The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

The Effect of High Dosage of Codeine-Containing Cough Syrup on Renal Function on Albino Rats

Codeine-containing cough syrup (CCS) is one of the most abused drugs in the world especially among the youths. However, there is need to study the nephrotoxic effect associated with oral administration of the drug and to ascertain its effect on the kidney. Consequently, understanding the renal abnormalities in chronic use of CCS will be crucial for effective development of interventions. This study assessed the nephrotoxic effect associated with oral administration of codeine-containing cough syrup (Tutolin with Codeine) in albino rats, using the level of creatinine, urea, sodium, potassium and chloride ions as biomarker in the serum of albino rats. The rats were administered orally with Tutolin and Codeine at a dose of 80mg/kg, 160mg/kg, 240 mg/kg and 320mg/kg body weight. After three weeks of oral administration of the syrup to all the groups, there was no difference (P> 0.05) in the levels of sodium ion, chloride ion and creatinine among all the study groups and levels of urea and potassium ion in the group administered with 80 mg/kg, 160 mg/kg and 240 mg/kg body weight of tutolin with codeine compared with the control. After three weeks of oral administration of 80 mg/kg, 160 mg/kg, 240 mg/kg and 320 mg/kg body weight tutolin with codeine cough syrup, urea and potassium ion concentrations were higher (p<0.05) in group given 320mg/kg body weight of tutolin with codeine cough syrup compared with the control. This suggests that at higher doses, tutolin with codeine containing cough syrup may have effect on the kidney.

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.

New trend of drugs abused by secondary school students in Nigeria

Background: It appears that there is a new trend in the types of drugs abused by secondary school students in Nigeria that makes it difficult to identify current drug abusers. Objectives: This study was conducted to reveal the trends with regards to the types of drugs abused by these students in the country. Methods: This is an online and desktop review of published articles about the types of drugs abused by secondary school students during the period that spanned from 2010–2020. Results: In all, 17 research reports were identified as having data on the types of drugs abused by secondary students in the Nigeria. It was found that 18 different drugs were empirically identified as being abused by secondary school students in 9 different states of Nigeria. The observed trend is that alcohol, cannabis, tobacco and cigarettes are the most abused drugs, while drugs that were least abused were cocaine, caffeine, glue, heroine, energy drinks, miraa, rohypnol and tramadol. Conclusion: It was concluded that studies of drug abuse by secondary school students in Nigeria are not yet robust enough to reveal the types of drugs that are currently being abused. Keywords: Adolescent Health; Drug Abuse; Drug Effects; Drug Safety; Drug Utilisation.

Prevalence of substance misuse among students in a higher institution in the London, UK

Background: Although substance misuse pattern is of growing worldwide concern, European countries have not been left out as they are uniquely going through a dynamic phase of drug misuse pattern. It is perhaps appalling, that little or no attention has been given to university students in aspects of drug policy and adoption of potential interventions necessary to curb this act. Consequently, this study aims to study the prevalence of substance misuse among students at a post-92 university in London. Methods: A descriptive cross-sectional design using a convenience sampling technique was used. A sample of 150 students were required for the study. The recruitment process involved using a selfadministered questionnaire which was disseminated via email, classrooms and in the library. Results: The findings showed that majority of respondents were young people within the age group of 18-24 years and a higher proportion of respondents were female students. This study reveals the prevalence of substance use among students being 36 (24%), of the sample respondents who have taken drugs for non-medical purposes at least once. Cannabis and Cocaine remained the most commonly abused drugs in the university which is consistent with national evidence in the (United Kingdom) UK. Conclusion: It is therefore recommended that public health interventions targeted towards preventing substance misuse trends among students should be designed to raise awareness on its harmful implications thereby reducing its prevalence in younger generations. Keywords: prevalence; substance misuse; university; college; higher education.

