Daniel Hutcheson - Academia.edu (original) (raw)
Papers by Daniel Hutcheson
PLoS ONE, 2014
Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity a... more Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
Psychopharmacology, 2000
Rationale: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and-taking behavi... more Rationale: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and-taking behaviour. However, the importance of the "core" and "shell" subdivisions of the NAcc in heroin-seeking and-taking behaviour remains unclear. Objectives: To investigate the function of the NAcc core and shell in heroin self-administration and heroin-seeking behaviour. Methods: Male rats were trained to self-administer heroin (0.12 mg/kg per infusion) under a continuous reinforcement (CRF) schedule. After responding stabilised, rats were given excitotoxic (or sham) lesions of either the NAcc core or shell and after recovery were assessed for their retention of heroin self-administration under CRF. At this point a secondorder schedule of reinforcement was introduced, commencing at FR10 (FR1:S) and terminating at FR10 (FR10:S), in which ten lever presses resulted in presentation of the heroin-associated CS+, and completion of ten such units resulted in drug infusion. Results: Within 7 days, all groups re-acquired responding for heroin under CRF at rates similar to their pre-lesion performance. However, rats with lesions of the NAcc core, but not shell, were severely impaired in the acquisition of heroin-seeking behaviour. Conclusions: These results indicate an important role for the core of the NAcc in the acquisition of heroin-seeking behaviour under the control of drug-associated stimuli.
Neuroscience & Biobehavioral Reviews, 2013
The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of ... more The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders.
Journal of Pharmacological and Toxicological Methods, 2012
Journal of Pharmacological and Toxicological Methods, 2011
Journal of Pharmacological and Toxicological Methods, 2010
AAPS 25th Anniversary. Developing Science. Impacting health. American Association of Pharmaceutic... more AAPS 25th Anniversary. Developing Science. Impacting health. American Association of Pharmaceutical Scientists. About AAPS: Contact Us; Directions; Careers at AAPS; Policies & Governance; Awards, Fellows, and Travelships; Affiliate & links. Membership & Volunteers: ...
European Neuropsychopharmacology, 2007
European Journal of Pharmacology, 2004
Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indica... more Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.
European Journal of Pharmacology, 2000
European Journal of Pharmacology, 1999
Evidence suggests that the antinociceptive effects of selective delta-opioid receptor agonists ma... more Evidence suggests that the antinociceptive effects of selective delta-opioid receptor agonists may involve an activation of the mu-receptor in some experimental conditions. The aim of this study was to clarify the receptors involved in the antinociceptive responses of the selective and systemically active delta-opioid receptor agonist Tyr-D-Ser-(O-tert-butyl)-Gly-Phe-Leu-Thr-(O-tert-butyl) (BUBU). The antinociception induced by systemic (i.v.) or central (i.c.v.) administration of BUBU was measured in the hot plate (jumping and paw lick latencies) and tail immersion tests in mice. In both tests, the responses were more intense when BUBU was administered by central route. The pre-treatment with the mu-opioid receptor antagonist cyprodime blocked the effects induced by central BUBU in the hot plate and tail immersion tests. The delta-opioid receptor antagonist naltrindole had no effect on BUBU-induced antinociception in the hot plate but decreased BUBU responses in the tail immersion test. Further evidence for this dual receptor action of BUBU was demonstrated by using antisense oligodeoxynucleotides. Thus, a reduction in central BUBU-induced antinociception was observed in the tail immersion test after the administration of antisense probes that selectively blocked the expression of mu- or delta-opioid receptors. These findings clearly indicate using a dual pharmacological and molecular approach that BUBU mediates its antinociceptive effects via activation of both mu- and delta-opioid receptors.
European Journal of Pain, 2009
tetrodotoxin-insensitive sodium channel Nav 1.8 may be involved in inflammatory (Joshi 2006) and ... more tetrodotoxin-insensitive sodium channel Nav 1.8 may be involved in inflammatory (Joshi 2006) and neuropathic pain (Lai 2002). Our aim was to establish an appropriate mouse model of muscle pain and to analyze the involvement of Nav 1.8 channels in the development of muscle pain. Methods: Wildtype mice and NaV 1.8 knockout (ko) mice received a single intramuscular (i.m.) injection of either tumor necrosis factoralpha (TNFa), Complete Freund’s Adjuvant (CFA) or sodium chloride (NaCl). Motor deficiencies were monitored with rotarod. Spontaneous pain behavior was observed using Attal-Score (Attal 1990). With a remodeled Randall-Selitto test, pressure pain was measured at the hindlimb muscles. All behavioral tests were performed between 3 hours (h) and 14 days after injection. Results: The pressure pain test showed that TNF and CFA, but not NaCl, caused pressure hyperalgesia in the wildtype mice 6h, 9 h and 24h after i.m. injection. Whereas in the Nav 1.8 ko mice less pressure hyperalgesia could be observed (p < 0.05). No motor deficiencies or spontaneous pain behavior in both mice groups could be detected. Conclusion: TNF as well as CFA i.m. injections can be used as a mouse model of muscle pain. Nav 1.8 ko mice did not evolve muscle pain after TNF respectively CFA i.m. injection. Our results suggest that Nav 1.8 channels are probably involved in the pathophysiology of muscle pain.
European Journal of Neuroscience, 2001
We have previously shown that the antinociceptive effects produced by the delta opioid-selective ... more We have previously shown that the antinociceptive effects produced by the delta opioid-selective agonist deltorphin II are preserved in mu-opioid receptor (MOR)-deficient mice. We have now investigated rewarding effects and physical dependence produced by deltorphin II in these animals. Wild-type and MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induced by deltorphin II were then investigated using the place preference paradigm. Wild-type mice showed place preference for the compartment previously associated with deltorphin II and this effect was not observed in MOR-deficient mice. In a second experiment, mice received a chronic perfusion of deltorphin II over 6 days, via an Alzet minipump connected to the intraventricular cannula, and withdrawal was precipitated by naloxone administration. Wild-type animals showed a moderate but significant incidence of several somatic signs of withdrawal. This withdrawal response was suppressed in MOR-deficient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused chronically with deltorphin II showed a significant up-regulation of all these isozymes in the soluble fraction in wild-type but not in MOR-deficient mice. In conclusion, mu-opioid receptors, which are not involved in deltorphin II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.
Cerebral Cortex, 2007
The stop-signal reaction-time (SSRT) task measures inhibition of a response that has already been... more The stop-signal reaction-time (SSRT) task measures inhibition of a response that has already been initiated, that is, the ability to stop. Human subjects classified as ''impulsive,'' for example, those with attention deficit and hyperactivity disorder, are slower to respond to the stop signal. Although functional and structural imaging studies in humans have implicated frontal and basal ganglia circuitry in the mediation of this form of response control, the precise roles of the cortex and basal ganglia in SSRT performance are far from understood. We describe effects of excitotoxic fiber-sparing lesions of the orbitofrontal cortex (OF), infralimbic cortex (IL), and subthalamic nucleus (STN) in rats performing a SSRT task. Lesions to the OF slowed SSRT, whereas lesions to the IL or the STN had no effect. On the go-signal trials, neither cortical lesion affected gotrial reaction time (GoRT), but STN lesions speeded such latencies. The STN lesion also significantly reduced accuracy of stopping at all stop-signal delays, indicative of a generalized stopping impairment that was independent of the SSRT itself.
British Journal of Pharmacology, 1998
Tolerance and dependence induced by chronic D-9-tetrahydrocannabinol (THC) administration were in... more Tolerance and dependence induced by chronic D-9-tetrahydrocannabinol (THC) administration were investigated in mice. The eects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg 71 THC twice daily). A rapid tolerance to the acute eects was observed from the second THC administration. 2 The selective CB-1 receptor antagonist SR 141716A (10 mg kg 71) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. 3 Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was speci®cally observed in the cerebellum of these mice. 4 The motivational eects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg 71), without observing place preference at any of the doses used. 5 This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quanti®cation of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.
