Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD

Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5mg/kg) or water vehicle provided Monday-Friday from postnatal days 28-55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability.P50 DA005312 - NIDA NIH HHS; R01 DA011716 - NIDA NIH HHS; P50 DA05312 - NIDA NIH HH

Mecamylamine, dihydro-β-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine

Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors in the CS effects of nicotine (0.4 mg/kg) using antagonists with differential selectivity for β2*, α7*, α6β2*, and α3β4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHβE, each blocked conditioned responding when given 5 min before testing and still blocked conditioned responding when administered 200 min before testing. Two novel bis-picolinium analogs (N, N’-(3, 3′-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N’- (decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion were used to target α3β4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1 mg/kg). These results indicate that β2* and potentially α3β4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids

Mecamylamine, dihydro-β-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine

Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors in the CS effects of nicotine (0.4 mg/kg) using antagonists with differential selectivity for β2*, α7*, α6β2*, and α3β4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHβE, each blocked conditioned responding when given 5 min before testing and still blocked conditioned responding when administered 200 min before testing. Two novel bis-picolinium analogs (N, N’-(3, 3′-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N’- (decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion were used to target α3β4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1 mg/kg). These results indicate that β2* and potentially α3β4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids

An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic α6β2* antagonist r-bPiDI

Background Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the “price” of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions These results indicate that increasing the “price” of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy

Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor R-modafinil on co-use of ethanol and nicotine in female P rats.

Rationale: Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use. Objectives: Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.v. nicotine self-administration in three phases: (1) EtOH alone (0 vs. 15%, 2-bottle choice); (2) nicotine alone (0.03 mg/kg/infusion, active vs. inactive lever); and (3) concurrent access to both EtOH and nicotine. Using this model, we examined the effects of (1) varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist with high affinity for the α4β2 subtype; (2) r-bPiDI, a subtype-selective antagonist at α6β2* nAChRs; and (3) (R)-modafinil, an atypical inhibitor of the dopamine transporter (DAT). Results: In Phases 1 and 2, pharmacologically relevant intake of EtOH and nicotine was achieved. In the concurrent access phase (Phase 3), EtOH consumption decreased while nicotine intake increased relative to Phases 1 and 2. For drug pretreatments, in the EtOH access phase (Phase 1), (R)-modafinil (100 mg/kg) decreased EtOH consumption, with no effect on water consumption. In the concurrent access phase, varenicline (3 mg/kg), r-bPiDI (20 mg/kg), and (R)-modafinil (100 mg/kg) decreased nicotine self-administration, but did not alter EtOH consumption, water consumption, or inactive lever pressing. Conclusions: These results indicate that therapeutics which may be useful for smoking cessation via selective inhibition of α4β2 or α6β2* nAChRs, or DAT inhibition, may not be sufficient to treat EtOH and nicotine co-use

Tobacco\u27s Minor Alkaloids: Effects on Place Conditioning and Nucleus Accumbens Dopamine Release in Adult and Adolescent Rats

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated

Integrating data science into the translational science research spectrum: a substance use disorder case study

The availability of large healthcare datasets offers the opportunity for researchers to navigate the traditional clinical and translational science research stages in a nonlinear manner. In particular, data scientists can harness the power of large healthcare datasets to bridge from preclinical discoveries (T0) directly to assessing population-level health impact (T4). A successful bridge from T0 to T4 does not bypass the other stages entirely; rather, effective team science makes a direct progression from T0 to T4 impactful by incorporating the perspectives of researchers from every stage of the clinical and translational science research spectrum. In this exemplar, we demonstrate how effective team science overcame challenges and, ultimately, ensured success when a diverse team of researchers worked together, using healthcare big data to test population-level substance use disorder (SUD) hypotheses generated from preclinical rodent studies. This project, called Advancing Substance use disorder Knowledge using Big Data (ASK Big Data), highlights the critical roles that data science expertise and effective team science play in quickly translating preclinical research into public health impact.Published versio

Bupropion Increases Selection of High Effort Activity in Rats Tested on a Progressive Ratio/Chow Feeding Choice Procedure: Implications for Treatment of Effort-Related Motivational Symptoms

Background: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. Methods: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. Results: Bupropion (10.0–40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. Conclusion: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed