Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.

Preferential Gs protein coupling of the galanin Gal1 receptor in the µ-opioid-Gal1 receptor heterotetramer.

Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.

Role of agmatine in neurodegenerative diseases and epilepsy.

Agmatine, a cationic polyamine synthesized after decarboxylation of L-arginine by the enzyme arginine decarboxylase, is an endogenous neuromodulator that emerges as a potential agent to manage diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, there is increasing number of preclinical studies demonstrating the beneficial effects of exogenous agmatine administration on depression, anxiety, hypoxic ischemia, nociception, morphine tolerance, memory, Parkinson`s disease, Alzheimer`s disease, traumatic brain injury related alterations/disorders and epilepsy. The aim of this review is to summarize the knowledge about the effects of agmatine in CNS and point out its potential as new pharmacological treatment for diverse neurological and neurodegenerative diseases. Moreover, some molecular mechanisms underlying the neuroprotective effects of agmatine will be discussed.

A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice.

Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.