-glutamate release in the striatum of Fischer 344 rats.

In the present studies we used a multisite ceramic-based microelectrode for rapid (800 ms) and low level measures of L-glutamate in vivo. We measured the amplitude and clearance rate of phasic changes in L-glutamate release produced by local application of potassium by a micropipette placed adjacent to the recording sites in the striatum of young (6 month), late middle aged (18 month) and aged (24 month) Fischer 344 rats. Our results showed that the amplitudes and clearance rates of potassium-evoked release of L-glutamate in the striatum were significantly decreased in aged rats as compared to the other age groups. In addition, the sensitivity of glutamate fibers to depolarization with potassium was significantly decreased in the aged rats as compared to young animals. Taken together, these data are consistent with age-related alterations in glutamate release dynamics, which may involve a compensatory mechanism for maintaining static glutamate concentrations within the striatum.