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Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [ H]dihydrotetrabenazine binding, inhibition of [3 H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K i ϭ 45 nM) inhibiting vesicular [ 3 H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67-and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC 50 ϭ 0.65 M; I max ϭ 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC 50 ϭ 0.42 M, I max ϭ 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both transisomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a pharmacotherapeutic for methamphetamine abuse.

Stimulus-reward learning has been heavily linked to the reward-prediction error learning hypothesis and dopaminergic function. However, some evidence suggests dopaminergic function may not strictly underlie reward-prediction error learning, but may be specific to incentive salience attribution. Utilizing a Pavlovian conditioned approach procedure consisting of two stimuli that were equally reward-predictive (both undergoing reward-prediction error learning) but functionally distinct in regard to incentive salience (levers that elicited sign-tracking and tones that elicited goal-tracking), we tested the differential role of D1 and D2 dopamine receptors and nucleus accumbens dopamine in the acquisition of sign- and goal-tracking behavior and their associated conditioned reinforcing value within individuals. Overall, the results revealed that both D1 and D2 inhibition disrupted performance of sign- and goal-tracking. However, D1 inhibition specifically prevented the acquisition of sign-tracking to a lever, instead promoting goal-tracking and decreasing its conditioned reinforcing value, while neither D1 nor D2 signaling was required for goal-tracking in response to a tone. Likewise, nucleus accumbens dopaminergic lesions disrupted acquisition of sign-tracking to a lever, while leaving goal-tracking in response to a tone unaffected. Collectively, these results are the first evidence of an intraindividual dissociation of dopaminergic function in incentive salience attribution from reward-prediction error learning, indicating that incentive salience, reward-prediction error, and their associated dopaminergic signaling exist within individuals and are stimulus-specific. Thus, individual differences in incentive salience attribution may be reflective of a differential balance in dopaminergic function that may bias toward the attribution of incentive salience, relative to reward-prediction error learning only.

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.

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