Abstract Substance use disorders occur commonly in patients with schizophrenia and dramatically worsen their overall clinical course. While the exact mechanisms contributing to substance use in ...schizophrenia are not known, a number of theories have been put forward to explain the basis of the co-occurrence of these disorders. We propose here a unifying hypothesis that combines recent evidence from epidemiological and genetic association studies with brain imaging and pre-clinical studies to provide an updated formulation regarding the basis of substance use in patients with schizophrenia. We suggest that the genetic determinants of risk for schizophrenia (especially within neural systems that contribute to the risk for both psychosis and addiction) make patients vulnerable to substance use. Since this vulnerability may arise prior to the appearance of psychotic symptoms, an increased use of substances in adolescence may both enhance the risk for developing a later substance use disorder, and also serve as an additional risk factor for the appearance of psychotic symptoms. Future studies that assess brain circuitry in a prospective longitudinal manner during adolescence prior to the appearance of psychotic symptoms could shed further light on the mechanistic underpinnings of these co-occurring disorders while identifying potential points of intervention for these difficult-to-treat co-occurring disorders.
Adolescence is the transitional period between childhood and adulthood, during which extensive brain development occurs. Since this period also overlaps with the initiation of drug use, it is ...important to consider how substance use during this time might produce long-term neurobiological alterations, especially against the backdrop of developmental changes in neurotransmission. Alcohol, cannabis, nicotine, and opioids all produce marked changes in the expression and function of the neurotransmitter and receptor systems with which they interact. These acute and chronic alterations also contribute to behavioral consequences ranging from increased addiction risk to cognitive or neuropsychiatric behavioral dysfunctions. The current review provides an in-depth overview and update of the developmental changes in neurotransmission during adolescence, as well as the impact of drug exposure during this neurodevelopmental window. While most of these factors have been studied in animal models, which are the focus of this review, future longitudinal studies in humans that assess neural function and behavior will help to confirm pre-clinical findings. Furthermore, the neural changes induced by each drug should also be considered in the context of other contributing factors, such as sex. Further understanding of these consequences can help in the identification of novel approaches for preventing and reversing the neurobiological effects of adolescent substance use.
Adolescence is an important ontogenetic period that is characterized by behaviors such as enhanced novelty-seeking, impulsivity, and reward preference, which can give rise to an increased risk for ...substance use. While substance use rates in adolescence are generally on a decline, the current rates combined with emerging trends, such as increases in e-cigarette use, remain a significant public health concern. In this review, we focus on the neurobiological divergences associated with adolescent substance use, derived from cross-sectional, retrospective, and longitudinal studies, and highlight how use of these substances during adolescence may relate to behavioral outcomes. Identifying and understanding the associations between adolescent substance use and changes in cognition, mental health, and future substance use risk may assist our understanding of the consequences of drug exposure during this critical window.
Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal ...protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague-Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.
Global cannabis use has risen 23% since 2010, with 209 million reported users, most of whom are males of reproductive age. Delta-9-tetrahydrocannabinol (THC), the main psychoactive phytocannabinoid ...in cannabis, disrupts pro-homeostatic functions of the endocannabinoid system (ECS) within the male reproductive system. The ECS is highly involved in regulating morpho-functional and intrinsic sperm features that are required for fertilization and pre-implantation embryo development. Previous work by our group demonstrated that THC altered sperm capacitation and the transcriptome, including several fertility-associated microRNAs (miRs). Despite the prevalent use of cannabis among males of reproductive age, clinical and pre-clinical research investigating the impact of paternal cannabis on sperm function and the outcomes of artificial reproductive technologies (ARTs) remains inconclusive. Therefore, the present study investigates the impact of in vitro THC exposure on morpho-functional and intrinsic sperm functions, including contributions to embryo development following IVF. Bovine sperm were used as a translational model for human and treated with concentrations of THC that reflect plasma levels after therapeutic (0.032μM), and low (0.32μM)-high (4.8μM) recreational cannabis use. After 6-hours of treatment, THC did not alter the acrosomal reaction, but 4.8μM significantly reduced mitochondrial membrane potential (MMP) (p<0.05), primarily through agonistic interactions with CB-receptors. Fertilization of bovine oocytes with THC-treated sperm did not alter developmental rates, but blastocysts generated from sperm treated with 0.32-4.8μM THC had fewer trophoblasts (p<0.05), while blastocysts generated from sperm exposed to any concentration of THC had fewer cells in the inner cell mass (ICM), particularly within the 0.032μM group (p<0.001). Fertility associated miRs, including miR-346, miR-324, miR-33b, and miR-34c were analyzed in THC-exposed sperm and associated blastocysts generated by IVF, with lower levels of miRs-346, -324, and -33b found in sperm treated with 0.32μM THC, while miR-34c levels were higher in sperm treated with 0.032μM THC (p<0.05). Levels of miR-346 were also lower in sperm treated with 0.032μM THC, but higher in blastocysts generated from sperm exposed to 0.32μM THC (p<0.05). Our findings suggest that THC may alter key morpho-functional and epigenetic sperm factors involved in fertilization and embryo development. This is the first study to demonstrate that sperm exposed to THC in vitro negatively affects embryo quality following IVF.
