Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner

Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I40 selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I40. Finally, NGF was found to be upregulated in all regions after I40, while a selective upregulation was found in PFC and VTA for the I20 treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine.

Download Full-text

(R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz041 ◽

2019 ◽

Vol 22 (10) ◽

pp. 665-674 ◽

Cited By ~ 13

Author(s):

Yukio Ago ◽

Wataru Tanabe ◽

Momoko Higuchi ◽

Shinji Tsukada ◽

Tatsunori Tanaka ◽

...

Keyword(s):

Prefrontal Cortex ◽

Ampa Receptor ◽

Dopamine Release ◽

Molecular Mechanisms ◽

In Vivo Microdialysis ◽

Serotonin Release ◽

Dependent Manner ◽

Independent Mechanism ◽

Dose Dependent

Abstract Background Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine’s action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. Methods The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. Results (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. Conclusions (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

Download Full-text

Methamphetamine pre-exposure induces steeper escalation of methamphetamine self-administration with consequent alterations in hippocampal glutamate AMPA receptor mRNAs

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.173732 ◽

2020 ◽

Vol 889 ◽

pp. 173732

Author(s):

Michael R. Chojnacki ◽

Subramaniam Jayanthi ◽

Jean Lud Cadet

Keyword(s):

Ampa Receptor ◽

Self Administration ◽

Receptor Mrnas

Download Full-text

Comparison of the Effects of Convulsant and Depressant Barbiturate Stereoisomers on AMPA-type Glutamate Receptors

Anesthesiology ◽

10.1097/00000542-199906000-00028 ◽

1999 ◽

Vol 90 (6) ◽

pp. 1704-1713. ◽

Cited By ~ 23

Author(s):

Yoshinori Kamiya ◽

Tomio Andoh ◽

Ryosuke Furuya ◽

Satoshi Hattori ◽

Itaru Watanabe ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glutamate Receptors ◽

Ampa Receptor ◽

Ampa Receptors ◽

Dependent Manner ◽

Induced Current ◽

Gaba A ◽

The Central Nervous System

Background Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. Method The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. Results Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. Conclusions Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

Download Full-text

Previous Exposure to VTA Amphetamine Enhances Cocaine Self-administration under a Progressive Ratio Schedule in a D1 Dopamine Receptor Dependent Manner

Neuropsychopharmacology ◽

10.1016/s0893-133x(02)00379-2 ◽

2002 ◽

Vol 27 (6) ◽

pp. 970-979 ◽

Cited By ~ 60

Author(s):

N Suto

Keyword(s):

Dopamine Receptor ◽

Progressive Ratio ◽

Ratio Schedule ◽

Dependent Manner ◽

Progressive Ratio Schedule ◽

Previous Exposure ◽

Self Administration ◽

D1 Dopamine Receptor

Download Full-text

NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

Journal of Neurophysiology ◽

10.1152/jn.90754.2008 ◽

2009 ◽

Vol 101 (5) ◽

pp. 2290-2296 ◽

Cited By ~ 37

Author(s):

Felipe Espinosa ◽

Ege T. Kavalali

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Ampa Receptor ◽

Cortical Neurons ◽

Glutamate Release ◽

Receptor Activation ◽

Receptor Activity ◽

Resting Membrane Potential ◽

Nmda Current ◽

Nmda Receptor Activation

Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately −67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises ∼20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately −50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

Download Full-text

Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2011.10.021 ◽

2012 ◽

Vol 52 (1) ◽

pp. 165-174 ◽

Cited By ~ 18

Author(s):

Cordelia J. Barrick ◽

Patricia M. Lenhart ◽

Ryan T. Dackor ◽

Elizabeth Nagle ◽

Kathleen M. Caron

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Receptor Activity ◽

Dependent Manner

Download Full-text

Curcumin Protects Neurons from Glutamate-Induced Excitotoxicity by Membrane Anchored AKAP79-PKA Interaction Network

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/706207 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Kui Chen ◽

Yu An ◽

Lu Tie ◽

Yan Pan ◽

Xuejun Li

Keyword(s):

Ampa Receptor ◽

Drug Target ◽

Interaction Network ◽

Subcellular Location ◽

Dependent Manner ◽

Potential Drug Target ◽

Neuroprotective Effects ◽

Signal Relay ◽

Anchoring Protein ◽

Stimulation Of

Now stimulation of AMPA receptor as well as its downstream pathways is considered as potential central mediators in antidepressant mechanisms. As a signal integrator which binds to AMPA receptor, A-kinase anchoring protein 79-(AKAP79-) PKA complex is regarded as a potential drug target to exert neuroprotective effects. A well-tolerated and multitarget drug curcumin has been confirmed to exert antidepressant-like effects. To explore whether AKAP79-PKA complex is involved in curcumin-mediated antiexcitotoxicity, we detected calcium signaling, subcellular location of AKAP79-PKA complex, phosphorylation of glutamate receptor, and ERK and AKT cascades. In this study, we found that curcumin protected neurons from glutamate insult by reducing Ca2+influx and blocking the translocation of AKAP79 from cytomembrane to cytoplasm. In parallel, curcumin enhanced the phosphorylation of AMPA receptor and its downstream pathways in PKA-dependent manner. If we pretreated cells with PKA anchoring inhibitor Ht31 to disassociate PKA from AKAP79, no neuroprotective effects were observed. In conclusion, our results show that AKAP79-anchored PKA facilitated the signal relay from AMPA receptor to AKT and ERK cascades, which may be crucial for curcumin-mediated antiexcitotoxicity.

Download Full-text