Guo-Zhang Jin

Functional Coupling between the Prefrontal Cortex and Dopamine Neurons in the Ventral Tegmental Area

Stimulation of the prefrontal cortex (PFC) has been shown to have an excitatory influence on dopamine (DA) neurons. We report here that, under nonstimulated conditions, the activity of DA neurons in the ventral tegmental area (VTA) also covaries, on a subsecond timescale, with the activity of PFC cells. Thus, in 67% of VTA DA neurons recorded in chloral hydrate-anesthetized rats, the firing of the cell displayed a slow oscillation (SO) that was highly coherent with the activity of PFC neurons. The SO was suppressed by transections immediately caudal to the PFC or by intra-PFC infusion of tetrodotoxin, suggesting that it depends on inputs derived from the PFC. Unexpectedly, the SO in most VTA DA neurons was reversed in phase relative to PFC cell activity, suggesting that at least part of PFC information is transferred to DA neurons indirectly through inhibitory relay neurons. These results, together with those reported previously, suggest that the PFC can act through multiple pathways to exert both excitatory and inhibitory influences on DA neurons. The observed functional coupling between DA and PFC neurons further suggests that these pathways not only allow a bidirectional control of DA neurons by the PFC, but also enable action potential-dependent DA release to be coordinated, on a subsecond timescale, with glutamate release from PFC terminals. Further understanding of this coordinated activity may provide important new insights into brain functions and disorders thought to involve both VTA DA and PFC neurons.

Functional Nicotinic Acetylcholine Receptors Containing α6 Subunits Are on GABAergic Neuronal Boutons Adherent to Ventral Tegmental Area Dopamine Neurons

Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR α6 subunit message is abundant in the VTA, but α6*–nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for α6β2*–nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. α-Conotoxin (α-Ctx) MII labeling coupled with immunocytochemical staining localizes putative α6*–nAChRs to presynaptic GABAergic boutons on acutely dissociated, rat VTA DA neurons. Functionally, acetylcholine (ACh) induces increases in the frequency of bicuculline-, picrotoxin-, and 4-aminopyridine-sensitive miniature IPSCs (mIPSCs) mediated by GABAA receptors. These increases are abolished by α6*–nAChR-selective α-Ctx MII or α-Ctx PIA (1 nm) but not by α7 (10 nm methyllycaconitine) or α4* (1 μm dihydro-β-erythroidine)–nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR β2 knock-out mice. Moreover, ACh induces an α-Ctx PIA-sensitive elevation in intraterminal Ca2+ in synaptosomes prepared from the rat VTA. Subchronic exposure to 500 nm nicotine reduces ACh-induced GABA release onto the VTA DA neurons, as does 10 d of systemic nicotine exposure. Collectively, these results indicate that α6β2*–nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic α6β2*–nAChRs likely play important roles in nicotinic modulation of DA neuronal activity.

Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons

Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch‐clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole‐cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor‐mediated current had faster activation and decay constant and IIID receptor‐mediated current had larger current density. Pharmacologically, ID receptor‐mediated current was sensitive to the α4β2‐nAChR agonist RJR‐2403 and antagonist dihydro‐β‐erythroidine (DHβE); IID receptor‐mediated current was sensitive to the selective α7‐nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor‐mediated current was sensitive to the β4‐containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration–response relationships demonstrated that IID receptor‐mediated current exhibited the highest EC50 value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR‐mediated currents are predominately mediated by activation of α4β2‐nAChR, α7‐nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence.

Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (α2-α10) and three beta (β2, β3, and β4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although α4β2- and α7-nAChRs are the two major functional nAChR types in the CNS, α6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of α6*-nAChRs have been assessed with the use of α6 subunit blockers such as α-conotoxin MII and PIA, and also by using α6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), α6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, α6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinsons disease (PD). Thus, α6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of α6*-nAChR function, pharmacology and pathophysiology.

Estrogen regulates responses of dopamine neurons in the ventral tegmental area to cocaine

RationaleSex differences in cocaine abuse have been well documented. However, the underlying mechanism remains unclear.ObjectivesTo explore the potential role of ovarian hormones in the regulation of dopamine (DA) neuron firing activity in ventral tegmental area (VTA) induced by acute cocaine in intact female or ovariectomized (OVX) rats.ResultsThe basal firing activity of VTA DA neurons was changed in a manner phase-locked to the estrous cycle: being highest in estrus and lowest in proestrus. Acute cocaine produced greater inhibition (P < 0.05) on the firing of VTA DA neurons during proestrus than during estrus. The inhibitory effect was completely blocked by OVX and restored by replacement of 17-β-estradiol or, to a less extent, by replacement of progesterone. In addition, we also detected female hormone-associated changes in slow oscillation in VTA DA neurons. The results indicate that ovarian hormones, particularly estrogen, not only synergize with the inhibitory effect of cocaine on VTA DA neuron activity but also play an essential role in maintaining the sensitivity of DA neurons to cocaine-mediated inhibition on firing. Moreover, pretreatment of estrogen receptor (ER) antagonist raloxifene or a selective ERα antagonist Y134 largely attenuated the cocaine-inhibited DA neuron firing. We also found that cocaine-induced locomotor activity was estrous cycle dependant; 17-β-estradiol but not progesterone replacement restored the cocaine-induced locomotor activity in OVX rats.ConclusionThe present results demonstrated that ovarian hormones, particularly estrogen, produce profound effect on VTA DA neuron activity, which, in turn, may contribute to the sex differences in response to psychostimulants.

