Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors.

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days' supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher's tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p<.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p<.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Prolonged exposure to cocaine self-administration results in a continued progression of alterations in functional activity in a nonhuman primate model.

Background: Studies of nonhuman primates with exposures of up to 100 days of cocaine self-administration (SA) have provided evidence that the central effects of cocaine progress over time. These durations of cocaine exposure, however, may be insufficient to capture the extent of the neurobiological alterations observed in cocaine users, many of whom use the drug for years. The goal of the present study was to determine whether 1.5 years of cocaine SA would result in further progression of alterations in functional brain activity. Methods: Adult male rhesus monkeys were exposed to 300 sessions of high-dose cocaine SA over 1.5 years. Following the final session rates of local cerebral glucose utilization (LCGU) were assessed with the 2-[14C]-deoxyglucose method and compared to rates of LCGU in control monkeys who responded for food reinforcement. In addition, LCGU in these animals was compared to a previously published group of monkeys that had self-administered cocaine or food for 100 sessions over a 4-5 month period. Results: Compared to 100 days of exposure, 300 days of cocaine SA further reduced LCGU in the post-commissural striatum and produced reductions in areas unaffected by the shorter duration of exposure, such as the hypothalamus, all of the amygdala, and large expanses of cortex. Conclusions: These findings demonstrate a clear progression of the impact of cocaine on functional activity with increasing durations of drug experience and have important implications for the development of potential strategies for the treatment of cocaine use disorder.

Residual deficits in functional brain activity after chronic cocaine self-administration in rhesus monkeys.

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

Chronic phenmetrazine treatment promotes D2 dopaminergic and α2-adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain.

Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2Thr202/Tyr204, GSK3ßTyr216, and DARPP-32Thr34. Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[14C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN's activity, we performed [35S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D2 dopamine and α2-adrenergic, but not 5-HT1A, receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3ß levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use.

Novel Tumor Growth Rate Analysis in the Randomized CLARINET Study Establishes the Efficacy of Lanreotide Depot/Autogel 120 mg with Prolonged Administration in Indolent Neuroendocrine Tumors.

INTRODUCTION: Tumor quantity while receiving cancer therapy is the sum of simultaneous regression of treatment-sensitive and growth of treatment-resistant fractions at constant rates. Exponential rate constants for tumor regression/decay (d) and growth (g) can be estimated. Previous studies established g as a biomarker for overall survival; g increases after treatment cessation, can estimate doubling times, and can assess treatment effectiveness in small cohorts by benchmarking to large reference data sets. Using this approach, we analyzed data from the clinical trial CLARINET, evaluating lanreotide depot/autogel 120 mg/4 weeks (LAN) for treatment of neuroendocrine tumors (NETs). METHODS AND MATERIALS: Computed tomography imaging data from 97 LAN- and 101 placebo-treated patients from CLARINET were analyzed to estimate g and d. RESULTS: Data from 92% of LAN- and 94% of placebo-treated patients could be fit to one of the equations to derive g and d (p < .001 in most data sets). LAN-treated patients demonstrated significantly slower g than placebo recipients (p = .00315), a difference of 389 days in doubling times. No significant difference was observed in d. Over periods of LAN administration up to 700 days, g did not change appreciably. Simulated analysis with g as the endpoint showed a sample size of 48 sufficient to detect a difference in median g with 80% power. CONCLUSION: Although treatment of NETs with LAN can affect tumor shrinkage, LAN primarily slows tumor growth rather than accelerates tumor regression. Evidence of LAN efficacy across tumors was identified. The growth-retarding effect achieved with LAN was sustained for a prolonged period of time. IMPLICATIONS FOR PRACTICE: The only curative treatment for neuroendocrine tumors (NETs) is surgical resection; however, because of frequent late diagnosis, this is often impossible. Because of this, treatment of NETs is challenging and often aims to reduce tumor burden and delay progression. A novel method of analysis was used to examine data from the CLARINET trial, confirming lanreotide depot/autogel is effective at slowing tumor growth and extending progression-free survival. By providing the expected rate and doubling time of tumor growth early in the course of treatment, this method of analysis has the potential to guide physicians in their management of patients with NETs.

Medical record review of transition to lanreotide following octreotide for neuroendocrine tumors.

