6 research outputs found
Tobacco\u27s Minor Alkaloids: Effects on Place Conditioning and Nucleus Accumbens Dopamine Release in Adult and Adolescent Rats
Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated
The Novel Pyrrolidine Nor-Lobelane Analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] Inhibits VMAT2 Function, Methamphetamine-Evoked Dopamine Release, and Methamphetamine Self-Administration in RatsS⃞
Both lobeline and lobelane attenuate methamphetamine self-administration in rats by
decreasing methamphetamine-induced dopamine release via interaction with vesicular
monoamine transporter-2 (VMAT2). A novel derivative of nor-lobelane,
cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110), and
its trans-isomers,
(2R,5R)-trans-di-(2-phenethyl)-pyrrolidine
hydrochloride (UKCP-111) and
(2S,5S)-trans-di-(2-phenethyl)-pyrrolidine
hydrochloride (UKCP-112), were evaluated for inhibition of
[3H]dihydrotetrabenazine binding and [3H]dopamine uptake by
using a rat synaptic vesicle preparation to assess VMAT2 interaction. Compounds were
evaluated for inhibition of [3H]nicotine and
[3H]methyllycaconitine binding to assess interaction with the major
nicotinic receptor subtypes. In addition, compounds were evaluated for inhibition of
methamphetamine-evoked endogenous dopamine release by using striatal slices. The most
promising compound, UKCP-110, was evaluated for its ability to decrease
methamphetamine self-administration and methamphetamine discriminative stimulus cues
and for its effect on food-maintained operant responding. UKCP-110, UKCP-111, and
UKCP-112 inhibited [3H]dihydrotetrabenazine binding
(Ki = 2.66 ± 0.37, 1.05 ±
0.10, and 3.80 ± 0.31 μM, respectively) and had high potency
inhibiting [3H]dopamine uptake (Ki = 0.028
± 0.001, 0.046 ± 0.008, 0.043 ± 0.004
μM, respectively), but lacked affinity at nicotinic receptors. Although
the trans-isomers did not alter methamphetamine-evoked dopamine
release, UKCP-110 inhibited (IC50 = 1.8 ± 0.2 μM;
Imax = 67.18 ± 6.11 μM)
methamphetamine-evoked dopamine release. At high concentrations, UKCP-110 also
increased extracellular dihydroxyphenylacetic acid. It is noteworthy that UKCP-110
decreased the number of methamphetamine self-infusions, while having no effect on
food-reinforced behavior or the methamphetamine stimulus cue. Thus, UKCP-110
represents a new lead in the development of novel pharmacotherapies for the treatment
of methamphetamine abuse