From “Hunger Hormone” to “It’s Complicated”: Ghrelin Beyond Feeding Control

Discovered as a peptide involved in releasing growth hormone, ghrelin was initially characterized as the “hunger hormone.” However, emerging research indicates that ghrelin appears to play an important part in relaying information regarding nutrient availability and value and adjusting physiological and motivational processes accordingly. These functions make ghrelin an interesting therapeutic candidate for metabolic and neuropsychiatric diseases involving disrupted nutrition that can further potentiate the rewarding effect of maladaptive behaviors.

PHOSPHORYLATION OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKII) AND EXTRACELLULAR REGULATED KINASE (ERK) IN STRIATUM MEDIATE NICOTINE DEPENDENCE IN BALB/C MICE

Objective: Nicotine is an active compound in tobacco and has a rewarding effect in the central nervous system (CNS), which may lead to dependence. Although nicotine dependence is elucidated by brain mechanisms, synaptic molecular substrates underlying the dependence remain unclear. We hypothesized that reward signaling is mediated by dopamine and glutamate receptors, in where calcium/calmodulin-dependent kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) may mediate the synaptic signaling of dependence. Methods: To investigate the roles of both CaMKII and ERK on nicotine dependence were assessed by conditioned place preference (CPP) methods followed by dissection. One day after conditioning, preference scores were measured to evaluate nicotine dependence. Mice were sacrificed and their striatum were dissected out for immunoblotting analyses of CaMKII and ERK phosphorylation. Results: Nicotine-induced conditioned place preference as a symptom of nicotine dependence. CaMKII and ERK phosphorylation in striatum significantly increased along with the development of nicotine dependence. Conclusion: We should next apply pharmacological strategies to manipulate CaMKII and ERK signaling. In particular, disruption of reconsolidation by disrupting CaMKII and ERK signaling may propose an attractive therapeutic approach to inhibit nicotine dependence.

α-Conotoxin TxIB Inhibits Development of Morphine-Induced Conditioned Place Preference in Mice via Blocking α6β2* Nicotinic Acetylcholine Receptors

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations.

Anorectic Effect, Biochemical and Hematological Profiles of Alkaloid Extract from Mitragyna speciosa Korth. in Rats

There is an on-going debate about medicinal use of kratom plant (Mitragyna speciosa (MS)) on whether it has beneficial or adverse effects. This study aimed to examine long-term weight-reducing effects, toxicity, and dopamine pathway activation of MS alkaloid extract on adult male Wistar rats. In anorexic study, the rats were divided into 3 groups (n = 10), receiving intragastric administration once a day for 19 weeks as control (distilled water), chronic (20 mg/kg MS alkaloid extract) and withdrawal (20 mg/kg MS alkaloid extract for week 1-12 and distilled water for week 13-19) groups. Body weights were measured daily, and blood samples were collected at the end of study for biochemical and hematological tests. In immunohistochemistry, the effects of the extract (40 and 80 mg/kg) on the nucleus accumbens (NAc) and striatum (STr) were determined by using Fos-like immunoreactivity. From week 2 to 19, the results showed a significant reduction in body weight gain produced by the extract. Cessation of the treatment at week 12 did not result in a rebound weight gain. Chronic MS alkaloid extract treatment significantly decreased non-fasting blood sugar, triglyceride, uric acid and blood urea nitrogen (BUN). However, elevated SGOT may suggest possible hepatotoxicity. Chronic MSalkaloid extract treatment also produced baseline levels for most of the hematological parameters except a decrease of monocyte. In immunohistochemistry, the acute treatment did not induce Fos-like immunoreactivity in the NAc and STr.These data demonstrated the beneficial effects of the MS alkaloid extract for possible treatment of metabolic syndromes without toxicity and rewarding effect.

Rewarding compounds identified from the medicinal plant Rhodiola rosea

ABSTRACTPreparations of Rhodiola rosea root are widely used in traditional medicine. They can increase life span in worms and flies, and have various effects related to nervous system function in different animal species and humans. However, which of the compounds in R. rosea is mediating any one of these effects has remained unknown in most cases. Here, an analysis of the volatile and non-volatile low-molecular-weight constituents of R. rosea root samples was accompanied by an investigation of their behavioral impact on Drosophila melanogaster larvae. Rhodiola rosea root samples have an attractive smell and taste to the larvae, and exert a rewarding effect. This rewarding effect was also observed for R. rosea root extracts, and did not require activity of dopamine neurons that mediate known rewards such as sugar. Based on the chemical profiles of R. rosea root extracts and resultant fractions, a bioactivity-correlation analysis (AcorA) was performed to identify candidate rewarding compounds. This suggested positive correlations for – among related compounds – ferulic acid eicosyl ester (FAE-20) and β-sitosterol glucoside. A validation using these as pure compounds confirmed that the correlations were causal. Their rewarding effects can be observed even at low micromolar concentrations and thus at remarkably lower doses than for any known taste reward in the larva. We discuss whether similar rewarding effects, should they be observed in humans, would indicate a habit-forming or addictive potential.

Zinc enhances the expression of morphine-induced conditioned place preference through dopaminergic and serotonergic systems

The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.