Behavioural Pharmacology, 2005
novelty and later to the plus-maze (5 min) as a measure of anxiety. On the basis of these measure... more novelty and later to the plus-maze (5 min) as a measure of anxiety. On the basis of these measures, rats were classified into low-high initial reactivity to novelty (first 15 min of CC), low-high delayed reactivity to novelty (last 15 min of CC), or low and high anxiety. Then they were assigned to three groups, receiving saline (VEH, n ¼ 14), 1.5 mg/kg (AMP-1.5, n¼ 32) or 5 mg/kg (AMP-5, n¼ 34) of D-amphetamine sulphate. Two hours after the injection, rats were killed and their brain perfused to quantify Fos-like immunoreactivity. AMP-5 injection induced a greater c-fos expression than AMP-1.5 in several brain areas (i.e. accumbens shell vertex, paraventricular hypothalamic nucleus, central and medial amygdala or dorsal raphe, dorsal part). Interestingly, the lower AMP dose induced a greater c-fos expression in other structures (prelimbic cortex, accumbens cone and dorsomedial and ventromedial caudateputamen). Finally, in other brain regions both doses resulted in comparable degrees of activation (cingulate, infralimbic and piriform cortex, accumbens shell cone, dorsolateral caudateputamen, basolateral amygdala, ventral tegmental area and dorsal raphe, ventrolateral part). In most of the brain areas, AMP-induced Fos expression was unrelated to individual differences in locomotor reactivity to novelty or anxiety. In a few structures, a differential Fos expression was observed in function of 'initial activity', whereas no statistically significant differences were found in function of 'delayed activity'. Rats with higher 'initial activity' had lower Fos expression in the ventral tegmental area, regardless of anxiety levels or AMP dose. The same was shown in the accumbens shell vertex and the piriform cortex, but in these two cases, the differences were dependent on anxiety.
Behavioural Pharmacology, 2005
Behavioural Pharmacology, 2008
Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which b... more Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D 4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D 4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D 4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
Behavioural Pharmacology, 2011
ABSTRACT Preclinical evidence suggests an important role of the brain orexin system in behaviours... more ABSTRACT Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.
Annals of the New York Academy of Sciences, 2007
In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction.... more In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of cocaine-seeking behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.
PLoS ONE, 2014
Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity a... more Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
Psychopharmacology, 2000
Rationale: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and-taking behavi... more Rationale: Evidence has implicated the nucleus accumbens (NAcc) in drug-seeking and-taking behaviour. However, the importance of the "core" and "shell" subdivisions of the NAcc in heroin-seeking and-taking behaviour remains unclear. Objectives: To investigate the function of the NAcc core and shell in heroin self-administration and heroin-seeking behaviour. Methods: Male rats were trained to self-administer heroin (0.12 mg/kg per infusion) under a continuous reinforcement (CRF) schedule. After responding stabilised, rats were given excitotoxic (or sham) lesions of either the NAcc core or shell and after recovery were assessed for their retention of heroin self-administration under CRF. At this point a secondorder schedule of reinforcement was introduced, commencing at FR10 (FR1:S) and terminating at FR10 (FR10:S), in which ten lever presses resulted in presentation of the heroin-associated CS+, and completion of ten such units resulted in drug infusion. Results: Within 7 days, all groups re-acquired responding for heroin under CRF at rates similar to their pre-lesion performance. However, rats with lesions of the NAcc core, but not shell, were severely impaired in the acquisition of heroin-seeking behaviour. Conclusions: These results indicate an important role for the core of the NAcc in the acquisition of heroin-seeking behaviour under the control of drug-associated stimuli.
Neuroscience & Biobehavioral Reviews, 2013
The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of ... more The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders.
Journal of Pharmacological and Toxicological Methods, 2012
Journal of Pharmacological and Toxicological Methods, 2011
Journal of Pharmacological and Toxicological Methods, 2010
AAPS 25th Anniversary. Developing Science. Impacting health. American Association of Pharmaceutic... more AAPS 25th Anniversary. Developing Science. Impacting health. American Association of Pharmaceutical Scientists. About AAPS: Contact Us; Directions; Careers at AAPS; Policies & Governance; Awards, Fellows, and Travelships; Affiliate & links. Membership & Volunteers: ...
