Does compulsion explain addiction?

One of the leading drug addiction theories states that habits and the underlying neural process of a ventral to dorsal striatal shift are the building blocks of compulsive drug-seeking behaviour and that compulsion is the maladaptive persistence of responding despite adverse consequences. Here we discuss that compulsive behaviour as defined primarily from the perspective of animal experimentation falls short of the clinical phenomena and their neurobiological correlates. Thus for the human condition, the concept of compulsive habbits should be critically addressed and potentially revised.

High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats.

Drug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats.

BACKGROUND: Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic receptors' type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. METHODS: In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-L-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. RESULTS: Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5-5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. CONCLUSIONS: Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

Opioid craving does not incubate over time in inpatient or outpatient treatment studies: Is the preclinical incubation of craving model lost in translation?

Within addiction science, incubation of craving is an operational label used to describe time-dependent increases in drug seeking during periods of drug deprivation. The purpose of this systematic review was to describe the preclinical literature on incubation of craving and the clinical literature on craving measured over extended periods of abstinence to document this translational homology and factors impacting correspondence. Across the 44 preclinical studies that met inclusion criteria, 31 reported evidence of greater lever pressing, nose pokes, spout licks, or time spent in drug-paired compartments (i.e., drug seeking) relative to neutral compartments after longer periods of abstinence relative to shorter periods of abstinence, labelled as "incubation of craving." In contrast, no clinical studies (n = 20) identified an increase in opioid craving during longer abstinence periods. The lack of clinical evidence for increases in craving in clinical populations weakens the translational utility of operationalizing the time-dependent increase in drug-seeking behavior observed in preclinical models as models of incubation of "craving".

Rebuilding the behavioral inhibition circuit to prevent opioid relapse.

Failure in behavioral suppression is a key feature in substance use disorders, potentially leading to compulsive drug seeking and relapse. In this issue of Neuron, Paniccia et al.1 elucidated a heroin-damaged paraventricular nucleus of the thalamus (PVT)-accumbal circuit and how recovery of PVT function could prevent heroin relapse.

A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats.

Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Environmental Enrichment during Abstinence Reduces Oxycodone Seeking and c-Fos Expression in a Subpopulation of Medial Prefrontal Cortex Neurons.

BACKGROUND: Several preclinical studies have demonstrated that environmental enrichment (EE) during abstinence reduces drug seeking for psychostimulant and opioid drugs. Drug seeking is dependent on activity within the dorsomedial prefrontal cortex, and enrichment has been able to reduce drug seeking-associated increases in c-Fos in this region. In this study, we tested the hypothesis that EE during abstinence from oxycodone self-administration would reduce drug seeking and c-Fos immunoreactivity within the prefrontal cortex in a cell-type specific manner. METHODS: Male rats self-administered oxycodone in two-hours sessions for three weeks, then underwent an initial drug seeking test under extinction conditions after one week of forced abstinence. Following this test, rats received either EE or remained individually housed in their home cage, then a second drug seeking test, with tissue collection immediately afterward. RESULTS: Compared to rats in standard housing, environmentally enriched rats had lower oxycodone seeking. In the prelimbic and infralimbic prefrontal cortices, the number of c-Fos+ cells was reduced, and this reduction was predominantly in inhibitory cells neurons, as evidenced by a reduction in the proportion of c-Fos+ cells in GAD+, but not CamKII+ cells. There was also a robust positive relationship between the number of c-Fos+ cells and persistence of oxycodone seeking in both the PrL and IL. CONCLUSIONS: These findings further support the effectiveness of enriched environments to reduce reactivity to drug-associated stimuli and contexts and provide a potential mechanism by which this occurs.

Electric barrier-induced voluntary abstinence reduces alcohol seeking in male, but not female, iP rats.

