Neural basis of smoking-induced relief of craving and negative affect: Contribution of nicotine.

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal.

N,N-Dimethyltryptamine-Induced Psychosis.

BACKGROUND: N,N-dimethyltryptamine (DMT) is a 5-hydroxytryptamine 2A and 1A receptor agonist that exhibits potent psychoactive properties in humans. Recreational use of this drug has increased precipitously and is likely to result in an increase in patients presenting with substance-induced psychoses. The present case provides an early example of substance-induced psychosis attributable to repeated use of DMT. CASE: A 42-year-old white man, with no significant past psychiatric history, was brought to the emergency department by the police and was found to exhibit disinhibited behavior, elevated affect, disorganized thought process, and delusions of reference. Laboratory studies revealed elevated creatinine kinase level indicative of rhabdomyolysis. The patient endorsed recent and repeated use of DMT, as well as long-term Cannabis (marijuana) use. Over the course of the next 3 weeks, the patient was successfully treated with quetiapine for psychosis, divalproex sodium (Depakote) for impulsivity, gabapentin for anxiety, and hydroxyzine for sleep, which resulted in the resolution of his symptoms and development of reasonable insight and judgment. Approximately 6 months after discharge, the patient remained treatment compliant, as well as drug and symptom free. CONCLUSIONS: This case report illustrates an important example of substance-induced psychosis that resolved with antipsychotic treatment in a 42-year-old white man with no past psychiatric history likely attributable to the use of DMT. Given the increasing use of this substance, the emergency department, primary care, and inpatient services are likely to see a significant increase in similar cases.

Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline. OBJECTIVE: The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility. METHODS: BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli. RESULTS: Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls. CONCLUSIONS: Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients.

Dopamine D3 receptors as a therapeutic target for methamphetamine dependence.

BACKGROUND: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. OBJECTIVES: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. METHODS: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily). RESULTS: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. CONCLUSION: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.

Assessment of substance abuse liability in rodents: self-administration, drug discrimination, and locomotor sensitization.

Assessing abuse liability is a crucial step in the development of a novel chemical entity (NCE) with central nervous system (CNS) activity or with chemical or pharmacological properties in common with known abused substances. Rodent assessment of abuse liability is highly attractive due to its relatively low cost and high predictive validity. Described in this unit are three rodent assays commonly used to provide data on the potential for abuse liability based on the acute effects of NCEs: specifically, self-administration, drug discrimination, and locomotor sensitization. As these assays provide insight into the potential abuse liability of NCEs as well as in vivo pharmacological mechanism(s) of action, they should form a key part of the development process for novel therapeutics aimed at treating CNS disorders.

Chemistry and behavioral studies identify chiral cyclopropanes as selective α4ß2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.

Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4ß2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at α4ß2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4ß2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

Impulsive action and impulsive choice are mediated by distinct neuropharmacological substrates in rat.

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity.

Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380.

RATIONALE: Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans. OBJECTIVES: The study determined whether the antidepressant-like effect of the nAChR ß2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of ß2* nAChRs. The study also determined if sazetidine's behavioral responses in the forced swim test corresponded to ß2* nAChRs receptor occupancy and drug bioavailability. RESULTS: Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full ß2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective ß2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of ß2* nAChRs was confirmed by results showing: (1) reversal of sazetidine's antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-ß-erythroidine; (2) absence of sazetidine's effect in mice lacking the ß2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and ß2* receptor occupancy. ß2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine's long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing. CONCLUSIONS: Results demonstrate that activation of a small population of ß2* nAChRs (10-40%) is sufficient to elicit sazetidine's antidepressant-like actions without producing tolerance and suggest that ligands that activate ß2* nAChRs would be promising targets for the development of a new class of antidepressant.

Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats.

Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABA(B) receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABA(B) receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABA(B) receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABA(B) receptor agonists. Thus, GABA(B) receptor agonists and antagonists, and GABA(B) receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABA(B) receptor agonist CGP44532, the GABA(B) receptor antagonist CGP56433A, and the GABA(B) receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14days. ICSS thresholds were assessed 6h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30min prior to ICSS testing. Both GABA(B) receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABA(B) receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABA(B) receptors.

Translational research in addiction: toward a framework for the development of novel therapeutics.

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation.

Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone.

