Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain

Iyaniwura, Timothy T.; Wright, Adèle E.; Balfour, David J.K.

doi:10.1007/s002130100852

Cited by 55 publications

(47 citation statements)

References 23 publications

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“…In agreement with previous studies from our laboratory and others [19,83,84], nicotine increased the release of DA. This increase is consistent with enhanced activity of the DAergic system, effects that were decreased by pretreatment with NT69L.…”

Section: Effect Of Nt69l On Nicotine-and Alcohol-induced Biochemical supporting

confidence: 93%

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Boules¹,

Stennett²,

Muhktar³

et al. 2013

J Addict Res Ther

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IntroductionNicotine and alcohol addiction are frequently co-morbid problems [1]. The co-dependence of nicotine and alcohol addiction complicates treatment and is often associated with significant morbidity and mortality. Prevalence of smoking in alcoholics is as high as 90% compared to 30% for the general population [2] and alcohol consumption is associated with high nicotine use [3,4]. Co-morbid cigarette smoking and alcoholism has been associated with higher rates of depression in comparison with non-alcoholic smokers [5] and increased cravings for nicotine in comparison with non alcohol dependent smokers [6]. Additionally, smoker alcoholics are more likely to die from smoking related diseases rather than directly from an alcohol related medical condition [7]. Pharmacotherapeutic options for the treatment of alcohol and tobacco co-dependence are limited. Thus, there is a critical need for the development of novel drugs implementing new therapeutic targets.Neurotensin (NT) is a neuropeptide that is closely associated with, and modulates dopamine (DA) [8], acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA) neurotransmission, all of which are involved in addiction and reward pathways. Local administration of NT in the prefrontal cortex (PFC) increases extracellular levels of ACh and GABA [9]. Similar data were obtained with the extracranial injection of the NT agonist NT69L [10], a compound that was developed in our laboratory. NT also enhances GABAergic activity in rat hippocampus [11] and reduces glutamatergic neurotransmission in dorsolateral striatum [12]. However, NT must be administered centrally to have an effect because it is easily degraded by peptidases. Our laboratory has developed many NT agonists that can be administered extracranially and mimic the central effects of NT. The most studied of these agonists is NT69L, which binds with equal affinity to the two well-characterized NT receptors, subtype 1 (NTS1) and subtype 2 (NTS2). Our work with NT69L shows that it blocks nicotine-induced sensitization and nicotine self-administration [13][14][15].In addition to its role in animal models for nicotine addiction, the NT system has been strongly implicated in the neurochemical and behavioral effects of alcohol use [16,17]. Chronic administration of NT69L reduces alcohol preference and consumption in mice through modulation of the NTS1 [18]. Biochemically, NT69L normalizes the nicotine-induced changes in DA [19], the neurotransmitter that promotes the motivational process for both nicotine and alcohol, and the alcohol-induced increase in DA and glutamate in the striatum [20]. Additionally, NT modulates other neurotransmitters implicated in alcohol use disorder (AUD). It causes neurochemical changes similar to acamprosate (the calcium salt of acetylhomotaurine), which is one of three FDA-approved drugs to treat AUD. Administration of acamprosate or NT69L increases extracellular concentration of DA in striatum [10,11] and both acamprosate and NT69L modulate glutamate [21,22].Considering the behav...

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Section: Effect Of Nt69l On Nicotine-and Alcohol-induced Biochemical supporting

confidence: 93%

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Boules¹,

Stennett²,

Muhktar³

et al. 2013

J Addict Res Ther

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“…Although nicotine-mediated DARPP32 activation was not observed in the NAc in the current work, this may have resulted from tissue sampling that did not distinguish between core and shell subregions. Because DARPP32 T34 phosphorylation occurs downstream of dopamine D 1 receptor activation (Greengard et al, 1999), and nicotine leads to sensitization of dopamine release in the core and not the shell (Iyaniwura et al, 2001), nicotinemediated DARPP32 activation would be more likely to occur in the NAc core. Thus, samples containing both NAc core and shell tissue may have diluted the effect of a core-specific increase in phosphorylated DARPP32.…”