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

The medial prefrontal cortex (mPFC) plays an important role in regulating executive functions including reward seeking, task flexibility, and compulsivity. Studies in humans have demonstrated that drugs of abuse, including heroin, cocaine, methamphetamine, and alcohol, alter prefrontal function resulting in the consequential loss of inhibitory control and increased compulsive behaviors, including drug seeking. Within the mPFC, layer V pyramidal cells, which are delineated into two major subtypes (type I and type II, which project to subcortical or commissurally to other cortical regions, respectively), serve as the major output cells which integrate information from other cortical and subcortical regions and mediate executive control. Preclinical studies examining changes in cellular physiology in the mPFC in response to drugs of abuse, especially in regard to layer V pyramidal subtypes, are relatively sparse. In the present study, we aimed to explore how heroin, cocaine, methamphetamine, ethanol, and 3,4-methylenedioxypyrovalerone (MDPV) alter the baseline cellular physiology and excitability properties of layer V pyramidal cell subtypes. Specifically, animals were exposed to experimenter delivered [intraperitoneal (i.p.)] heroin, cocaine, the cocaine-like synthetic cathinone MDPV, methamphetamine, ethanol, or saline as a control once daily for five consecutive days. On the fifth day, whole-cell physiology recordings were conducted from type I and type II layer V pyramidal cells in the mPFC. Changes in cellular excitability, including rheobase (i.e., the amount of injected current required to elicit action potentials), changes in input/output curves, as well as spiking characteristics induced by each substance, were assessed. We found that heroin, cocaine, methamphetamine, and MDPV decreased the excitability of type II cells, whereas ethanol increased the excitability of type I pyramidal cells. Together, these results suggest that heroin, cocaine, MDPV, and methamphetamine reduce mPFC commissural output by reducing type II excitability, while ethanol increases the excitability of type I cells targeting subcortical structures. Thus, separate classes of abused drugs differentially affect layer V pyramidal subtypes in the mPFC, which may ultimately give rise to compulsivity and inappropriate synaptic plasticity underlying substance use disorders.

The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration

A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine’s reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect—reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.

Addiction biology research on miRNAs, and their role in the pathophysiology of addiction is enabling gene therapy opportunities

This article lists known miRNAs that may be used one day to diagnose and treat addiction. Besides miRNAs associated with a particular abuse drug, miR132/212, miR124 and miR9 all have a distinct expression profile in various abuse drugs. Based on our research, these miRNAs appear to be pleiotropic, meaning they are regulated in their environment by several different variables or chemicals. Substance consumption, drug type, and the paradigm (i.e., acute vs. chronic) under which they are consumed all affect the addiction manifestation. MiRNA levels appear to change for acute and chronic use, indicating that miRNA isoforms involved in numerous abuse drugs and brain areas (e.g. let7, miR212/132) may function as regulatory hubs for addictive behavior. MiRNA strands compete with each other, work hierarchically, and some miRNA targets have stronger binding affinities than others. Future addiction biology research should focus on miRNAs, and how miRNA expression changes over time. Research investigating how miRNA's expression differs in drug intoxication and recovery should take precedence. Another topic for future research is using polydrugs. Drug studies that analyze many substances together are well known. This is of particular importance, as the presence of several abused drugs increases the likelihood of upregulating or downregulating miRNAs. If miRNAs are linked to nicotine, alcohol, marijuana and opiates, understanding their role in polydrug use is vital. We created a map to highlight miRNAs influenced by drug use in the context of synaptic plasticity pathway genes. These miRNAs and their pathways may open the door to new addictive behavior therapies.Currently, preclinical investigations using miRNAs as biomarkers or disorder therapies, but no clinical trials and only a few preclinical trials are being undertaken. Biomarkers would make it one of today's most researched areas. Research shows promise for miRNAs in rehabilitation despite several roadblocks. MiRNAs can have many downstream effects, making them challenging to use. Indeed, interesting research on circRNAs has shown that they function as a miRNA sponge, possibly limiting the effects of a particular miRNA increase. Like miRNAs, CircRNAs can produce unforeseen results. Because miRNAs' functions vary widely, absorbing miRNAs via circRNAs may hinder therapeutic development. Because of nucleases and phospholipid bilayers, distribution of miRNA to humans was challenging. Passing the delivery barriers using organic and inorganic nanoparticles like peptides, gold, mesoporous silicon, graphene oxide, and iron oxide is a popular technique. MiRNA-based lipid nanoparticles delivery vectors were found to be successful. In our future studies, the main EVs are naturally occurring, biolabeled, and targeted with little toxicity and antigenicity. EVs can pass the essential blood-brain barrier to help cure drug addiction.