Prefrontal cortical dopamine (DA) and norepinephrine (NE) are implicated in multiple aspects of cognitive function assessed via the 5-choice serial reaction time task (5-CSRTT) in rodents. The present studies assessed the effects of the NE reuptake inhibitor atomoxetine (0.5-2.0 mg/kg), the mixed DA/NE reuptake inhibitor methylphenidate (0.1-2.0 mg/kg), the catecholamine releaser D-amphetamine (0.1-1.0 mg/kg) and the catecholamine-o-methyl-transferase (COMT) inhibitor tolcapone (3.0-30.0 mg/kg) in rats that exhibited sub-optimal performance (reduced accuracy: <70% correct) in the 5-CSRTT. Increased ITI durations were associated with increased premature responding. Decreased ITI durations resulted in increased percent omissions, increased perseverative responses and increased response latencies, but had no effects on magazine latencies or percent correct. Atomoxetine decreased premature responding at prolonged ITI durations and methylphenidate decreased percent omissions at low doses (0.1 and 0.5 mg/kg). By contrast, D-amphetamine increased premature and perseverative responding in a dose-dependent manner (0.3-1.0 mg/kg). Finally, tolcapone had no effects on sub-optimal performance in the variable ITI 5-CSRTT. These results suggest minimal potential of tolcapone as a therapeutic agent for ADHD and implicate cortical NE, not DA, in impulsive action.

The triple reuptake inhibitor DOV216,303 exhibits limited antidepressant-like properties in the differential reinforcement of low-rate 72-second responding assay, likely due to dopamine reuptake inhibition.

There is a need for antidepressants with novel mechanisms of action. One approach has been to develop compounds that inhibit reuptake of all three monoamines in the central nervous system, for example DOV216,303. Differential reinforcement of low-rate (72-s) responding is a behavioral test that is predictive of antidepressant-like properties. The effects of antidepressant compounds belonging to multiple classes, the anxiolytic diazepam and the antipsychotic haloperidol, were assessed in the DRL-72s task. Subsequently, the antidepressant-like properties of acute DOV216,303 were assessed. The selective serotonin reuptake inhibitor fluvoxamine, the preferential norepinephrine reuptake inhibitor desipramine and the tricyclic antidepressant imipramine exhibited antidepressant-like properties in the DRL-72s task. The atypical antidepressant bupropion, which inhibits dopamine and norepinephrine reuptake, and the selective dopamine transporter inhibitor GBR12909, changed reinforcement and response rates and inter-response time distribution in an opposite direction compared with the antidepressant compounds tested. The antipsychotic haloperidol exhibited antidepressant-like properties by increasing reinforcement rate, but failed to alter inter-response time distribution. Diazepam did not change reinforcement or response rates or inter-response time distribution. The triple reuptake inhibitor DOV216,303 significantly enhanced reinforcement rate at one intermediate dose, but exhibited similar effects as bupropion and GBR12909 on inter-response time distribution. The studies identified limited antidepressant-like properties of the triple reuptake inhibitor DOV216,303, likely due to dopamine transporter inhibition counteracting the effects of norepinephrine and serotonin transporter inhibition.

The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.

Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter, and serotonin transporter are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. We describe a novel TRI, 2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3-methylpiperidin-1-yl)-ethanone (JZAD-IV-22), that inhibits all three monoamine transporters with approximately equal potency in vitro. (+/-)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride (DOV 216,303), a TRI shown to be an effective antidepressant in a clinical trial, shows reuptake inhibition similar to that of JZAD-IV-22 in vitro. Furthermore, both JZAD-IV-22 and DOV 216,303 increase levels of dopamine, norepinephrine, and serotonin in the mouse prefrontal cortex when administered by peripheral injection. JZAD-IV-22 and DOV 216,303 exhibited antidepressant-like efficacy in the mouse forced-swim and tail-suspension tests at doses that increased neurotransmitter levels. Because development of DAT inhibitors could be hindered by abuse liability, both JZAD-IV-22 and DOV 216,303 were compared in two assays that are markers of abuse potential. Both JZAD-IV-22 and DOV 216,303 partially substituted for cocaine in a drug discrimination assay in rats, and high doses of DOV 216,303 produced locomotor sensitization in mice. JZAD-IV-22 showed no evidence of sensitization at any dose tested. These results demonstrate that JZAD-IV-22 is a TRI with antidepressant-like activity similar to that of DOV 216,303. The striking feature that distinguishes the two TRIs is that locomotor sensitization, a common underlying feature of drugs of abuse, is seen with DOV 216,303 but is completely lacking in JZAD-IV-22. These findings may have implications for the potential for abuse liability in humans.

The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats.

