Antidepressant-like actions of intra-accumbens infusions of allopregnanolone in ovariectomized Wistar rats

Molina-Hernández, Miguel; Téllez-Alcántara, N. Patricia; García, Julián Pérez; Lopez, Jorge Ivan Olivera; Jaramillo, M. Teresa

doi:10.1016/j.pbb.2004.11.017

Cited by 35 publications

(18 citation statements)

References 72 publications

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“…A recent study showed that infusion of allopregnanolone into the NAc produced antidepressant-like effects in ovariectomized rats [105]. Allopregnanolone is a neurosteroid, which is known to be an agonist for GABA A receptors.…”

Section: Gabamentioning

confidence: 99%

Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents

Shirayama

Chaki²

2006

190

111

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There is accumulating evidence that the nucleus accumbens (NAc) plays an important role in the pathophysiology of depression. Given that clinical depression is marked by anhedonia (diminished interest or pleasure), dysfunction of the brain reward pathway has been suggested as contributing to the pathophysiology of depression.Since the NAc is the center of reward and learning, it is hypothesized that anhedonia might be produced by hampering the function of the NAc. Indeed, it has been reported that stress, drug exposure and drug withdrawal, all of which produce a depressive-phenotype, alter various functions within the NAc, leading to inhibited dopaminergic activity in the NAc.In this review, we describe various factors as possible candidates within the NAc for the initiation of depressive symptoms. First, we discuss the roles of several neurotransmitters and neuropeptides in the functioning of the NAc, including dopamine, glutamate, gamma-aminobutyric acid (GABA), acetylcholine, serotonin, dynorphin, enkephaline, brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART). Second, based on previous studies, we propose hypothetical relationships among these substances and the shell and core subregions of the NAc.

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Section: Gabamentioning

confidence: 99%

Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents

Shirayama

Chaki²

2006

190

111

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“…128 Allopregnanolone itself has been shown to have an antidepressant-like effect in rat and mouse forced swim tests. 129,130 These effects are thought to be mediated by GABA A receptors as they are blocked by GABA A receptor antagonists. 129 Levels of allopregnanolone are also reduced in the frontal cortex of mice that have undergone protracted isolation--a behavioral manipulation that induces depression-like behaviors.…”

Section: The Role Of Gaba In Depression-targets For Novel Antidepressmentioning

confidence: 99%

Innovative approaches for the development of antidepressant drugs: Current and future strategies

Schechter¹,

Ring²,

Beyer³

et al. 2005

Neurotherapeutics

183

100

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Summary: Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2C , ␣-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT 2C , 5-HT 6 ) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.

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Section: Antidepressant-like Effect Of 3α5α-thp In the Forced Swim Tmentioning

confidence: 99%

“…Most recently, the nucleus accumbens was shown to mediate the antidepressant-like effect of 3α,5α-THP (Molina-Hernandez et al 2005). Focal application as well as systemic administration of 3α,5α-THP in the nucleus accumbens of ovariectomized rats produced a significant decrease in the immobility time in the FST by increasing climbing behavior (Molina-Hernandez et al 2005). Moreover, combining doses of intranucleus accumbens 3α,5α-THP that per se failed to produce an antidepressive-like effect with subthreshold systemic doses of 3α,5α-THP, muscimol, and fluoxetine resulted in reduced immobility time by increasing climbing behavior.…”

Section: Antidepressant-like Effect Of 3α5α-thp In the Forced Swim Tmentioning

confidence: 99%

“…Moreover, combining doses of intranucleus accumbens 3α,5α-THP that per se failed to produce an antidepressive-like effect with subthreshold systemic doses of 3α,5α-THP, muscimol, and fluoxetine resulted in reduced immobility time by increasing climbing behavior. An involvement of a complex GABAergic mechanism in the observed synergism is suggested by differential attenuation of the antidepressant-like effects of combination treatments of the GABA A receptor antagonists picrotixin and bicuculline (Molina-Hernandez et al 2005).…”

Section: Antidepressant-like Effect Of 3α5α-thp In the Forced Swim Tmentioning

confidence: 99%

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Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action

2005

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The naturally occurring 3alpha-reduced neurosteroids allopregnanolone and its isomer pregnanolone are among the most potent positive allosteric modulators of gamma-aminobutyric acid type A receptors. They play a critical role in the maintenance of physiological GABAergic tone and display a broad spectrum of neuropsychopharmacological properties. We have reviewed existing evidence implicating the relevance of endogenous 3alpha-reduced neuroactive steroids to depression and to the mechanism of action of antidepressants. A wide range of preclinical and clinical evidence suggesting the antidepressant potential of 3alpha-reduced neuroactive steroids and a possible involvement of a deficiency and a disequilibrium of neuroactive steroid levels in pathomechanisms underlying the etiology of major depressive disorder have emerged in recent years. Antidepressants elevate 3alpha-reduced neurosteroid levels in rodent brain, and clinically effective antidepressant pharmacotherapy is associated with normalization of plasma and cerebrospinal fluid (CSF) concentrations of endogenous neuroactive steroids in depressed patients, unveiling a possible contribution of neuroactive steroids to the mechanism of action of antidepressants. In contrast, recent studies using nonpharmacological antidepressant therapy suggest that changes in plasma neuroactive steroid levels may not be a general mandatory component of clinically effective antidepressant treatment per se, but may reflect distinct properties of pharmacotherapy only. While preclinical studies offer convincing evidence in support of an antidepressant-like effect of 3alpha-reduced neuroactive steroids in rodent models of depression, current clinical investigations are inconclusive of an involvement of neuroactive steroid deficiency in the pathophysiology of depression. Moreover, clinical evidence is merely suggestive of a role of neuroactive steroids in the mechanism of action of clinically effective antidepressant therapy. Additional clinical studies evaluating the impact of successful pharmacological and nonpharmacological antidepressant therapies on changes in neuroactive steroid levels in both plasma and CSF samples of the same patients are necessary in order to more accurately address the relevance of 3alpha-reduced neuroactive steroids to major depressive disorder. Finally, proof-of-concept studies with drugs that are known to selectively elevate brain neurosteroid levels may offer a direct assessment of an involvement of neurosteroids in the treatment of depressive symptomatology.

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Antidepressant-like actions of intra-accumbens infusions of allopregnanolone in ovariectomized Wistar rats

Cited by 35 publications

References 72 publications

Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents

Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents

Innovative approaches for the development of antidepressant drugs: Current and future strategies

Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action

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