Reduced Behavioral Effects of Cocaine in Heterozygous Brain-Derived Neurotrophic Factor (BDNF) Knockout Mice

Hall, F. Scott; Drgonová, Jana; Goeb, Michelle; Uhl, George R.

doi:10.1038/sj.npp.1300192

Cited by 166 publications

(121 citation statements)

References 39 publications

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“…Unlike previous studies with this strain (Duan et al, 2003;Kernie et al, 2000) and with forebrain-specific deletion (Monteggia et al, 2004;Monteggia et al, 2006;Rios et al, 2001;Zorner et al, 2003), these mice did not differ in basal locomotor activity but showed enhanced activity in response to ethanol injection. This is in contrast to cocaine sensitivity, where BDNF +/− mice show reduced locomotor effects and decreased conditioned place preference (Hall et al, 2003). The increased consumption of ethanol in haplodeficient mice could be reversed by systemic delivery of TAT-RACK1.…”

Section: Bdnf In Animal Models Of Anxiety Depression and Addictionmentioning

confidence: 89%

“…BDNF potentiates psychostimulant-induced increases in DA both acutely and during sensitization (Altar et al, 1994;Pu et al, 2006;Horger et al, 1999). Conditioned place preference in response to psychostimulants is also reduced in BDNF haplodeficient mice (Hall et al, 2003). Amphetamine increases TrkB expression (Meredith and Steiner, 2006) and BDNF participates in the rewarding properties of psychostimulants by potentiating pre and post synaptic activity (Horger et al, 1999).…”

Section: Bdnf In Animal Models Of Anxiety Depression and Addictionmentioning

confidence: 99%

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Ethanol–BDNF interactions: Still more questions than answers

Davis

2008

Pharmacology & Therapeutics

128

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Brain Derived Neurotrophic Factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism.

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Section: Bdnf In Animal Models Of Anxiety Depression and Addictionmentioning

confidence: 89%

Section: Bdnf In Animal Models Of Anxiety Depression and Addictionmentioning

confidence: 99%

Ethanol–BDNF interactions: Still more questions than answers

Davis

2008

Pharmacology & Therapeutics

128

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“…Role m In satiety; m water reward (Horger et al, 1999;Kernie et al, 2000;Nakagawa et al, 2003); improvement in glucose metabolism (Tonra et al, 1999;Nakagawa et al, 2000;Ono et al, 2000) m Drug reward (Horger et al, 1999) K BDNF in mesolimbic pathways regulates appetitive behavior (Eisch et al, 2003;Itoh et al, 2004); BDNF within hypothalamus regulates energy balance by enhancing catabolic processes (Xu et al, 2003) K BDNF may play a role in behavioral sensitization to drugs (Guillin et al, 2001) and potentially to palatable food via its dopaminergic and opioidergic (Siuciak et al, 1994;Siuciak et al, 1995) effects Repeated exposure kIn the hippocampus (Molteni et al, 2002;Molteni et al, 2004) m In mesocorticolimbic areas including, hypothalamus (Meredith et al, 2002;Butovsky et al, 2005); m and upregulation of BDNF receptors during withdrawal (Toda et al, 2002;Grimm et al, 2003); incubation of drug craving, accompanied by m in BDNF (Grimm et al, 2003) BDNF gene knockout animals m In food intake and obesity (Lyons et al, 1999;Kernie et al, 2000;Rios et al, 2001;Xu et al, 2003) k Drug reward (Hall et al, 2003;Horger et al, 1999) Orexin m Food intake (Edwards et al, 1999;Harris et al, 2005) Relapse to drug seeking behavior (Harris et al, 2005) Activated by SGAs ( Ibanez-Rojo et al, 1993;Bencherif et al, 2005) are available, though, to extend preclinical palatable food opioid findings to humans. Neuroimaging studies in obese people reported in...…”

Section: Bdnfmentioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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“…In addition, BDNF and NT3 potently influence behavioral sensitization to cocaine and the regulation of dopaminergic transmission to the NAc (Martin-Iverson and Altar 1996;Pierce et al 1999). Behavioral studies have shown that heterozygous BDNF knockout throughout the brain delays the development of cocaine sensitization (Horger et al 1999;Messer et al 2000) and attenuates the rewarding effects of cocaine in conditioned-place preference (Hall et al 2003). As BDNF is implicated in synaptic plasticity, primarily through its receptor TrkB (Bibel and Barde 2000;Bonhoeffer 1996;Kryl et al 1999;Patapoutian and Reichardt 2001;Thoenen 2000), BDNF-mediated neuroadaptations in mesolimbic areas are therefore probably involved in the persistent cocaine seeking induced by exposure to drug cues after withdrawal (Lu et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats

et al. 2008

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Background Brain-derived neurotrophic factor (BDNF) is involved in the survival and function of midbrain DA neurons. BDNF action is mediated by the TrkB receptortyrosine kinase, and both BDNF and TrkB transcripts are widely expressed in the rat mesolimbic pathway, including the nucleus accumbens (NAc) and the ventral tegmentum area (VTA). Objective BDNF was previously shown to be involved in cocaine reward and relapse, as assessed in rat models. The goal of this study is to explore the role of BDNF and TrkB in the rat nucleus accumbens (NAc) in cocaine-induced psychomotor sensitization and in conditioned-place preference acquisition, expression, and reinstatement. Materials and methods In vivo genetic manipulations of BDNF and TrkB were performed using a lentiviral gene delivery approach to over-express these genes in the NAc and siRNA-based technology to locally knockdown gene expression. Behavioral experiments consisted of locomotor activity monitoring or cocaine-induced conditioned-place preference (CPP). Results BDNF and/or its receptor TrkB in the NAc enhance drug-induced locomotor activity and induce sensitization in rats. Furthermore, LV-BDNF-and LV-TrkB-treated rats display enhanced cocaine-induced CPP, delayed CPPextinction upon repeated measurements, and increased CPP reinstatement. In contrast, expression of TrkT1 (truncated form of TrkB, acting as a dominant negative) inhibits these behavioral changes. This inhibition is also observed when rats are fed doxycycline (to block lentivirusmediated gene expression) or when injected with siRNAsexpressing lentiviruses against TrkB. In addition, we investigate the establishment, maintenance, extinction, and reinstatement of cocaine-induced CPP. We show that BDNF and TrkB-induced CPP takes place during the learning period (conditioning), whereas extinction leads to the loss of CPP. Extinction is delayed when rats are injected LV-BDNF or LV-TrkB, and in turn, priming injections of 2 mg/kg of cocaine reinstates it. Conclusions These results demonstrate the crucial function of BDNF-through its receptor TrkB-in the enhancement of locomotor activity, sensitization, conditioned-place preference, CPP-reinstatement, and rewarding effects of cocaine in the mesolimbic dopaminergic pathway.

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Reduced Behavioral Effects of Cocaine in Heterozygous Brain-Derived Neurotrophic Factor (BDNF) Knockout Mice

Cited by 166 publications

References 39 publications

Ethanol–BDNF interactions: Still more questions than answers

Ethanol–BDNF interactions: Still more questions than answers

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats

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