L-Stepholidine

Neuroreport. 2014 Jan 8;25(1):7-11.

L-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates heroin self-administration and cue-induced reinstatement in rats.[Pubmed: 24145772]

Opiate addiction is a chronic, relapsing brain disease characterized by persistent and uncontrolled drug-seeking behavior despite negative effects. L-Stepholidine (L-SPD) is an alkaloid extract of the Chinese herb Stephania intermedia with dopamine D1 receptor partial agonistic and D2 receptor antagonistic dual actions. The unique pharmacological profile of L-SPD suggests that L-SPD may be effective for the treatment of opiate addiction.
METHODS AND RESULTS:
The aim of this study was to characterize the effects of L-SPD on heroin self-administration on a fixed-ratio 1 schedule and cue-induced reinstatement under an extinction/reinstatement protocol. The effect of L-SPD on the locomotor activity of heroin-free rats was also tested. We found that 2.5, 5, and 10 mg/kg of L-SPD attenuated heroin self-administration and cue-induced reinstatement without affecting locomotor activity.
CONCLUSIONS:
These results showed that L-SPD, which has dual actions on dopamine D1 and D2 receptors, attenuates heroin self-administration and cue-induced reinstatement.

Neurobiol Aging. 2010 Jun;31(6):926-36.

L-stepholidine reduced L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease.[Pubmed: 18707801]

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinson's disease (PD) drug therapy.
METHODS AND RESULTS:
In the present study, we examined the effect of L-Stepholidine (L-SPD), a known dual dopamine receptor agent, on LID in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model. Daily administration of L-DOPA to PD rats for 22 days induced steady expression of LID, co-administration of L-Stepholidine with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA, indicating that L-Stepholidine attenuated LID development. L-Stepholidine alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of L-Stepholidine to rats with established LID produced significant relief of dyskinesia; this effect was mimicked by D(2) receptor antagonist haloperidol, but blunted by 5-HT(1A) receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT(1A) decreased significantly on 6-OHDA-lesioned striata, whereas chronic L-Stepholidine treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata.
CONCLUSIONS:
The present data demonstrated that L-Stepholidine elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.

Synapse. 2011 May;65(5):379-87.

l-Stepholidine-induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5-HT(1A) receptor partial agonistic activity.[Pubmed: 20803620]

We studied the effects of L-Stepholidine on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single-unit recording technique in rats.
METHODS AND RESULTS:
We found that L-Stepholidine increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, L-Stepholidine, not clozapine, reversed d-amphetamine-induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of L-Stepholidine is associated with its partial agonistic action for the 5-HT(1A) receptor since the 5-HT(1A) receptor antagonist WAY100635 could block the L-Stepholidine-induced excitatory effect. However, activation of 5-HT(1A) receptor alone by specific agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin (8-OH-DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8-OH-DPAT on VTA DA neurons was elicited in the presence of D₂-like receptors antagonist raclopride. Collectively, these results indicate that l-SPD excited VTA DA neurons requiring its D₂-like receptors antagonistic activity and 5-HT(1A) receptor agonistic activity.
CONCLUSIONS:
The present data demonstrate that D₂ receptor antagonist/5-HT(1A) receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between L-Stepholidine and other atypical antipsychotic drugs.

Neurosci Lett. 2014 Jan 24;559:67-71.

L-stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced reinstatement.[Pubmed: 24269875]

L-Stepholidine (l-SPD), an alkaloid extract of the Chinese herb Stephania intermedia, is the first compound known to exhibit mixed dopamine D1 receptor agonist/D2 antagonist properties and is a potential medication for the treatment of opiate addiction. The aim of the present study was to investigate the effects of pretreatment with L-SPD on heroin-seeking behavior induced by heroin priming.
METHODS AND RESULTS:
Male Sprague-Dawley rats were trained to self-administer heroin (0.05mg/kg per infusion) under a fixed ratio 1 schedule for 12 consecutive days and nose-poke responding was extinguished for 12 days, after which reinstatement of drug seeking was induced by heroin priming. Pretreatment with L-SPD (2.5, 5.0 and 10.0mg/kg, i.p.) inhibited the heroin-induced reinstatement of heroin-seeking behavior. Importantly, L-SPD did not affect locomotion, indicating that the observed effects of L-SPD on reinstatement are not the result of motor impairments.
CONCLUSIONS:
The present data suggested that l-SPD inhibits heroin-induced reinstatement and its potential for the treatment of heroin relapse.