Medication of l-tetrahydropalmatine Significantly Ameliorates Opiate Craving and Increases the Abstinence Rate in Heroin Users: A Pilot Study

AbstractAim:Drug addiction is a chronic brain disease with constant relapse requiring long-term treatment. New pharmacological strategies focus on the development of an effective antirelapse drug. This study examines the effects of levotetrahydropalmatine (l-THP) on reducing heroin craving and increasing the abstinence rate among heroin-dependent patients.Methods:In total, 120 heroin-dependent patients participated in the randomized, double-blinded, and placebo-controlled study using l-THP treatment. The participants remained in a ward during a 4-week period of l-THP treatment, followed by 4 weeks of observation after treatment. The patients were followed for 3 months after discharge. Outcome measures are the measured severity of the protracted abstinence withdrawal syndrome (PAWS) and the abstinence rate.Results:Four weeks of l-THP treatment significantly ameliorated the severity of PAWS, specifically, somatic syndrome, mood states, insomnia, and drug craving, in comparison to the placebo group. Based on the 3 month follow-up observation, participants who survived the initial 2 weeks of l-THP medication and remained in the trial program had a significantly higher abstinence rate of 47.8% (95% confidence interval [CI]: 33%–67%) than the 15.2% in the placebo group (95% CI: 7%-25%), according to a log-rank test (P<0.0005).Conclusion:l-THP significantly ameliorated PAWS, especially reducing drug craving. Furthermore, it increased the abstinence rate among heroin users. These results support the potential use of l-THP for the treatment of heroin addiction.

Recent Developments in Studies of l-Stepholidine and its Analogs: Chemistry, Pharmacology and Clinical Implications

Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinsons disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.

l-Stepholidine reduced l-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinsons disease (PD) drug therapy. 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-SPD with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA, indicating that L-SPD attenuated LID development. L-SPD alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of L-SPD 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-SPD treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata. The present data demonstrated that L-SPD elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.

Effects of (-)stepholidine in animal models for schizophrenia

AbstractAim:(-)Stepholidine (SPD) is an active ingredient of the Chinese herb Stephania intermedia, which binds to the dopamine D1 and D2 like receptors. Biochemical, electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D1 and a D2 antagonist, which could make SPD a unique antipsychotic drug. The present study aimed to investigate the antipsychotic properties of SPD in two animal models for schizophrenia.Methods:The effects of SPD, clozapine and haloperidol in increasing forelimb and hindlimb retraction time in the paw test and in reversing the apomorphine and MK801-induced disruption of prepulse inhibition was investigated.Results:In the paw test, clozapine and SPD increased the hindlimb retraction time, with only a marginal effect on the forelimb retraction time, whereas haloperidol potently increased both. In the prepulse inhibition paradigm, all three drugs reverse the apomorphine-induced disruption in prepulse inhibition, while none of the drugs could reverse the MK801-induced disruption. SPD even slightly, but significantly, potentiated the effects of MK801.Conclusion:The data show that SPD showed antipsychotic-like effects in both the prepulse inhibition paradigm and in the paw test. Moreover, the results of the paw test suggest that SPD has an atypical character with a relatively small potency to induce extrapyramidal side effects.

Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand

Bi-acetylated l-stepholidine (l-SPD-A), a novel derivate of l-stepholidine (l-SPD), possesses a pharmacological profile of D(1)/5-HT(1A) agonism and D(2) antagonism. In the present study, we examined the potential antipsychotic effect of l-SPD-A in a phencyclidine (PCP)-induced rat model of schizophrenia. Pretreatment with l-SPD-A blocked acute PCP-induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Chronic l-SPD-A administration (i.p., 10mg/kg/day for 14 days) improved social interaction and novel object recognition impairments in rats that were pretreated with PCP (i.p., 5mg/kg/day for 14 days). Moreover, in a conditioned avoidance response (CAR) test, l-SPD-A, with either i.p. or oral administration, significantly decreased active avoidance without affecting the escape response of rats. Importantly, compared to that of the parent compound l-SPD, l-SPD-A showed stronger suppression of CARs. Lastly, using a [(35)S]GTPgammaS binding assay, we demonstrated that l-SPD-A improved impaired dopamine D(1) receptor function in the prefrontal cortex (PFC) in chronic PCP-treated rats. Taken together, these results indicate that l-SPD-A was not only effective against the hyperactivity, but also improved the sensorimotor gating deficit, social withdrawal and cognitive impairment in an animal model of schizophrenia. The present data suggest that l-SPD-A, a potential neurotransmitter stabilizer, is a promising novel candidate drug for the treatment of schizophrenia.