BACKGROUND: Octreotide has been used for decades in the United States (US) and Europe to treat patients with advanced neuroendocrine tumors (NETs). Lanreotide was approved in 2014 to improve progression-free survival (PFS) in patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic NETs. Therefore, clinicians and patients may consider sequencing therapy from octreotide to lanreotide. However, current real-world outcomes data on patients who have made this transition is limited. METHODS: We conducted a multicenter, noninterventional, retrospective medical record review of patients with locally advanced or metastatic gastroenteropancreatic NETs (NCT03112694). Included patients had been treated with long-acting octreotide monotherapy for ≥90 days before transitioning to lanreotide monotherapy and continued on lanreotide for ≥90 days. Abstractors entered patient demographic and clinical data into a customized, web-based case report form. We assessed clinically defined PFS and other tumor-related outcomes while patients were treated with lanreotide. Outcomes were analyzed according to level of response at the time of transition from octreotide to lanreotide: progressive disease, nonprogressive disease, or unknown. Statistical analyses were descriptive. Clinically defined PFS and duration of treatment with lanreotide were estimated using the Kaplan-Meier method. RESULTS: Data were abstracted for 91 patients with gastroenteropancreatic NETs who received long-acting octreotide followed by lanreotide at six US based sites. At initial diagnosis, 71.4% of patients had stage IV disease. Small intestine (63.7%) and pancreas (14.3%) were the most common primary tumor sites. Mean [standard deviation (SD)] duration of follow-up from diagnosis was 70.6 (41.3) months. Patients received long-acting octreotide for a mean (SD) of 38.4 (32.8) months. When patients transitioned to lanreotide, 57.1% had nonprogressive disease on octreotide, 30.8% had progressive disease, and the remainder had unknown disease status. The most common reasons for switching from octreotide to lanreotide were progressive disease (22.0%), formulary change (15.4%), and patient preference (9.9%). Patients received lanreotide for a median (95% CI) duration of 24.7 (16.7-59.9) months. At the end of follow-up, 74% of patients remained on lanreotide monotherapy. Progression occurred in 24.2% of patients during lanreotide treatment. Overall median (95% CI) clinician-defined PFS following the transition to lanreotide was estimated to be 23.7 months [20.2 months-NE (not estimable)]. Patients with nonprogressive disease when they transitioned to lanreotide experienced a median clinician-defined PFS of 24.7 (17.0-NE) months. Among patients reported to have progressive disease when they transitioned to lanreotide, median (95% CI) clinician-defined PFS was estimated to be 15.2 (11.4-NE) months. There were no material differences in adverse events recorded during the long-acting octreotide and lanreotide treatment periods. CONCLUSIONS: Our study suggests that lanreotide monotherapy is well tolerated and may contribute to stabilization of disease in a subset of patients with locally advanced or metastatic gastroenteropancreatic NETs previously treated with long-acting octreotide.

Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration.

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.

The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy.

PURPOSE: To explore how follicle-stimulating hormone (FSH) may contribute to cardiovascular, metabolic, skeletal, and cognitive events in men treated for prostate cancer, with various forms of androgen deprivation therapy (ADT). MATERIALS AND METHODS: A colloquium of prostate cancer experts was convened in May 2015, to discuss the role of FSH in the development of unwanted effects associated with ADT. Subsequently, a literature review (Medline, PubMed, and relevant congress abstract databases) was performed to further explore and evaluate the collected evidence. RESULTS: It has become evident that, in the setting of ADT, FSH can promote the development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance. Data also suggest that FSH is an important mediator of bone remodeling, particularly bone resorption, and thereby increases the risk for bone fracture. Additional evidence implicates a role for FSH in bone metastasis as well. The influence of FSH on ADT-induced cognitive deficits awaits further elucidation; however, the possibility that FSH may be involved therein cannot be ruled out. CONCLUSIONS: The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine.

BACKGROUND: The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. METHODS: The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75mg/kg/infusion), and following LY379268 (0.03 or 0.30mg/kg; i.p.), phenmetrazine (25mg/kg/day; osmotic minipump), and a combination of the two drugs. RESULTS: LY379268 and phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%. CONCLUSIONS: These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs.

Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure.

Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain.

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-ß (pGSK3ß(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3ß(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system.

Effects of the dopamine/norepinephrine releaser phenmetrazine on cocaine self-administration and cocaine-primed reinstatement in rats.

