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1.  Visceral analgesic effect of 5-HT4 receptor agonist in rats involves the rostroventral medulla (RVM) 
Neuropharmacology  2013;79:345-358.
The 5-HT4 receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. In male rats, visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD). Inflammation was induced by intracolonic injection of tri-nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not spinal, injection of TEG attenuated the VMR. While GR113808, (selective 5-HT4 antagonist) blocked the effect, naloxone (NLX) an opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT4 receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.
PMCID: PMC4321751  PMID: 24334068
5-HT4 receptors; RVM; Visceral pain; Colon; Descending modulation
2.  [No title available] 
PMCID: PMC3865025  PMID: 24120838
3.  [No title available] 
PMCID: PMC3865178  PMID: 24067924
4.  [No title available] 
PMCID: PMC3866097  PMID: 24012658
5.  [No title available] 
PMCID: PMC3866371  PMID: 24095990
6.  [No title available] 
PMCID: PMC3867233  PMID: 24176392
7.  [No title available] 
PMCID: PMC3872110  PMID: 24212058
8.  [No title available] 
PMCID: PMC3873141  PMID: 24157490
9.  [No title available] 
PMCID: PMC3874885  PMID: 24067926
10.  [No title available] 
PMCID: PMC3876483  PMID: 24067922
11.  [No title available] 
PMCID: PMC3880158  PMID: 24184417
12.  [No title available] 
PMCID: PMC3888085  PMID: 24090766
13.  [No title available] 
PMCID: PMC3894780  PMID: 24157491
14.  [No title available] 
PMCID: PMC3934363  PMID: 24144909
15.  [No title available] 
PMCID: PMC3934570  PMID: 24035918
16.  [No title available] 
PMCID: PMC3934827  PMID: 24490227
17.  [No title available] 
PMCID: PMC3970824  PMID: 24035916
18.  Nicotine Dependence Produces Hyperalgesia: Role of Corticotropin-Releasing Factor-1 Receptors (CRF1Rs) in the Central Amygdala (CeA) 
Neuropharmacology  2013;77:217-223.
Because tobacco use has a large negative health and financial impact on society, it is critical to identify the factors that drive excessive use. These factors include the aversive withdrawal symptoms that manifest upon cessation of tobacco use, and may include increases in nociceptive processing. Corticotropin-releasing factor (CRF) signalling in the central amygdala (CeA) has been attributed an important role in: (1) central processing of pain, (2) excessive nicotine use that results in nicotine dependence, and (3) in mediating the aversive symptoms that manifest following cessation of tobacco exposure. Here, we describe three experiments in which the main hypothesis was that CRF/CRF1 receptor (CRF1R) signalling in the CeA mediates nicotine withdrawal-induced increases in nociceptive sensitivity in rats that are dependent on nicotine. In Experiment 1, nicotine-dependent rats withdrawn from chronic intermittent (14-h/day) nicotine vapor exhibited decreased hindpaw withdrawal latencies in response to a painful thermal stimulus in the Hargreaves test, and this effect was attenuated by systemic administration of the CRF1R antagonist, R121919. In Experiment 2, nicotine-dependent rats withdrawn from nicotine vapor exhibited robust increases in mRNA for CRF and CRF1Rs in CeA. In Experiment 3, intra-CeA administration of R121919 reduced thermal nociception only in nicotine-dependent rats. Collectively, these results suggest that nicotine dependence increases CRF/CRF1R signalling in the CeA that mediates withdrawal-induced increases in sensitivity to a painful stimulus. Future studies will build on these findings by exploring the hypothesis that nicotine withdrawal-induced reduction in pain thresholds drive excessive nicotine use via CRF/CRF1R signalling pathways.
PMCID: PMC4144034  PMID: 24107576
Nicotine Dependence; CRF1 Receptor; R121919; Hargreaves; Withdrawal
19.  The role of group II metabotropic glutamate receptors in cognition and anxiety: Comparative studies in GRM2−/−, GRM3−/− and GRM2/3−/− knockout mice 
Neuropharmacology  2015;89:19-32.
Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by GRM2 and GRM3) have been implicated in both cognitive and emotional processes, although their precise role remains to be established. Studies with knockout (KO) mice provide an important approach for investigating the role of specific receptor genes in behaviour. In the present series of experiments we extended our prior characterisation of GRM2/3−/− double KO mice and, in complementary experiments, investigated the behavioural phenotype of single GRM2−/− and GRM3−/− mice. We found no consistent effect on anxiety in either the double or single KO mice. The lack of an anxiety phenotype in any of the lines contrasts with the clear anxiolytic effects of mGlu2/3 ligands. Motor co-ordination was impaired in GRM2/3−/− mice, but spared in single GRM2−/− and GRM3−/− mice. Spatial working memory (rewarded alternation) testing on the elevated T-maze revealed a deficit in GRM2−/− mice throughout testing, whereas GRM3−/− mice exhibited a biphasic effect (initially impaired, but performing better than controls by the end of training). A biphasic effect on activity levels was seen for the GRM2−/− mice. Overall, the phenotype in both GRM2−/− and GRM3−/− mice was less pronounced – if present at all – compared to GRM2/3−/− mice, across the range of task domains. This is consistent with possible redundancy of function and/or compensation in the single KO lines. Results are discussed with reference to a possible role for group II metabotropic glutamate receptors at the interface between arousal and behavioural performance, according to an inverted U-shaped function.
•GRM2−/− mice exhibited impaired spatial short-term memory (rewarded alternation).•GRM3−/− mice displayed bi-directional effects on this spatial short-term memory task.•GRM2−/− mice displayed bi-directional effects on activity levels.•There was no consistent anxiety effect in either double or single knockout mice.•Behavioural phenotypes were weaker (or absent) in single than in double knockout mice.
PMCID: PMC4259517  PMID: 25158312
Hippocampus; Spatial memory; Anxiety; Arousal
20.  Functional reduction of SK3-mediated currents precedes AMPA-receptor-mediated excitotoxicity in dopaminergic neurons 
Neuropharmacology  2010;60(0):1176-1186.
In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (ISK) in this system and evaluated their role on homeostasis against excitotoxicity. ISK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of ISK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two ISK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, ISK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses.
This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.
PMCID: PMC4301957  PMID: 21044638
Dopaminergic; SK channels; Apamin; 1-Ebio; CyPPA; NS8593 AMPA; Excitotoxicity; Neuroprotection
21.  Transition from ‘model-based’ to ‘model-free’ behavioral control in addiction: involvement of the orbitofrontal cortex and dorsolateral striatum 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.05.033.
Cocaine addiction is a complex and multidimensional process involving a number of behavioral and neural forms of plasticity. The behavioral transition from voluntary drug use to compulsive drug taking may be explained at the neural level by drug-induced changes in function or interaction between a flexible planning system, associated with prefrontal cortical regions, and a rigid habit system, associated with the striatum. The dichotomy between these two systems is operationalized in computational theory by positing model-based and model-free learning mechanisms, the former relying on an “internal model” of the environment and the latter on pre-computed or cached values to control behavior. In this review, we will suggest that model-free and model-based learning mechanisms appear to be differentially affected, at least in the case of psychostimulants such as cocaine, with the former being enhanced while the latter are disrupted. As a result, the behavior of long-term drug users becomes less flexible and responsive to the desirability of expected outcomes and more habitual, based on the long history of reinforcement. To support our specific proposal, we will review recent neural and behavioral evidence on the effect of psychostimulant exposure on orbitofrontal and dorsolateral striatum structure and function.
PMCID: PMC3809026  PMID: 23752095
22.  Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.07.031.
Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be more exacerbated by other factors that affect the metabolism of cytosolic DA.
PMCID: PMC3811113  PMID: 23978383
Transgenic mice; Gene knockout; Dopamine; Aging; Amphetamine; Cocaine
23.  Environmental Modulation of Drug Taking: Nonhuman Primate Models of Cocaine Abuse and PET Neuroimaging 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.05.044.
The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables – both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse.
PMCID: PMC3812308  PMID: 23748095
animal models; dopamine; social variables; alternative reinforcers; punishment; PET imaging; nonhuman primates
24.  A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.04.055.
Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females.
PMCID: PMC3812395  PMID: 23684991
sex; tobacco; adolescent; withdrawal; dependence; reward
25.  Addiction Science: Uncovering Neurobiological Complexity 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.05.007.
Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g., optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to systematically interrogate “all” genes, epigenetic marks, and neuronal circuits. These advances, combined with imaging technologies (both for preclinical and clinical studies) and a paradigm shift towards open access have spurred an unlimited growth of datasets transforming the way we investigate the neurobiology of substance use disorders (SUD) and the factors that modulate risk and resilience.
PMCID: PMC3818510  PMID: 23688927

Results 1-25 (749)