Maintaining abstinence and preventing relapse are key to the successful recovery from alcohol use disorder. There are two main ways individuals with alcohol use disorder abstain from alcohol use: forced (e.g., incarceration) and voluntary. Voluntary abstinence is often evoked due to the negative consequences associated with excessive alcohol consumption. This study investigated relapse-like behavior to alcohol seeking following acute, forced, and voluntary abstinence. Male rats had increased operant self-administration responding throughout training compared to females; however, females consumed greater amounts of alcohol in g/kg. Both male and female rats achieved voluntary abstinence, which was induced using an electric barrier on the operant chamber floor with alcohol readily available during this period. Interestingly, male rats that underwent voluntary abstinence displayed reduced alcohol seeking compared to males in the acute and forced abstinence groups. This difference in alcohol seeking behavior across abstinence groups was not observed in female rats. Quantification of neuronal activation (Fos protein) revealed numerous brain regions (e.g., ventral subiculum and lateral habenula) to be associated with the reduced reinstatement propensity seen in male rats that underwent voluntary abstinence. Additionally, hierarchical clustering found enhanced functional connectivity and coordination in the male voluntary abstinence group compared to the male forced abstinence group. Collectively, these data implicate a sexual dimorphism in the effect that voluntary abstinence, at least in the model employed here, has on relapse-like behavior. This maybe driven by reduced neuronal activation at a network level and enhanced functional connectivity and integration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence and altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

Synthesis of α3ß4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3ß4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3ß4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

Blockade of the orexin-2 receptors within the ventral tegmental area facilitates the extinction and prevents the reinstatement of methamphetamine-seeking behavior.

Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 µl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency.

RTI-263, a biased neuropeptide S receptor agonist that retains an anxiolytic effect, attenuates cocaine-seeking behavior in rats.

Neuropeptide S (NPS) is a neuromodulatory peptide that acts via a G protein-coupled receptor. Centrally administered NPS suppresses anxiety-like behaviors in rodents while producing a paradoxical increase in arousal. In addition, NPS increases drug-seeking behavior when administered during cue-induced reinstatement. Conversely, an NPS receptor (NPSR) antagonist, RTI-118, decreases cocaine-seeking behavior. A biased NPSR ligand, RTI-263, produces anxiolytic-like effects and has memory-enhancing effects similar to those of NPS but without the increase in arousal. In the present study, we show that RTI-263 decreased cocaine seeking by both male and female rats during cue-induced reinstatement. However, RTI-263 did not modulate the animals' behaviors during natural reward paradigms, such as palatable food intake, feeding during a fasting state, and cue-induced reinstatement of sucrose seeking. Therefore, NPSR biased agonists are a potential pharmacotherapy for substance use disorder because of the combined benefits of decreased drug seeking and the suppression of anxiety.

Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15-day abstinence in female rats.

Relapse to oxycodone seeking progressively increases after abstinence in rats, a phenomenon termed incubation of oxycodone craving. We have previously shown that the orbitofrontal cortex (OFC) plays a critical role in incubation of oxycodone craving in male rats. Here, we examined the effect of oestrous cycle on incubated oxycodone seeking in female rats, and whether the critical role of OFC in incubated oxycodone seeking generalizes to female rats. We first assessed oxycodone self-administration and incubated oxycodone seeking on abstinence day 15 across the oestrous cycle. Next, we determined the effect of chemogenetic inactivation of OFC by JHU37160 (J60), a novel agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), on incubated oxycodone seeking on abstinence day 15. Finally, we determined the effect of J60 alone on incubated oxycodone seeking on abstinence day 15. We found no difference in oxycodone intake across oestrus, pro-oestrus, and metoestrus stages during oxycodone self-administration training. Incubated oxycodone seeking was also similar between nonoestrus and oestrus female rats. Moreover, chemogenetic inactivation of OFC by J60 decreased incubated oxycodone seeking on abstinence day 15, while J60 alone had no effect on incubated oxycodone seeking in no-DREADD control rats. Taken together, results here show that the oestrous cycle has no effect on oxycodone intake and incubated oxycodone seeking in female rats under our experimental conditions. Furthermore, consistent with our previous findings in male rats, results here show that OFC also plays a critical role in incubated oxycodone seeking in female rats.

Trastorno por consumo de sustancias en adolescentes: reporte de un caso / Substance use disorders in adolescents: A case report

Introduction: Adolescence is a critical period of development during which young people are vulnerable to engaging in risky be haviors, including drug use. Early use of psychoactive substances can interfere with normal development and have both short-term and long-term social and health problems. Objectives: This case report aims to review important aspects of the substance abuse disorder treatment in teenage patients, based on the detailed description of a clinical case. Methods: Description of a clinical case of an 18-year-old patient who began using psychoactive substances at the age of 13. The information used in the review was gathered from relevant publications found through a selective search in PubMed on substance use disorders in children and adolescents. Results: This case report describes the substance use disorder of an 18-year-old female patient, who began using psychoactive substances at the age of 13. The patient had a history off loss of her mother, depressive symptoms and self-injurious behavior, which likely contributed to her increased risk for substance use. The patient’s substance use began with tobacco and gradually progressed to cannabinoids, ecstasy, opioids, and cocaine. Due to her continued substance use, she was referred for consultation at a specialized treatment team. The patient received a combination of psychotherapeutic interventions for substance use and individual therapy. The plan included also coordination with social work and psychology, and the involvement of the individual’s family in the process.Despite these efforts, the patient was ultimately hospitalized for severe self-harm behaviors and entered a therapeutic community.Discussion and Conclusion: This case highlights the complexity of substance use disorders in adolescents and the importance of addressing multiple individual and environmental factors in order...(AU)

Introducción: La adolescencia es un período crítico del desarrollo durante el cual los jóvenes son vulnerables a adoptar conductas de riesgo, incluyendo el consumo de drogas. El uso temprano de sustancias psicoactivas puede interferir con el desarrollo normal y tener problemas sociales y de salud, tanto a corto como a largo plazo.Metas: Este reporte de caso tiene como objetivo revisar aspectos fundamentales del tratamiento del trastorno por abuso de sustancias en pacientes adolescentes, a partir de la descripción detallada de un caso clínico.Métodos: Descripción de un caso clínico de una paciente de 18 años que empezó a consumir sustancias psicoactivas a partir de los 13 años. La información utilizada en esta revisión se obtuvo de publicaciones relevantes encontradas mediante una búsqueda selectiva, en la plataforma PubMed, sobre trastornos por consumo de sustancias en niños y adolescentes.Resultados: Este reporte de caso describe el trastorno por consumo de sustancias de una paciente de sexo femenino de 18 años, que empezó a consumir sustancias psicoactivas a partir de los 13 años. La paciente tenía antecedentes de pérdida de su madre, síntomas depresivos y comportamiento autoagresivo, que probablemente contribuyó a su mayor riesgo de consumo de sustancias. El consumo de sustancias de la paciente empezó con el tabaco y progresó gradualmente a cannabinoides, éxtasis, opioides y cocaína.Debido al consumo continuado de sustancias, fue derivada a consulta, a un equipo de tratamiento especializado. La paciente recibió una combinación de intervenciones psicoterapéuticas para el uso de sustancias y terapia individual. El plan incluía también la coordinación con trabajo social y psicología, y la participación de la familia en el proceso. A pesar de estos esfuerzos, la paciente finalmente fue hospitalizada por conductas autolesivas severas y ingresó a una comunidad terapéutica.(AU)

Isradipine, an L-type calcium channel inhibitor, attenuates cue-associated methamphetamine-seeking in mice.

Methamphetamine (meth) is an addictive psychostimulant and there are no FDA-approved treatment options for patients suffering from meth use disorders. In addition to being addictive, meth is also neurotoxic and chronic administration results in degeneration of substantia nigra pars compacta (SNc) dopamine and locus coeruleus (LC) norepinephrine neurons in mice. Optimal treatment strategies for meth use disorders would attenuate maladaptive meth-seeking behavior as well as provide neuroprotection. The L-type calcium channel inhibitor isradipine and the monoamine oxidase (MAO) inhibitor rasagiline both prevent chronic meth-induced SNc and LC degeneration but effects on meth-seeking are unknown. To test whether these clinically available compounds can mitigate meth-seeking, mice were implanted with chronic indwelling jugular vein catheters and allowed to self-administer meth (0.1 mg/kg/infusion) for 10 consecutive days (2-hrs/day) on a fixed ratio (FR) 1 schedule of reinforcement with meth infusions paired to a cue light. One day after the last self-administration session mice were tested for cue-associated meth-seeking behavior wherein the meth-associated cue light was contingently presented but meth reinforcement withheld. Isradipine (3 mg/kg) attenuated cue-associated meth-seeking in both male and female mice. In contrast, rasagiline (1 mg/kg) had no effect on seeking in either sex. These results suggest that isradipine may have the potential to serve as a dual-purpose pharmacotherapy for meth use disorders by attenuating seeking behavior and providing neuroprotection.