Patients with a serious mental illness often use cannabis at higher rates than the general population and are also often diagnosed with cannabis use disorder. Clinical studies reveal a strong ...association between the psychoactive effects of cannabis and the symptoms of serious mental illnesses. Although some studies purport that cannabis may treat mental illnesses, others have highlighted the negative consequences of use for patients with a mental illness and for otherwise healthy users. As epidemiological and clinical studies are unable to directly infer causality or examine neurobiology through circuit manipulation, preclinical animal models remain a valuable resource for examining the causal effects of cannabis. This is especially true considering the diversity of constituents in the cannabis plant contributing to its effects. In this mini-review, we provide an updated perspective on the preclinical evidence of shared neurobiological mechanisms underpinning the dual diagnosis of cannabis use disorder and a serious mental illness. We present studies of cannabinoid exposure in otherwise healthy rodents, as well as rodent models of schizophrenia, depression, and bipolar disorder, and the resulting impact on electrophysiological indices of neural circuit activity. We propose a consolidated neural circuit-based understanding of the preclinical evidence to generate new hypotheses and identify novel therapeutic targets.
Maternal stress can result in changes in the hypothalamic-pituitary-adrenal (HPA) axis and lead to stress-related behaviours in offspring. Under physiological conditions, delta-9 tetrahydrocannabinol ...(THC) appears to be detrimental for fertility. However, cannabis is also commonly used for stress-relief. THC acts on the endocannabinoid receptors in granulosa cells (GCs), which affect oocyte competency. The objective of this study was to evaluate the effects of THC on in vitro bovine granulosa cell viability, apoptosis, and stress response pathway. GCs were cultured in vitro in the presence of clinically relevant therapeutic and recreational plasma doses of THC. Cortisol doses reflecting normal and elevated plasma levels were used to evaluate the effects of THC under induced stress in vitro. No effect of THC was observed on cell viability or apoptosis. High and low cortisol concentrations caused significant increases in 11β-HSD1 mRNA expression (n = 6, p < 0.0001). Interestingly, when combined with high THC, there was a significant decrease in 11β-HSD1 expression compared to high and low cortisol treatments alone (p < 0.001, p < 0.05). GR expression was unaffected by cortisol treatments, and low THC treatment maintained increased expression in the presence of high and low cortisol treatments (n = 6, p < 0.01, p < 0.0001). Our findings represent a foundation to obtain useful data for evaluating THC potential therapeutic benefit.
•THC treatment does not affect granulosa cell viability or apoptosis.•Cortisol treatments increase 11β-HSD1 gene expression.•11β-HSD1 gene expression is reduced by THC treatment in combination with cortisol.•Glucocorticoid receptor gene expression is increased in response to THC.
Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with ...schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.
Abstract
Purpose
Nicotine and alcohol-containing products are some of the most commonly used substances of abuse and are both leading causes of preventable death. These substances also have ...significant interactions that have additive and, in some cases, multiplicative effects on the health consequences of their use. Thus, to reduce these negative consequences, it is important to understand the abuse liability of nicotine and alcohol in combination, especially in the most relevant use cases among those who are most vulnerable. Specifically, as tobacco cigarette use is continually decreasing, vaping is quickly replacing cigarettes as the primary mode of nicotine use. This pattern is especially true in adolescent populations in which vaping has grown considerably. Particularly concerning is that adolescents are more vulnerable than adults to the negative consequences of substance use. It is therefore imperative to revisit the literature as it relates to the rising state of co-use of vaping products with alcohol. Here, we review the clinical outcomes of nicotine and alcohol co-use as they relate to the abuse liability of each individually. Special attention is paid to adolescent findings, where available, as well as investigations that use nontobacco nicotine products as these may more accurately reflect the more recent trends of co-use.
Implications
Though nicotine alone has previously been considered a proxy for tobacco and tobacco cigarette use, combustible routes of administration have been decreasing. They are, instead, being replaced by e-cigarettes that do not involve other tobacco constituents and contain additional nonnicotine constituents of their own. Unfortunately, the literature remains limited with regard to e-cigarettes and their interactions with other substances, especially their prevalent co-use with alcohol. This review attempts to discuss the current literature on nicotine and alcohol co-use in the context of the vaping epidemic, predominantly focusing on addiction-related outcomes and why e-cigarette use may be unique.
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