Varenicline (Chantix®, Champix®) is a nicotinic acetylcholine receptor (nAChR) partial agonist clinically approved for smoking cessation, yet its potential abuse liability properties have not been fully characterized. The nAChR ligand sazetidine-A has been reported as a selective full or partial agonist at α4ß2* nAChR subtypes in in vitro studies. In the present studies, varenicline, sazetidine-A and nicotine exhibited inverted U-shaped dose-response functions under fixed-ratio (peak responding at 30, 60 and 10-30 µg/kg/inf, respectively) or progressive-ratio (peak responding at 30-60, 30-100 and 30 µg/kg/inf, respectively) schedules in rats trained to self-administer nicotine. Varenicline (ED(50) 0.2 mg/kg) and sazetidine-A (ED(50) 0.44 mg/kg) fully substituted for nicotine (ED(50) 0.09 mg/kg) in rats trained to discriminate nicotine (0.4 mg/kg, i.p.) from saline. The reinforcing and discriminative stimulus (DS) properties of sazetidine-A, varenicline and nicotine were attenuated by acute pretreatment with the non-selective neuronal non-competitive nAChR antagonist mecamylamine or the α4* nAChR-selective antagonist dihydro-ß-erythroidine, but not by the α7 nAChR subtype antagonist methyllycaconitine. Drug-naïve rats acquired stable self-administration of varenicline (30 µg/kg/inf), and sazetidine-A (60 µg/kg/inf), at doses that supported peak responding under a fixed-ratio 3 schedule in nicotine-trained rats. Nonetheless, self-administration and re-acquisition of varenicline and sazetidine-A were less robust than nicotine. Thus, partial activation of α4ß2* nAChRs by varenicline or sazetidine-A is sufficient to mimic the DS and reinforcing properties of nicotine in nicotine-experienced rats, although the reinforcing properties of partial agonists are diminished in nicotine-naïve rats. Future studies should assess nicotine withdrawal measures in animals chronically exposed to varenicline or sazetidine-A.

Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents.

UNLABELLED: The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. METHODS: Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. RESULTS: Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the mu-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. CONCLUSIONS: Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.

Comparison of the predictive validity of the mirror chamber and elevated plus maze tests in mice.

The mirror chamber (MC) is a putative test of anxiety-like behavior in mice, and is increasingly popular. Nonetheless, it is unclear whether the observed behaviors rely on the presence of mirrored panels. If so, it is unclear whether the behaviors are sensitive to clinically effective anxiolytics, and how the test compares to the elevated plus maze (EPM) in terms of predictive validity. The present studies assessed anxiety-like behaviors in different mouse strains in the MC using mirrored and non-mirrored panels, under variable lighting conditions. We also assessed the pharmacological validity of the MC and EPM tests, and the locomotor properties of active test compounds. Seven mouse strains exhibited different levels of anxiety-like behaviors in the MC, and differential sensitivity to panel and light conditions. DBA/2J mice appeared most sensitive to the mirrored, versus black or white, panels and were therefore used in pharmacological MC studies. The mGlu5 receptor antagonist MPEP significantly decreased anxiety-like behaviors, similar to an intermediate dose of the benzodiazepine diazepam. The benzodiazepines chlordiazepoxide and alprazolam and the 5HT(1A) partial agonist buspirone had no effects on anxiety-like behaviors in the MC. None of the MC effects of active test compounds were attributable to non-specific/locomotor effects. The antidepressants fluoxetine and venlafaxine increased anxiety-like behaviors in the MC. By contrast, the anxiolytic-like effects of chlordiazepoxide, diazepam and MPEP were revealed in the EPM in C57Bl6/J mice. In conclusion, the EPM test exhibits superior predictive validity compared to the MC test, despite the sensitivity of the MC to mouse strain differences.

The modified Geller-Seifter test in rats was insensitive to GABAB receptor positive modulation or blockade, or 5-HT1A receptor activation.

RATIONALE: Both the GABA(B) receptor positive modulator GS39783 and the GABA(B) receptor antagonist CGP46381 exhibit anxiolytic-like properties in animal models. In the present studies, the effects of GS39783 and CGP46381 in the modified Geller-Seifter task were assessed. First, the predictive validity of the task was confirmed by assessing the effects of multiple anxiolytic and non-anxiolytic compounds on punished and unpunished responding. METHODS: Rats were trained in the modified Geller-Seifter task. After successful acquisition of the task, chlordiazepoxide, diazepam, MPEP, haloperidol, GS39783, 8-OH-DPAT, alprazolam and CGP46381 were tested consecutively. For each test compound, doses were administered in a randomized, counter-balanced, within-subjects design. Drug tests were performed only when rats exhibited baseline performance (the punished and time-out response rates were less than 10% of the unpunished response rate). RESULTS: Chlordiazepoxide, diazepam, alprazolam and MPEP released punished responding with variable effects on unpunished responding. Haloperidol had a small but significant effect on punished responding at an intermediate dose, and decreased unpunished responding at the highest dose tested. In contrast, administration of the GABA(B) receptor positive modulator GS398783 or the GABA(B) receptor antagonist CGP46381 at doses up to 30 mg/kg had no effects on either punished or unpunished responding. The 5-HT(1A) agonist 8-OH-DPAT did not release punished responding, but significantly decreased unpunished responding at the highest dose tested. SUMMARY: The modified Geller-Seifter task generally exhibits good predictive validity for anxiolytic-like compounds. Neither GABA(B) receptor positive allosteric modulation nor blockade exhibited anxiolytic-like properties in the modified Geller-Seifter task. The 5-HT(1A) partial agonist buspirone was similarly ineffective.