European Neuropsychopharmacology, 2007
European Journal of Pharmacology, 2004
Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indica... more Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.
European Journal of Pharmacology, 2000
European Journal of Pharmacology, 1999
Evidence suggests that the antinociceptive effects of selective delta-opioid receptor agonists ma... more Evidence suggests that the antinociceptive effects of selective delta-opioid receptor agonists may involve an activation of the mu-receptor in some experimental conditions. The aim of this study was to clarify the receptors involved in the antinociceptive responses of the selective and systemically active delta-opioid receptor agonist Tyr-D-Ser-(O-tert-butyl)-Gly-Phe-Leu-Thr-(O-tert-butyl) (BUBU). The antinociception induced by systemic (i.v.) or central (i.c.v.) administration of BUBU was measured in the hot plate (jumping and paw lick latencies) and tail immersion tests in mice. In both tests, the responses were more intense when BUBU was administered by central route. The pre-treatment with the mu-opioid receptor antagonist cyprodime blocked the effects induced by central BUBU in the hot plate and tail immersion tests. The delta-opioid receptor antagonist naltrindole had no effect on BUBU-induced antinociception in the hot plate but decreased BUBU responses in the tail immersion test. Further evidence for this dual receptor action of BUBU was demonstrated by using antisense oligodeoxynucleotides. Thus, a reduction in central BUBU-induced antinociception was observed in the tail immersion test after the administration of antisense probes that selectively blocked the expression of mu- or delta-opioid receptors. These findings clearly indicate using a dual pharmacological and molecular approach that BUBU mediates its antinociceptive effects via activation of both mu- and delta-opioid receptors.
European Journal of Pain, 2009
tetrodotoxin-insensitive sodium channel Nav 1.8 may be involved in inflammatory (Joshi 2006) and ... more tetrodotoxin-insensitive sodium channel Nav 1.8 may be involved in inflammatory (Joshi 2006) and neuropathic pain (Lai 2002). Our aim was to establish an appropriate mouse model of muscle pain and to analyze the involvement of Nav 1.8 channels in the development of muscle pain. Methods: Wildtype mice and NaV 1.8 knockout (ko) mice received a single intramuscular (i.m.) injection of either tumor necrosis factoralpha (TNFa), Complete Freund’s Adjuvant (CFA) or sodium chloride (NaCl). Motor deficiencies were monitored with rotarod. Spontaneous pain behavior was observed using Attal-Score (Attal 1990). With a remodeled Randall-Selitto test, pressure pain was measured at the hindlimb muscles. All behavioral tests were performed between 3 hours (h) and 14 days after injection. Results: The pressure pain test showed that TNF and CFA, but not NaCl, caused pressure hyperalgesia in the wildtype mice 6h, 9 h and 24h after i.m. injection. Whereas in the Nav 1.8 ko mice less pressure hyperalgesia could be observed (p < 0.05). No motor deficiencies or spontaneous pain behavior in both mice groups could be detected. Conclusion: TNF as well as CFA i.m. injections can be used as a mouse model of muscle pain. Nav 1.8 ko mice did not evolve muscle pain after TNF respectively CFA i.m. injection. Our results suggest that Nav 1.8 channels are probably involved in the pathophysiology of muscle pain.
European Journal of Neuroscience, 2001
We have previously shown that the antinociceptive effects produced by the delta opioid-selective ... more We have previously shown that the antinociceptive effects produced by the delta opioid-selective agonist deltorphin II are preserved in mu-opioid receptor (MOR)-deficient mice. We have now investigated rewarding effects and physical dependence produced by deltorphin II in these animals. Wild-type and MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induced by deltorphin II were then investigated using the place preference paradigm. Wild-type mice showed place preference for the compartment previously associated with deltorphin II and this effect was not observed in MOR-deficient mice. In a second experiment, mice received a chronic perfusion of deltorphin II over 6 days, via an Alzet minipump connected to the intraventricular cannula, and withdrawal was precipitated by naloxone administration. Wild-type animals showed a moderate but significant incidence of several somatic signs of withdrawal. This withdrawal response was suppressed in MOR-deficient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused chronically with deltorphin II showed a significant up-regulation of all these isozymes in the soluble fraction in wild-type but not in MOR-deficient mice. In conclusion, mu-opioid receptors, which are not involved in deltorphin II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.
Cerebral Cortex, 2007
The stop-signal reaction-time (SSRT) task measures inhibition of a response that has already been... more The stop-signal reaction-time (SSRT) task measures inhibition of a response that has already been initiated, that is, the ability to stop. Human subjects classified as ''impulsive,'' for example, those with attention deficit and hyperactivity disorder, are slower to respond to the stop signal. Although functional and structural imaging studies in humans have implicated frontal and basal ganglia circuitry in the mediation of this form of response control, the precise roles of the cortex and basal ganglia in SSRT performance are far from understood. We describe effects of excitotoxic fiber-sparing lesions of the orbitofrontal cortex (OF), infralimbic cortex (IL), and subthalamic nucleus (STN) in rats performing a SSRT task. Lesions to the OF slowed SSRT, whereas lesions to the IL or the STN had no effect. On the go-signal trials, neither cortical lesion affected gotrial reaction time (GoRT), but STN lesions speeded such latencies. The STN lesion also significantly reduced accuracy of stopping at all stop-signal delays, indicative of a generalized stopping impairment that was independent of the SSRT itself.
British Journal of Pharmacology, 1998
Tolerance and dependence induced by chronic D-9-tetrahydrocannabinol (THC) administration were in... more Tolerance and dependence induced by chronic D-9-tetrahydrocannabinol (THC) administration were investigated in mice. The eects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg 71 THC twice daily). A rapid tolerance to the acute eects was observed from the second THC administration. 2 The selective CB-1 receptor antagonist SR 141716A (10 mg kg 71) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. 3 Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was speci®cally observed in the cerebellum of these mice. 4 The motivational eects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg 71), without observing place preference at any of the doses used. 5 This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quanti®cation of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.
Behavioural Pharmacology, 2005
novelty and later to the plus-maze (5 min) as a measure of anxiety. On the basis of these measure... more novelty and later to the plus-maze (5 min) as a measure of anxiety. On the basis of these measures, rats were classified into low-high initial reactivity to novelty (first 15 min of CC), low-high delayed reactivity to novelty (last 15 min of CC), or low and high anxiety. Then they were assigned to three groups, receiving saline (VEH, n ¼ 14), 1.5 mg/kg (AMP-1.5, n¼ 32) or 5 mg/kg (AMP-5, n¼ 34) of D-amphetamine sulphate. Two hours after the injection, rats were killed and their brain perfused to quantify Fos-like immunoreactivity. AMP-5 injection induced a greater c-fos expression than AMP-1.5 in several brain areas (i.e. accumbens shell vertex, paraventricular hypothalamic nucleus, central and medial amygdala or dorsal raphe, dorsal part). Interestingly, the lower AMP dose induced a greater c-fos expression in other structures (prelimbic cortex, accumbens cone and dorsomedial and ventromedial caudateputamen). Finally, in other brain regions both doses resulted in comparable degrees of activation (cingulate, infralimbic and piriform cortex, accumbens shell cone, dorsolateral caudateputamen, basolateral amygdala, ventral tegmental area and dorsal raphe, ventrolateral part). In most of the brain areas, AMP-induced Fos expression was unrelated to individual differences in locomotor reactivity to novelty or anxiety. In a few structures, a differential Fos expression was observed in function of 'initial activity', whereas no statistically significant differences were found in function of 'delayed activity'. Rats with higher 'initial activity' had lower Fos expression in the ventral tegmental area, regardless of anxiety levels or AMP dose. The same was shown in the accumbens shell vertex and the piriform cortex, but in these two cases, the differences were dependent on anxiety.
Behavioural Pharmacology, 2005
Behavioural Pharmacology, 2008
Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which b... more Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D 4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D 4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D 4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
Behavioural Pharmacology, 2011
ABSTRACT Preclinical evidence suggests an important role of the brain orexin system in behaviours... more ABSTRACT Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.
Annals of the New York Academy of Sciences, 2007
In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction.... more In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of cocaine-seeking behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.