Typical and atypical neuroleptic drug effects on dopamine and other neurotransmitter functions in rodents

The antischizophrenic effect of neuroleptic drugs probably arises from blockade of central dopamine receptors which also leads to extrapyramidal side effects (EPSEs). The aim of the work described in this thesis was to elucidate how some drugs, the so-called atypical neuroleptics, alleviate the symptoms of schizophrenia without producing marked EPSEs. An intracerebral microdialysis system was developed and used to monitor the acute effects of neuroleptic drugs on dopamine release and metabolism in the caudate putamen (CP), nucleus accumbens (NAc) and medial prefrontal cortex (MPFC) of halothane-anaesthetised rats. Dopamine and its metabolites DOPAC and HVA were estimated in brain dialysates by HPLC with electrochemical detection. In other studies extracellular recording techniques were used to assess the effects of neuroleptics and dopamine agonists on the spontaneous activity of neurons in the CP and MPFC. Both haloperidol (typical neuroleptic) and clozapine (atypical) elevated the efflux of dopamine metabolites in the CP, NAc and MPFC although only clozapine significantly facilitated dopamine efflux and this was restricted to the MPFC. Neither neuroleptic showed any consistent effects on neuronal activity in the CP, however, unlike haloperidol, but similar to the dopamine agonist apomorphine, clozapine both stimulated and inhibited neuronal activity in the MPFC. The ability of these agents to antagonise the effects of apomorphine was also evaluated. Apomorphine produced a dose-dependent inhibition of neuronal activity and efflux of dopamine and metabolites in both the CP and the MPFC. Although fewer cells in the MPFC showed any response to apomorphine compared with those in the CP, those that did, were markedly more sensitive to the inhibitory effects of this agent. The effects of apomorphine were reversed by haloperidol but only partially reduced by clozapine. Since clozapine did not alter the time course of apomorphine appearance in CP dialysates and haloperidol only reduced the appearance at one dose level, it was concluded that the antagonism of apomorphine's actions in the CP and MPFC were directly mediated. The differential effects of haloperidol and clozapine on dopamine function in the CP and MPFC are discussed in respect of their typical and atypical profiles. The weak dopamine (apomorphine) antagonism shown by clozapine in the CP would account for the low incidence of EPSEs seen with this compound although its relatively weak action in the MPFC implies that its antischizophrenic action must stem, at least in part, from other actions. The ability of clozapine to enhance the efflux (release?) of dopamine in the MPFC could explain its efficacy against the negative symptoms of schizophrenia. A possible mechanism to account for the ability of clozapine to alleviate the positive aspects of this disorder (despite weak dopamine receptor antagonism) is also discussed. In other experiments designed to reveal the nature of clozapine's atypical action its effects on 5-HT3 mediated release of dopamine in the NAc as well as on the contraction of guinea-pig ileum in-vitro were studied. It was also compared with other atypical and typical neuroleptics on muscarinic, a-adrenergic and tachykinin receptors in the guinea- pig ileum and rat vas-deferens. The effects of typical and atypical neuroleptics in all these preparations is discussed in an attempt to explain their differential clinical effects

Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task.

RATIONALE: Maladaptive impulsivity is symptomatic of several neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and substance abuse disorders; paradigms designed to assess the underlying neurobiology of this behavior are essential for the discovery of novel therapeutic agents. Various models may be used to assess impulsivity as measured by the five-choice serial reaction time task (5-CSRTT), including variable inter-trial interval (ITI) sessions, the selection of extreme high and low impulsivity phenotypes from a large outbred population of rats, as well as pharmacological challenges. OBJECTIVES: The aim of this study is to evaluate if pharmacological challenge models for impulsivity are biased by underlying differences in impulsivity phenotype. METHODS: Extreme high and low impulsivity phenotypes were selected in the 5-CSRTT, and dose-dependent effects of various pharmacological challenges, namely MK-801, yohimbine, and cocaine, were evaluated on task performance, specifically accuracy and premature responses. RESULTS: All three compounds increased premature responding, while a decrease in attentional performance occurred following MK-801 and yohimbine administration. No differences in drug-induced impulsivity between rats selected for high or low impulsivity or in parameters indicative of attentional performance could be determined. CONCLUSIONS: Our findings indicate that different pharmacological challenges increase impulsivity on the 5-CSRTT, with modest effects on attention. These effects were not influenced by underlying differences in impulsivity phenotype, which is an important prerequisite to reliably use these challenge models to screen and profile compounds with putative anti-impulsive characteristics

Ramping single unit activity in the medial prefrontal cortex and ventral striatum reflects the onset of waiting but not imminent impulsive actions.

The medial prefrontal cortex (mPFC) and ventral striatum (VS), including the nucleus accumbens, are key forebrain regions involved in regulating behaviour for future rewards. Dysfunction of these regions can result in impulsivity, characterized by actions that are mistimed and executed without due consideration of their consequences. Here we recorded the activity of single neurons in the mPFC and VS of 16 rats during performance on a five-choice serial reaction time task of sustained visual attention and impulsivity. Impulsive responses were assessed by the number of premature responses made before target stimuli were presented. We found that the majority of cells signalled trial outcome after an action was made (both rewarded and unrewarded). Positive and negative ramping activity was a feature of population activity in the mPFC and VS (49.5 and 50.4% of cells, respectively). This delay-related activity increased at the same rate and reached the same maximum (or minimum) for trials terminated by either correct or premature responses. However, on premature trials, the ramping activity started earlier and coincided with shorter latencies to begin waiting. For all trial types the pattern of ramping activity was unchanged when the pre-stimulus delay period was made variable. Thus, premature responses may result from a failure in the timing of the initiation of a waiting process, combined with a reduced reliance on external sensory cues, rather than a primary failure in delay activity. Our findings further show that the neural locus of this aberrant timing signal may emanate from structures outside the mPFC and VS.This research was funded in part by a Medical Research Council grant to J.W.D. (G0701500) and by a joint award from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. N.A.D. was funded by the University of Cambridge School of Clinical Medicine MB/PhD Program. The authors would like to thank Alan Lyon and David Theobald for assistance with histology, Tim Harris and the Applied Physics and Instrumentation Group at HHMI Janelia Farm for providing electrodes, Ken Harris and the Klustateam at UCL for providing software for spike detection and sorting, and Tahl Holtzman for technical assistance with training in surgical procedures.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/ejn.1289

Endocannabinoids and striatal function: implications for addiction-related behaviours.

Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents. However, compounds acting on the endocannabinoid system may have broader application in treating drug addiction by ameliorating associated traits and symptoms such as impulsivity and anxiety that perpetuate drug use and interfere with rehabilitation. As a trait, impulsivity is known to predispose to addiction and facilitate the emergence of addiction to stimulant drugs. In contrast, anxiety and elevated stress responses accompany extended drug use and may underlie the persistence of drug intake in dependent individuals. In this article we integrate and discuss recent findings in rodents showing selective pharmacological modulation of impulsivity and anxiety by cannabinoid agents. We highlight the potential of selective inhibitors of endocannabinoid metabolism, directed at fatty acid amide hydrolase and monoacylglycerol lipase, to reduce anxiety and stress responses, and discuss novel mechanisms underlying the modulation of the endocannabinoid system, including the attenuation of impulsivity, anxiety, and drug reward by selective CB2 receptor agonists.RCUK, Wellcome, OtherThis is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1097/FBP.000000000000010

Promoting and supporting credibility in neuroscience

No abstract available

Promoting and supporting credibility in neuroscience.

No abstract available

Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease?

Apathy and impulsivity are two major comorbid syndromes of Parkinson's disease (PD) that may represent two extremes of a behavioral spectrum modulated by dopamine-dependent processes. PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta to which are attributed the cardinal motor symptoms of the disorder. Dopamine replacement therapy (DRT), used widely to treat these motor symptoms, is often associated with deficits in hedonic processing and motivation, including apathy and depression, as well as impulse control disorders (ICDs). ICDs comprise pathological gambling, hypersexuality, compulsive shopping, binge eating, compulsive overuse of dopaminergic medication, and punding. More frequently observed in males with early onset PD, ICDs are associated not only with comorbid affective symptoms, such as depression and anxiety, but also with behavioral traits, such as novelty seeking and impulsivity, as well as with personal or familial history of alcohol use. This constellation of associated risk factors highlights the importance of inter-individual differences in the vulnerability to develop comorbid psychiatric disorders in PD patients. Additionally, withdrawal from DRT in patients with ICDs frequently unmasks a severe apathetic state, suggesting that apathy and ICDs may be caused by overlapping neurobiological mechanisms within the cortico-striato-thalamo-cortical networks. We suggest that altered hedonic and impulse control processes represent distinct prodromal substrates for the development of these psychiatric symptoms, the etiopathogenic mechanisms of which remain unknown. Specifically, we argue that deficits in hedonic and motivational states and impulse control are mediated by overlapping, yet dissociable, neural mechanisms that differentially interact with DRT to promote the emergence of ICDs in vulnerable individuals. Thus, we provide a novel heuristic framework for basic and clinical research to better define and treat comorbid ICDs in PD.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fpsyt.2016.00091/full

Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism.

RATIONALE: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. OBJECTIVE: This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. METHODS: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. RESULTS: RO4917523 (0.1-1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. CONCLUSIONS: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out in the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University with joint support from the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z) and at Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. We thank David Theobald, Johannes Freudenreich, Peter Schorn, Alfie Wearn and Benjamin Jaehnke for technical support and Gert Kramer, Dr. Holger Rosenbrock and Dr. Cornelia Dorner-Ciossek for helpful scientific discussions. The authors declare that the experiments performed in this manuscript followed the principles of laboratory animal care and are in compliance with the current laws of the UK and Germany.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-3984-

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out at Boehringer Ingelheim Pharma GmbH & Co. KG in Germany and the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University. The BCNI is jointly supported by the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z)

The Pharmacological Effects and Pharmacokinetics of Active Compounds of Artemisia capillaris.

Artemisia capillaris Thunb. (A.capillaris, Yin-Chen in Chinese) is a traditional medicinal herb with a wide spectrum of pharmacological properties ranging from effects against liver dysfunction to treatments of severe cirrhosis and cancer. We used relevant keywords to search electronic databases, including PubMed, Medline, and Google Scholar, for scientific contributions related to this medicinal herb and the pharmacokinetics of its components. The pharmaceutical effects of A.capillaris contribute to the treatment not only of viral hepatitis, cirrhosis, and hepatocellular hepatoma, but also metabolic syndrome, psoriasis, and enterovirus in the clinic. The bioactive compounds, including scoparone, capillarisin, scopoletin, and chlorogenic acid, exhibit antioxidant, anti-inflammatory, antisteatotic, antiviral, and antitumor properties, reflecting the pharmacological effects of A.capillaris. The pharmacokinetics of the main bioactive compounds in A. capillaris can achieve a maximum concentration within 1 hour, but only chlorogenic acid has a relatively long half-life. Regarding the use of the A. capillaris herb by health professionals to treat various diseases, the dosing schedule of this herb should be carefully considered to maximize therapeutic outcomes while lessening possible side effects