Pharmacological characterization of harmaline-induced tremor activity in mice.

Harmaline-induced tremor in rodents is a model of essential tremor. We utilized a novel assay to quantify tremor activity in mice and found that tremor activity was dependent on harmaline dose. The first-line clinical essential tremor treatments propranolol, primidone and gabapentin and gamma-hydroxybutyrate (GHB) significantly attenuated harmaline-induced tremor. The anticonvulsants valproate and carbamazepine and the mood stabilizer lithium suppressed harmaline-induced tremor. The gamma-amino-butyric acid (GABA) receptor subtype A receptor agonist muscimol attenuated harmaline-induced tremor. By contrast, the GABA(B) receptor agonist R-baclofen increased tremor at the lowest dose tested, but had no effects at higher doses. Administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists phencyclidine or 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801) attenuated harmaline-induced tremor. The competitive NMDA antagonist D-4-[(2E)-3-phosphono-2-propenyl]-2-piperazinecarboxylic acid (d-CPPene) dose-dependently blocked harmaline-induced tremor, as did the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX). The metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) was inactive against tremor. The dopamine reuptake inhibitor GBR12909 and the dopamine D(1)/D(2) receptor agonist apomorphine attenuated harmaline-induced tremor. Follow-up studies indicated that dopamine D(2)/D(3) but not dopamine D(1) receptor activation likely mediates the effects of apomorphine and GBR12909. Administration of compounds with sedative side-effects had no effect on tremor activity. In summary, the present data confirm the pharmacological validity of harmaline-induced tremor in mice, quantified via a novel assay, as an animal model of essential tremor. Further, these data provide additional evidence for the roles of ionotropic glutamate, GABA(A) and dopamine D(2)/D(3) receptors in the neurobiology of harmaline-induced tremor.

The neuropharmacological substrates of nicotine reward: reinforcing versus reinforcement-enhancing effects of nicotine.

Compulsive nicotine use is thought to be maintained by the acute reinforcing effects of nicotine and the reinforcement-enhancing effects of nicotine, in addition to the negative consequences of nicotine abstinence. Nicotine self-administration and nicotine-induced enhancement of non-nicotine reinforcers such as intracranial self-stimulation provide measures of these dual rewarding properties of nicotine. First, pharmacological manipulations that modulate the reinforcing and reinforcement-enhancing effects of nicotine are identified and discussed. Second, the interpretation and implications of data that identified shared and specific pharmacological substrates underlying the dual rewarding effects of nicotine are discussed, including implications for the preclinical testing of putative antismoking medications. In conclusion, reinforcement-related behaviors that are mediated by central reinforcement processes are likely to, and generally do, exhibit a number of common pharmacological substrates. Interestingly, however, a few pharmacological classes of compounds seem to exert selective effects on components of the dual nicotine reward mechanisms, indicating differences in the pharmacological substrates of the reinforcing and reinforcement-enhancing effects of nicotine. Further characterization of such compounds may ultimately lead to the identification of novel medications for nicotine dependence in humans.

Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: recent preclinical and clinical insights.

Ongoing studies continue to explore the behavioural and pharmacological effects of bupropion in smoking cessation studies and animal models of nicotine dependence. In the present review, the components of nicotine dependence that form the most likely targets of bupropion are identified within the context of an expanding preclinical and clinical literature regarding the anti-addictive properties of bupropion. Second, preclinical and clinical data that implicate specific pharmacological modes of action of bupropion in mediating the anti-smoking effects of the compound are discussed. Third, it is suggested that the unique mixed pharmacological profile of bupropion provides (1) attenuation of the multiple negative consequences of withdrawal via blockade of dopamine and noradrenaline reuptake; (2) replacement of the reward-facilitating and subjective effects of nicotine via blockade of dopaminergic reuptake; (3) attenuation of the rewarding effects of acute nicotine by nicotinic acetylcholine receptor blockade. The importance of species differences in bupropion metabolism in the interpretation of preclinical studies is highlighted. Finally, future studies are suggested to address identified gaps in the knowledge: most importantly, to provide stronger evidence for the role of noradrenaline reuptake inhibition in bupropion-induced attenuation of nicotine withdrawal. Future studies aimed at providing more evidence for the three-fold nature of the anti-smoking effects of bupropion are also suggested, along with the possibility of utilizing adjunct therapies to improve smoking cessation rates.