Section: Discussionmentioning

confidence: 99%

Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

Addy¹,

Fornasiero²,

Stevens³

et al. 2007

J. Neurosci.

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Calcineurin is a serine/threonine phosphatase that contributes to the effects of nicotine on calcium signaling in cultured cortical neurons; however, the role of calcineurin in behavioral responses to nicotine in vivo has not been examined. We therefore determined whether calcineurin blockade could alter nicotine-mediated locomotor sensitization in Sprague Dawley rats using systemic or brain regionspecific administration of the calcineurin inhibitors cyclosporine or FK506. Systemic cyclosporine administration decreased calcineurin activity in the brain, attenuated nicotine-mediated locomotor sensitization, and blocked the effects of nicotine on DARPP32 (dopamineand cAMP-regulated phosphoprotein-32) activation in the striatum. Direct infusion of calcineurin inhibitors cyclosporine or FK506 into the ventral tegmental area (VTA) also attenuated nicotine-mediated locomotor sensitization, whereas infusion of rapamycin, which binds to FK-binding protein but does not inhibit calcineurin, did not affect sensitization. Together, the data suggest that activation of calcineurin, particularly in the VTA, is a novel signaling event important for nicotine-mediated behavior and intracellular signaling.

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“…Interestingly, the NAc is a heterogeneous region most often divided into two distinct anatomically and functionally different regions, that is the central core and the surrounding shell compartment [65][66][67][68][69] and it has been suggested that dopaminergic innervation of the NAc core is associated with the nigrostriatal system, while that of the NAc shell is related to the mesolimbic system [70]. Alcohol has been shown to increase the release of dopamine in NAc shell, but not in the core [71][72][73]. Studies are also emerging suggesting the need for further division of this brain region since it was demonstrated that a borderline region between the core and shell of the NAc is the region most responsive to alcohol [74].…”

Section: Preclinical Evidence: Acute Alcohol Exposure and Dopaminementioning

confidence: 99%

Dopamine and Alcohol Dependence: From Bench to Clinic

Jayaram‐Lindström¹,

Ericson²,

Steensland³

et al. 2016

Recent Advances in Drug Addiction Research and Clinical Applications

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Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity. The role of dopamine in alcohol-induced reward as well in the development of alcohol dependence is reviewed herein. Both preclinical and clinical studies have suggested that alcohol activates the mesolimbic dopamine system (defined as a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. ventral striatum)) leading to a euphoric sensation. Alcohol dependence is characterized by a disruption in the reward-related brain areas including fewer dopamine D2 receptors in ventral striatum. Investigations of the underlying dopaminergic mechanisms involved during the development and maintenance of alcohol dependence could identify novel targets. Human and rodent experimental studies show that dopamine receptor antagonists, agonists and partial agonists as well as dopamine stabilizers influencing dopamine transmission, alter alcohol-mediated behaviours and thus may be potential treatment targets for alcohol dependence. Although there exists promising preclinical results, the majority of placebo-controlled randomized clinical trials with traditional dopamine antagonists and agonists have so far have been discouraging. Furthermore, the severe side-effect profiles of many of these compounds may limit their clinical use. Newer dopamine agents, such as partial agonists and dopamine stabilizers, attenuate alcohol-mediated behaviours in rodents as well as humans. Preclinical as well as clinical studies have shown that substances indirectly targeting the mesolimbic dopamine system may be potential targets for attenuation of alcohol reward. Collectively, the data reviewed herein may contribute to further understanding the complex mechanisms involved in development of alcohol dependence and we suggest that the newer dopamine agents as well as indirect modulators of dopamine signalling deserve to be further evaluated for treatment of alcohol dependence.

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Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain

Cited by 55 publications

References 23 publications

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

Dopamine and Alcohol Dependence: From Bench to Clinic

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