RATIONALE: Like other monoamine releasers such as D-amphetamine, chronic treatment with phenmetrazine can attenuate cocaine self-administration in monkeys. OBJECTIVES: The present studies extended this finding to rodents and to cocaine-primed reinstatement, a putative laboratory animal model of relapse. METHODS: In experiment 1, rats self-administered food pellets or injections of 0.19 mg/kg cocaine (i.v.) under a progressive-ratio schedule. When responding was stable, subcutaneous osmotic pumps were implanted containing saline or (+)-phenmetrazine (25 or 50 mg/kg per day). In experiment 2, rats self-administered injections of 0.75 mg/kg cocaine under a fixed-ratio 1 schedule in daily 6-h sessions. When responding was stable, rats were removed from the self-administration environment for 7 days and treated continuously with saline, 5 mg/kg per day D-amphetamine or phenmetrazine (25 or 50 mg/kg per day) via osmotic pumps. Rats were then returned to the self-administration context while treatment continued, and responding was extinguished by removing response-contingent stimulus changes and cocaine injections. Once responding was extinguished, reinstatement tests were conducted using cocaine injections (10 mg/kg i.p.). RESULTS: Phenmetrazine decreased self-administration of cocaine, but not food pellets, during the 14-day treatment period; effects persisted for several days after treatment was discontinued. Moreover, cocaine-induced increases in responding during the reinstatement test were attenuated by D-amphetamine and both phenmetrazine doses. CONCLUSIONS: These results extend the study of the effects of phenmetrazine on cocaine self-administration to a rodent model, and provide further support for the use of monoamine releasers as agonist medications for cocaine abuse.

The effects of GSK-3ß blockade on ketamine self-administration and relapse to drug-seeking behavior in rats.

RATIONALE: The role of glycogen synthase kinase-3 (GSK-3) has recently been implicated in the neurochemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance. OBJECTIVES: The primary goal of the present study was to determine the role of GSK-3ß in ketamine self-administration (SA) and relapse to drug-seeking behavior after abstinence. METHODS: In Experiment 1, the level of phosphorylated GSK-3ß (p-GSK-3ß) and total GSK-3ß (t-GSK-3ß) was determined in various brain areas following 14 days of ketamine SA. In Experiments 2 and 3, the effects of a GSK-3ß inhibitor, SB216763 (2 and 4 mg/kg) and a GSK-3 inhibitor, lithium (LiCl, 100mg/kg) on the responding maintained by 0.5mg/kg/infusion ketamine SA were evaluated. In Experiments 4 and 5, rats underwent ketamine SA for 14 days followed by a 10-day abstinence period. The animals were treated with 2 or 4 mg/kg GSK-3ß inhibitor, or 100mg/kg LiCl during the cue-induced relapse test. Seven days later, animals received the same drug treatment and underwent the drug-induced relapse test. Finally, the effect of saline and DMSO on locomotor activity was evaluated in Experiment 6. RESULTS: Ketamine SA significantly decreased the ratio p-GSK-3ß and t-GSK-3ß (p-GSK-3ß:t-GSK-3ß) in the caudate putamen, nucleus accumbens, and ventral tegmental area. Both SB216763 and LiCl decreased responding on a progressive ratio schedule, but not on a fixed ratio schedule. Cue-induced relapse was suppressed only by 4mg/kg SB216763, whereas drug-induced relapse was inhibited by 2, 4 mg/kg SB216763 and LiCl. However, inactive responses were also suppressed by LiCl during progressive ratio and drug-induced relapse testing. CONCLUSIONS: SB216763 was effective at decreasing ketamine SA under the PR schedule and reducing drug-seeking behavior after abstinence.

Chronic methylphenidate treatment during early life is associated with greater ethanol intake in socially isolated rats.

BACKGROUND: Methylphenidate (MPH) is a stimulant prescribed to treat attention-deficit/ hyperactivity disorder. Its primary mechanism of action is in the dopamine system, alterations of which are associated with vulnerability to alcohol abuse. There are concerns that juvenile MPH treatment may influence adult drinking behavior. This study examined the interaction of MPH treatment and environmental rearing conditions, which are known to independently influence ethanol (EtOH) drinking behavior, on anxiety-like behavior and vulnerability to alcohol abuse in a juvenile rodent model. METHODS: Male Sprague-Dawley rats were housed in enriched, standard, or isolated conditions for 4 weeks, starting at postnatal day 21. Rats were concurrently treated with 8 mg/kg/d MPH or saline, delivered via osmotic minipump. Anxiety-like behavior was determined at the end of the treatment session, and 5 weeks later. After MPH treatment, rats were exposed to a 2-bottle choice EtOH drinking procedure that lasted 3 weeks. RESULTS: Early life chronic MPH treatment was associated with greater EtOH intake and greater EtOH preference, but only in socially isolated animals. Isolated animals had greater levels of anxiety-like behavior than standard-housed or enriched animals after 4 weeks of exposure to the housing conditions, a difference that persisted even after all animals had been individually housed for an additional 5 weeks and exposed to EtOH. CONCLUSIONS: These results suggest that early life MPH treatment may increase vulnerability to EtOH drinking in adulthood in a subset of the population. Additionally, this study highlights the importance of early rearing condition for establishing long-lasting behavioral phenotypes. Environmental histories should be considered when prescribing MPH treatment to young children.

