Novel Addiction Treatments

BACKGROUND: Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. METHODS: We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features...

BACKGROUND: Neuropeptides are contained in nearly every neuron in the central nervous system and can be released not only from nerve terminals but also from somatodendritic sites. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Despite this high expression, CCK function within the ventral tegmental area (VTA) is not well understood. METHODS: We confirmed CCK expression in VTA dopamine neurons through immunohistochemistry and in situ hybridization and detected optogenetically induced CCK release using an enzyme-linked immunosorbent assay...

BACKGROUND: Anxiety disorders are associated with an altered perception of the body's internal state. Therefore, understanding the neuronal basis of interoception can foster novel anxiety therapies. In rodents, the feeding status bidirectionally modulates anxiety-like behavior but how the sensing of gastrointestinal state affects anxiety remains unclear. METHODS: We combined chemogenetics, neuropharmacology, and behavioral approaches in male and female rats to test whether vagal afferents terminating in the gastrointestinal tract mediate feeding-induced tuning of anxiety...

Repetitive bouts of binge drinking can lead to neuroplastic events that alter ethanol's pharmacologic effects and perpetuate excessive consumption. The corticotropin-releasing factor (CRF) system is an example of ethanol-induced neuroadaptations that drive excessive ethanol consumption. Our laboratory has previously shown that CRF antagonist, when infused into the central amygdala (CeA), reduces binge-like ethanol consumption. The present study extends this research by assessing the effects of silencing CRF-producing neurons in CeA on binge-like ethanol drinking stemming from "Drinking in the Dark" (DID) procedures...

As the smallest mammal with a gyrencephalic cerebral cortex, ferrets are becoming increasingly important animal models to study neurological disorders. In order for them to be optimally used, typical behavioral measurements are highly desirable. To ascertain a baseline level of behavior, we conducted a battery of tests assessing motor, social, memory, headache, and aspects of depressive-like behavior. Adult male ferrets participated in open field, beam walk, sucrose preference, eye contact, light/dark box, socialization, and novel object recognition tests...

The mechanisms underlying chronic psychiatric-like impairments after traumatic brain injury (TBI) are currently unknown. The goal of the present study was to assess the role of diet and the gut microbiome in psychiatric symptoms after TBI. Rats were randomly assigned to receive a high-fat diet (HFD) or calorie-matched low-fat diet (LFD). After 2 weeks of free access, rats began training on the rodent gambling task (RGT), a measure of risky decision-making and motor impulsivity. After training, rats received a bilateral frontal TBI or a sham procedure and continued postinjury testing for 10 weeks...

Newly emerging synthetic cannabinoid compounds continue to be found in the designer drug market. They are often targeted as a 'legal high' alternative to traditional cannabinoids via 'darknet' markets and their increased potency and efficacy are becoming a growing concern internationally. The purpose of this study was to determine whether 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA exhibited similar behavioral effects as Δ9-tetrahydrocannabinol (Δ9-THC). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice...

Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR). Despite early promising data, it recently failed to facilitate cocaine abstinence in patients and has been compared with dopamine antagonist medications (antipsychotics). Here, we review the effects of both classes on drug reinforcement. In addition to not being effective treatments for cocaine use disorder, both dopamine antagonists and lorcaserin can have biphasic effects on dopamine and reward behavior. Lower doses can cause enhanced drug taking with higher doses causing reductions...

Gamma-aminobutyric acid (GABA) and its precursor glutamate play signaling roles in a range of tissues. Both function as neurotransmitters in the central nervous system, but they also modulate pancreatic and immune functioning, for example. Besides endogenous production, both compounds are found in food products, reaching relatively high levels in tomatoes. Recent studies in rodents suggest beneficial effects of oral GABA on glucose homeostasis and blood pressure. However, the bioavailability from food remains unknown...

Brain ageing has been related to a decrease in cellular metabolism, to an accumulation of misfolded proteins and to an alteration of the lipid membrane composition. These alterations act as contributive aspects of age-related memory decline by reducing membrane excitability and neurotransmitter release. In this sense, precursors of phospholipids (PLs) can restore the physiological composition of cellular membranes and ameliorate the cellular defects associated with brain ageing. In particular, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) have been shown to restore mitochondrial function, reduce the accumulation of amyloid beta (Aβ) and, at the same time, provide the amount of acetylcholine needed to reduce memory deficit...

OBJECTIVE: To identify the presence of unapproved pharmaceutical drugs in over-the-counter dietary supplements marketed to improve memory and cognitive function. METHODS: Supplements were identified by searching 2 supplement databases for products labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam, 4 drugs not approved for human use in the United States. Products were purchased online and analyzed using nontargeted liquid chromatography-quadrupole time-of-flight mass spectrometry methods...

To the Editor, The ongoing rise of New Psychoactive Substances (NPS), i.e. psychotropic molecules devised and synthesized to replicate the effects of traditional drugs of abuse in order to circumvent banned substances schedules, has been posing a challenge of enormous magnitude to substance detection systems and law enforcement worldwide. Still, it would be remiss to ignore the role played by the unprecedented public health emergency relating to the COVID-19 pandemic in the exacerbation of the NPS crisis. The diversion of resources has in fact hindered conventional approaches to drug monitoring, surveillance, control, and public health responses...

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse...

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects...

In the twentieth century, neuropsychiatric disorders have been perceived solely from a neurone-centric point of view, which considers neurones as the key cellular elements of pathological processes. This dogma has been challenged thanks to the better comprehension of the brain functioning, which, even if far from being complete, has revealed the complexity of interactions that exist between neurones and neuroglia. Glial cells represent a highly heterogeneous population of cells of neural (astroglia and oligodendroglia) and non-neural (microglia) origin populating the central nervous system...

The role of astrocytes in the nervous system pathology was early on embraced by neuroscientists at end of the nineteenth and the beginning of the twentieth century, only to be pushed aside by neurone-centric dogmas during most of the twentieth century. However, the last decade of the twentieth century and the twenty-first century have brought the astroglial "renaissance", which has put astroglial cells as key players in pathophysiology of most if not all disorders of the nervous system and has regarded astroglia as a fertile ground for therapeutic intervention...

Ongoing research continues to add new elements to the emerging picture of involvement of astrocyte energy metabolism in the pathophysiology of major psychiatric disorders, including schizophrenia, mood disorders, and addictions. This review outlines what is known about the energy metabolism in astrocytes, the most numerous cell type in the brain, and summarizes the recent work on how specific perturbations of astrocyte bioenergetics may contribute to the neuropsychiatric conditions. The role of astrocyte energy metabolism in mental health and disease is reviewed on the organism, organ, and cell level...

Astroglia are key regulators of synaptic function, playing central roles in homeostatic ion buffering, energy dynamics, transmitter uptake, maintenance of neurotransmitter pools, and regulation of synaptic plasticity through release of neuroactive chemicals. Given the myriad of crucial homeostatic and signaling functions attributed to astrocytes and the variety of neurotransmitter receptors expressed by astroglia, they serve as prime cellular candidates for establishing maladaptive synaptic plasticity following drug exposure...

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP]i ) and ketamine-induced modifications of stimulus-evoked Ca2+ signalling...

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects...