Predicting Youth and Young Adult Treatment Engagement in a Transdiagnostic Remote Intensive Outpatient Program: Latent Profile Analysis.

BACKGROUND: The youth mental health crisis in the United States continues to worsen, and research has shown poor mental health treatment engagement. Despite the need for personalized engagement strategies, there is a lack of research involving youth. Due to complex youth developmental milestones, there is a need to better understand clinical presentation and factors associated with treatment engagement to effectively identify and tailor beneficial treatments. OBJECTIVE: This quality improvement investigation sought to identify subgroups of clients attending a remote intensive outpatient program (IOP) based on clinical acuity data at intake, to determine the factors associated with engagement outcomes for clients who present in complex developmental periods and with cooccurring conditions. The identification of these subgroups was used to inform programmatic decisions within this remote IOP system. METHODS: Data were collected as part of ongoing quality improvement initiatives at a remote IOP for youth and young adults. Participants included clients (N=2924) discharged between July 2021 and February 2023. A latent profile analysis was conducted using 5 indicators of clinical acuity at treatment entry, and the resulting profiles were assessed for associations with demographic factors and treatment engagement outcomes. RESULTS: Among the 2924 participants, 4 profiles of clinical acuity were identified: a low-acuity profile (n=943, 32.25%), characterized by minimal anxiety, depression, and self-harm, and 3 high-acuity profiles defined by moderately severe depression and anxiety but differentiated by rates of self-harm (high acuity+low self-harm: n=1452, 49.66%; high acuity+moderate self-harm: n=203, 6.94%; high acuity+high self-harm: n=326, 11.15%). Age, gender, transgender identity, and sexual orientation were significantly associated with profile membership. Clients identified as sexually and gender-marginalized populations were more likely to be classified into high-acuity profiles than into the low-acuity profile (eg, for clients who identified as transgender, high acuity+low self-harm: odds ratio [OR] 2.07, 95% CI 1.35-3.18; P<.001; high acuity+moderate self-harm: OR 2.85, 95% CI 1.66-4.90; P<.001; high acuity+high self-harm: OR 3.67, 95% CI 2.45-5.51; P<.001). Race was unrelated to the profile membership. Profile membership was significantly associated with treatment engagement: youth and young adults in the low-acuity and high-acuity+low-self-harm profiles attended an average of 4 fewer treatment sessions compared with youth in the high-acuity+moderate-self-harm and high-acuity+high-self-harm profiles (ꭓ23=27.6, P<.001). Individuals in the high-acuity+low-self-harm profile completed treatment at a significantly lower rate relative to the other 2 high-acuity profiles (ꭓ23=13.4, P=.004). Finally, those in the high-acuity+high-self-harm profile were significantly less likely to disengage early relative to youth in all other profiles (ꭓ23=71.12, P<.001). CONCLUSIONS: This investigation represents a novel application for identifying subgroups of adolescents and young adults based on clinical acuity data at intake to identify patterns in treatment engagement outcomes. Identifying subgroups that differentially engage in treatment is a critical first step toward targeting engagement strategies for complex populations.

The Impact of Family Therapy Participation on Youths and Young Adult Engagement and Retention in a Telehealth Intensive Outpatient Program: Quality Improvement Analysis.

BACKGROUND:  Early treatment dropout among youths and young adults (28%-75%) puts them at risk for poorer outcomes. Family engagement in treatment is linked to lower dropout and better attendance in outpatient, in-person treatment. However, this has not been studied in intensive or telehealth settings. OBJECTIVE:  We aimed to examine whether family members' participation in telehealth intensive outpatient (IOP) therapy for mental health disorders in youths and young adults is associated with patient's treatment engagement. A secondary aim was to assess demographic factors associated with family engagement in treatment. METHODS:  Data were collected from intake surveys, discharge outcome surveys, and administrative data for patients who attended a remote IOP for youths and young adults, nationwide. Data included 1487 patients who completed both intake and discharge surveys and either completed or disengaged from treatment between December 2020 and September 2022. Descriptive statistics were used to characterize the sample's baseline differences in demographics, engagement, and participation in family therapy. Mann-Whitney U and chi-square tests were used to explore differences in engagement and treatment completion between patients with and those without family therapy. Binomial regression was used to explore significant demographic predictors of family therapy participation and treatment completion. RESULTS:  Patients with family therapy had significantly better engagement and treatment completion outcomes than clients with no family therapy. Youths and young adults with ≥1 family therapy session were significantly more likely to stay in treatment an average of 2 weeks longer (median 11 weeks vs 9 weeks) and to attend a higher percentage of IOP sessions (median 84.38% vs 75.00%). Patients with family therapy were more likely to complete treatment than clients with no family therapy (608/731, 83.2% vs 445/752, 59.2%; P<.001). Different demographic variables were associated with an increased likelihood of participating in family therapy, including younger age (odds ratio 1.3) and identifying as heterosexual (odds ratio 1.4). After controlling for demographic factors, family therapy remained a significant predictor of treatment completion, such that each family therapy session attended was associated with a 1.4-fold increase in the odds of completing treatment (95% CI 1.3-1.4). CONCLUSIONS:  Youths and young adults whose families participate in any family therapy have lower dropout, greater length of stay, and higher treatment completion than those whose families do not participate in services in a remote IOP program. The findings of this quality improvement analysis are the first to establish a relationship between participation in family therapy and an increased engagement and retention in remote treatment for youths and young patients in IOP programing. Given the established importance of obtaining an adequate dosage of treatment, bolstering family therapy offerings is another tool that could contribute to the provision of care that better meets the needs of youths, young adults, and their families.

Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual, and Other Minoritized Gender and Sexual Identities-Adapted Telehealth Intensive Outpatient Program for Youth and Young Adults: Subgroup Analysis of Acuity and Improvement Following Treatment.

BACKGROUND: Lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other minoritized gender and sexual identities (LGBTQIA+) youth have disproportionately high levels of depression, self-harm, and suicidal thoughts and behaviors. In addition, LGBTQIA+ youth frequently report lower levels of satisfaction or comfort with their health care providers because of stigmatization, which may prevent continuation of care, yet there is a lack of mental health treatment and outcome research addressing these disparities. However, there is some indication that LGBTQIA+ individuals feel more comfortable with web-based formats, indicating that telehealth services may be beneficial for this population. OBJECTIVE: This program evaluation explored the effectiveness of a remote intensive outpatient program with a curriculum tailored specifically to LGBTQIA+ youth with high-acuity depression, anxiety, and suicidality. This study sought to understand baseline acuity differences between LGBTQIA+ and non-LGBTQIA+ youth and young adult patients and to determine if there were differences in clinically significant improvement by subtypes within the LGBTQIA+ population following participation in LGBTQIA+-specific programming. METHODS: Data were collected from intake and discharge outcome surveys measuring depression, suicidality, and nonsuicidal self-injury (NSSI) in 878 patients who attended at least six sessions of a remote intensive outpatient program for youth and young adults. Of these 878 clients, 551 (62.8%) were identified as having at least one LGBTQIA+ identity; they participated in an LGBTQIA+-adapted program of the general curriculum. RESULTS: LGBTQIA+ patients had more clinically severe intake for depression, NSSI, and suicidal ideation. Nonbinary clients had greater NSSI within the LGBTQIA+ sample at intake than their binary counterparts, and transgender clients had significantly higher depressive scores at intake than their nontransgender counterparts. LGBTQIA+ patients demonstrated improvements in all outcomes from intake to discharge. The Patient Health Questionnaire for Adolescents depression scores improved from 18.15 at intake to 10.83 at discharge, representing a 41.5% reduction in depressive symptoms. Overall, 50.5% (149/295) of the LGBTQIA+ youth who endorsed passive suicidal ideation at intake no longer reported it at discharge, 72.1% (160/222) who endorsed active suicidal ideation at intake no longer reported it at discharge, and 55.1% (109/198) of patients who met the criteria for clinical NSSI no longer met the criteria at discharge. In the subgroup analysis, transgender patients were still 2 times more likely to report clinical NSSI at discharge. CONCLUSIONS: This program evaluation found substantial differences in rates of depression, NSSI, and suicidal ideation between LGBTQIA+ clients compared with their non-LGBTQIA+ counterparts. In addition, this evaluation showed a considerable decrease in symptoms when clients attended LGBTQIA+-affirming care. The findings provide support for the role of LGBTQIA+-specific programming to meet the elevated mental health needs of these youth and that more research is needed to understand barriers that may negatively affect transgender clients, specifically.

Individuals Reporting Past 3-month Smoked Stimulant Use Are Placed at Risk for Infection and Injury Amid COVID-19.

OBJECTIVES: Smoking stimulants, such as methamphetamine and "crack" cocaine, can spread infections, including hepatitis C and COVID-19, and lead to injuries, particularly when individuals share or use makeshift pipes. The purpose of the study was to assess the practices of people who inhale ("smoke") stimulants to guide future clinical harm reduction efforts. METHODS: Anonymous surveys were administered to participants reporting inhalation of crack cocaine and/or methamphetamine in the past 3 months. Participants were eligible if they sought services from an outreach team staffed by a municipal syringe service program (SSP) or if they were patients at a low-threshold substance use disorder treatment program, the Massachusetts General Hospital Bridge Clinic. RESULTS: The survey was administered to 68 total participants, 30% of whom were recruited in the Massachusetts General Hospital Bridge Clinic and 70% through SSP outreach. Unsafe smoking practices were reported by 93% of participants. Among the 46% of participants surveyed who both smoked and injected stimulants, 61% of those participants stated that they injected instead of smoked stimulants because of lack of access to pipes. Amid COVID-19, 35% of participants adopted safer smoking practices. Most participants reported that they would be more likely to attend an SSP or health center if pipes were provided. CONCLUSIONS: Inhalational practices that place participants at risk of injury and illness are common. Providing safer smoking equipment may promote health and engage individuals in care.

The Bronze Age of drug checking: barriers and facilitators to implementing advanced drug checking amidst police violence and COVID-19.

OBJECTIVES: Unpredictable fluctuations in the illicit drug market increase overdose risk. Drug checking, or the use of technology to provide insight into the contents of illicit drug products, is an overdose prevention strategy with an emerging evidence base. The use of portable spectrometry devices to provide point-of-service analysis of the contents of illicit drugs been adopted by harm reduction organizations internationally but is only emerging in the United States. This study aimed to identify barriers and facilitators of implementing drug checking services with spectrometry devices in an urban harm reduction organization and syringe service program serving economically marginalized people who use drugs in Boston, Massachusetts (USA). METHODS: In-vivo observations and semi-structured interviews with harm reduction staff and participants were conducted between March 2019 and December 2020. We used the consolidated framework for implementation research to identify implementation barriers and facilitators. RESULTS: This implementation effort was facilitated by the organization's shared culture of harm reduction-which fostered shared implementation goals and beliefs about the intervention among staff persons-its horizontal organizational structure, strong identification with the organization among staff, and strong relationships with external funders. Barriers to implementation included the technological complexity of the advanced spectroscopy devices utilized for drug checking. Program staff indicated that commercially available spectroscopy devices are powerful but not always well-suited for drug checking efforts, describing their technological capacities as "the Bronze Age of Drug Checking." Other significant barriers include the legal ambiguity of drug checking services, disruptive and oppositional police activity, and the responses and programmatic changes demanded by the COVID-19 pandemic. CONCLUSIONS: For harm reduction organizations to be successful in efforts to implement and scale drug checking services, these critical barriers-especially regressive policing policies and prohibitive costs-need to be addressed. Future research on the impact of policy changes to reduce the criminalization of substance use or to provide explicit legal frameworks for the provision of this and other harm reduction services may be merited.

Results from a mobile drug checking pilot program using three technologies in Chicago, IL, USA.

BACKGROUND: Opioid overdose deaths in the United States continue to rise, with the majority of deaths involving fentanyl. Drug checking has been used in Europe and Canada to assess adulteration of the illegal drug supply, but faces legal barriers in the United States. We are presenting information from a pilot mobile program offering drug checking services to participants of a harm reduction program in Chicago, Illinois, USA. METHODS: Drug checking services were provided at five mobile outreach and one fixed-point drop-in location in Chicago, IL, between March 2019 and August 2020. Three technologies were used: a Fourier transform infrared spectroscopy (FTIR) spectrometer, a handheld high-pressure mass spectrometer (HPMS), and immunoassay fentanyl test strips (FTS). We report on results generated by this combination of technology during the study period. RESULTS: During the study period, 422 total samples were tested, the majority of which were sold as dope/heroin (66.7 %). Of the 282 samples sold as dope/heroin, 12.8 % matched to fentanyl on the FTIR, 47.5 % had fentanyl identified on the HPMS, and 57.8 % produced a positive FTS. CONCLUSIONS: This pilot program demonstrated the feasibility of using three technologies to assess for the presence of fentanyl in user-submitted samples, revealed discordant results from the technologies, and provided information on the local drug market.

Use of promethazine, gabapentin and clonidine in combination with opioids or opioid agonist therapies among individuals attending a syringe service program.

BACKGROUND: Clonidine, gabapentin, and promethazine are commonly used by people who use opioids, including heroin, raising concern for increased morbidity and mortality in a vulnerable population. We aimed to characterize how and why individuals use opioids in combination with these three psychoactive medications (PAMs). METHODS: Participants (n = 103) were a convenience sample of adults attending a syringe service program who reported using a PAM in addition to opioids or opioid agonist therapies (buprenorphine or methadone). Face-to-face structured interviews consisted of closed and open-ended questions. RESULTS: Patterns of PAM use varied. Risky use, including use of high doses and with other sedating medications, was common. Most individuals reported multiple medical reasons for use, even while reporting the PAM had mind-altering effects. Use of high doses of PAMs was associated with a history of overdose. Among those with a history of overdose, 32% reported that a PAM was involved. CONCLUSION: The use of clonidine, gabapentin and promethazine among individuals who use opioids is complex. Providers should take individualized approaches to PAM prescribing, recognizing both the risks of PAMs and the potential unintended consequences of supply-side interventions in the era of the overdose crisis. Harm reduction interventions are needed to prevent PAM-involved overdoses.

Synaptic Depotentiation and mGluR5 Activity in the Nucleus Accumbens Drive Cocaine-Primed Reinstatement of Place Preference.

Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The NAc serves as a critical substrate for reward and motivated behavior, in part due to alterations in excitatory synaptic strength within cortical-accumbens pathways. The present studies investigated a causal link between cocaine-induced reinstatement of conditioned place preference and rapid reductions of cocaine-dependent increases in NAc shell synaptic strength in male mice. Cocaine-conditioned place preference behavior and ex vivo whole-cell electrophysiology showed that cocaine-primed reinstatement and synaptic depotentiation were disrupted by inhibiting AMPAR internalization via intra-NAc shell infusion of a Tat-GluA23Y peptide. Furthermore, reinstatement was driven by an mGluR5-dependent reduction in AMPAR signaling. Intra-NAc shell infusion of the mGluR5 antagonist MTEP blocked cocaine-primed reinstatement and corresponding depotentiation, whereas infusion of the mGluR5 agonist CHPG itself promoted reinstatement and depotentiated synaptic strength in the NAc shell. Optogenetic examination of circuit-specific plasticity showed that inhibition of infralimbic cortical input to the NAc shell blocked cocaine-primed reinstatement, whereas low-frequency stimulation (10 Hz) of this pathway in the absence of cocaine triggered a reduction in synaptic strength akin to that observed with cocaine, and was sufficient to promote reinstatement in the absence of a cocaine challenge. These data support a model in which mGluR5-mediated reduction in GluA2-containing AMPARs at NAc shell synapses receiving input from the infralimbic cortex is a critical factor in triggering reinstatement of cocaine-primed conditioned approach behavior.SIGNIFICANCE STATEMENT These studies identified a sequence of neural events whereby reexposure to cocaine activates a signaling cascade that alters synaptic strength in the NAc shell and triggers a behavioral response driven by a drug-associated memory.

Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement.

Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type-specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10-14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies.

A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation.

Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models, including evaluation of more clinically relevant nicotine dosing regimens and other measures of nicotine withdrawal (e.g., anxiety-like behavior, somatic signs), may be useful for understanding the development of the nicotine withdrawal syndrome.

Blockade of cholinergic transmission elicits somatic signs in nicotine-naïve adolescent rats.

High doses of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine can elicit somatic signs resembling those associated with nicotine withdrawal in nicotine-naïve adult rats. Understanding this phenomenon, and its possible modulation by acute nicotine and age, could inform the use of mecamylamine as both an experimental tool and potential pharmacotherapy for tobacco dependence and other disorders. This study evaluated the ability of high-dose mecamylamine to elicit somatic signs in adolescent rats, and the potential for acute nicotine pretreatment to potentiate this effect as previously reported in adults. Single or repeated injections of mecamylamine (1.5 or 3.0 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents, but this effect was not influenced by 2 h pretreatment with acute nicotine (0.5 mg/kg, s.c.). In an initial evaluation of the effects of age in this model, mecamylamine (2.25 mg/kg, s.c.) elicited somatic signs in nicotine-naïve adolescents and adults. This effect was modestly enhanced following acute nicotine injections in adults but not in adolescents, even when a higher nicotine dose (1.0 rather than 0.5 mg/kg, s.c.) was used in adolescents to account for age differences in nicotine pharmacokinetics. These studies are the first to show that mecamylamine elicits somatic signs in nicotine-naïve adolescent rats, an effect that should be considered when designing and interpreting studies examining effects of high doses of mecamylamine in adolescents. Our findings also provide preliminary evidence that these signs may be differentially modulated by acute nicotine pretreatment in adolescents versus adults.

Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats.

BACKGROUND: While nicotine is the primary addictive compound in tobacco, other tobacco constituents including minor alkaloids (e.g., nornicotine, anabasine) may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine. Further evaluating the behavioral effects of minor alkaloids is essential for understanding their impact on tobacco addiction and informing development of tobacco product standards by the FDA. METHODS: This study compared the addiction-related effects of nicotine and the minor alkaloids nornicotine, anabasine, myosmine, anatabine, and cotinine on intracranial self-stimulation (ICSS) thresholds in rats. RESULTS: Acute injection of nicotine produced reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate doses, and reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high doses. Nornicotine and anabasine produced similar biphasic effects on ICSS thresholds, although with lower potency compared to nicotine. Myosmine only elevated ICSS thresholds at relatively high doses, while anatabine and cotinine did not influence ICSS thresholds at any dose. None of the alkaloids significantly influenced ICSS response latencies, indicating a lack of nonspecific motoric effects. CONCLUSIONS: These findings indicate that some minor tobacco alkaloids can either fully (nornicotine, anabasine) or partially (myosmine) mimic nicotine's addiction-related effects on ICSS, albeit at reduced potency. These findings emphasize the need for further study of the abuse potential of minor alkaloids, including evaluation of their effects when combined with nicotine and other tobacco constituents to better simulate tobacco exposure in humans. Such work is essential for informing FDA regulation of tobacco products and could also lead to the development of novel pharmacotherapies for tobacco addiction.

Animal models to assess the abuse liability of tobacco products: effects of smokeless tobacco extracts on intracranial self-stimulation.

BACKGROUND: Preclinical models are needed to inform regulation of tobacco products by the Food and Drug Administration (FDA). Typically, animal models of tobacco addiction involve exposure to nicotine alone or nicotine combined with isolated tobacco constituents (e.g. minor alkaloids). The goal of this study was to develop a model using extracts derived from tobacco products that contain a range of tobacco constituents to more closely model product exposure in humans. METHODS: This study compared the addiction-related effects of nicotine alone and nicotine dose-equivalent concentrations of aqueous smokeless tobacco extracts on intracranial self-stimulation (ICSS) in rats. Extracts were prepared from Kodiak Wintergreen, a conventional product, or Camel Snus, a potential "modified risk tobacco product". Binding affinities of nicotine alone and extracts at various nicotinic acetylcholine receptor (nAChR) subtypes were also compared. RESULTS: Kodiak and Camel Snus extracts contained levels of minor alkaloids within the range of those shown to enhance nicotine's behavioral effects when studied in isolation. Nonetheless, acute injection of both extracts produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, as well as similar reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high nicotine doses. Extracts and nicotine alone also had similar binding affinity at all nAChRs studied. CONCLUSIONS: Relative nicotine content is the primary pharmacological determinant of the abuse liability of Kodiak and Camel Snus as measured using ICSS. These models may be useful to compare the relative abuse liability of other tobacco products and to model FDA-mandated changes in product performance standards.

Effects of oxytocin on nicotine withdrawal in rats.

Development of medications that attenuate symptoms of nicotine withdrawal may be useful for facilitating smoking cessation. The neuropeptide oxytocin (OXY) decreases withdrawal signs and other addiction-related effects of several drugs of abuse in animals, but has not been examined in a preclinical model of nicotine addiction. The goal of this study was to examine the effects of OXY on nicotine withdrawal in rats, measured as increases in somatic signs and elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during antagonist-precipitated withdrawal from a chronic nicotine infusion. Effects of OXY on baseline ICSS thresholds in non-dependent rats were also evaluated. OXY (0.06 - 1.0mg/kg, i.p.) blocked withdrawal-induced elevations in somatic signs in nicotine-dependent rats without affecting somatic signs in non-dependent rats. In contrast, OXY did not affect nicotine withdrawal-induced elevations in ICSS thresholds. Relatively high doses of OXY (0.75 or 2.0mg/kg) elevated baseline ICSS thresholds in non-dependent rats. These findings demonstrate that OXY blocks somatic signs but not elevations in ICSS thresholds during antagonist-precipitated nicotine withdrawal. The ability of higher OXY doses to elevate baseline ICSS thresholds in non-dependent rats may reflect an aversive and/or motoric effect. These data suggest that OXY-based medications may be useful for treating the somatic component of the nicotine withdrawal syndrome, but may not be effective in attenuating withdrawal-induced anhedonia.

Mecamylamine elicits withdrawal-like signs in rats following a single dose of nicotine.

RATIONALE: The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established. OBJECTIVE: The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure. METHODS AND RESULTS: Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect. CONCLUSIONS: Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.