Functional consequences of cocaine re-exposure after discontinuation of cocaine availability.

Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self-administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n=4) or 90 days (n=3) during which experimental sessions were not conducted. Food-reinforced control animals (n=5) underwent identical schedules of reinforcement. Animals were then re-exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems.

Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

BACKGROUND: Neuroimaging studies of cocaine users have demonstrated white matter abnormalities associated with behavioral measures of impulsivity and decision-making deficits. The underlying bases for this dysregulation in white matter structure and function have yet to be determined. The aim of the present studies was to investigate the influence of prolonged cocaine self-administration on the levels of myelin-associated proteins and mRNAs in nonhuman primate white matter. METHODS: Rhesus monkeys (N=4) self-administered cocaine (0.3mg/kg/inj, 30 reinforcers per session) for 300 sessions. Control animals (N=4) responded for food. Following the final session monkeys were euthanized and white matter tissue at three brain levels was processed for immunoblotting analysis of proteolipid protein (PLP) and myelin basic protein (MBP), as well as for in situ hybridization histochemical analysis of PLP and MBP mRNAs. RESULTS: Both MBP and PLP immunoreactivities in white matter at the level of the precommissural striatum were significantly lower in tissue from monkeys self-administering cocaine as compared to controls. No significant differences were seen for either protein at the levels of the prefrontal cortex or postcommissural striatum. In addition, no differences were observed in expression of mRNA for either protein. CONCLUSIONS: These preliminary findings, in a nonhuman model of prolonged cocaine self-administration, provide further evidence that compromised myelin may underlie the deficits in white matter integrity described in studies of human cocaine users.

Withdrawal from extended-access cocaine self-administration results in dysregulated functional activity and altered locomotor activity in rats.

Much work has focused on determining the consequences of cocaine self-administration on specific neurotransmitter systems, thus neglecting the global changes that occur. Previous imaging studies have focused on the effects of cocaine self-administration in the presence of high blood levels of cocaine, but have not determined the functional effects of cocaine self-administration after cocaine has cleared. Extended-access cocaine self-administration, where animals administer cocaine for 6 h each day, results in escalation in the rate of cocaine intake and is believed to model the transition from recreational use to addiction in humans. We aimed to determine the functional changes following acute (48 h) withdrawal from an extended-access, defined-intake self-administration paradigm (5 days, 40 injections/day, 6 h/day), a time point when behavioral changes are present. Using the 2-[(14) C]deoxyglucose method to measure rates of local cerebral glucose metabolism, an indicator of functional activity, we found reductions in circuits related to learning and memory, attention, sleep, and reward processing, which have important clinical implications for cocaine addiction. Additionally, lower levels of functional activity were found in the dorsal raphe and locus coeruleus, suggesting that cocaine self-administration may have broader effects on brain function than previously noted. These widespread neurochemical reductions were concomitant with substantial behavioral differences in these animals, highlighted by increased vertical activity and decreased stereotypy. These data demonstrate that behavioral and neurochemical impairments following cocaine self-administration are present in the absence of drug and persist after cocaine has been cleared.

The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats.

BACKGROUND: Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. METHODS: Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6 h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. RESULTS: Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. CONCLUSIONS: LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.

The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats.

Rearing young rodents in socially isolated or environmentally enriched conditions has been shown to affect numerous components of the dopamine system as well as behavior. Methylphenidate (MPH), a commonly used dopaminergic agent, may affect animals differently based on rearing environment. Here we examined the interaction between environment and chronic MPH treatment at clinically relevant doses, administered via osmotic minipump. Young Sprague Dawley rats (PND 21) were assigned to environmentally enriched, pair-housed, or socially isolated rearing conditions, and treated with either 0, 2, 4, or 8 mg/kg/day MPH for 3 weeks. At the end of the treatment period, animals were tested for locomotor activity and anxiety-like behavior. The densities of D1-like and D2-like receptors were measured in the striatum using in vitro receptor autoradiography. Locomotor activity and anxiety-like behavior were increased in isolated animals compared to pair-housed and enriched animals. The density of D1-like receptors was greater in isolated animals, but there were no differences between groups in D2-like receptor density. Finally, there were no effects of MPH administration on any reported measure. This study provides evidence for an effect of early rearing environment on the dopamine system and behavior, and also suggests that MPH administration may not have long-term consequences.