Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats

Abstract

Evidence from both animal and human studies suggests a role for dopamine in the therapeutic effect of antidepressant drugs. Consistently, dopamine receptor antagonists antagonize the effect of antidepressant drugs in different experimental models of depression. Neurosteroids, and in particular allopregnanolone, seem to be involved both in the pathophysiology of depression and in the mechanism of action of antidepressant drugs, and their role seems to be particularly important in the understanding of mood disturbances related to the different phases of the reproductive life in women. The aim of this study was to investigate the possible role of dopamine on the antidepressant-like effect of allopregnanolone in a model of depression. Thus, we examined (i) the behaviour of female Sprague-Dawley rats in the forced swimming test during estrus and diestrus and their response to allopregnanolone treatment (0.5, 1 and 2 mg/kg), and (ii) the effect of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01 and 0.025 mg/kg) and raclopride (0.05 and 0.2 mg/kg) on the antidepressant-like effect of allopregnanolone (2 mg/kg) in the same experimental model. We failed to observe differences in depressive-like behaviour between estrous phases, and allopregnanolone administration in both estrus and diestrus resulted in an antidepressant-like effect consisting in an increase of swimming behaviour. The allopregnanolone effect was unaffected by a dose of the dopamine D1-like receptor antagonist SCH 23390 displaying a marked inhibitory effect on basal activity, while it was turned into a potentiation of the depressive-like behaviour of the forced swimming condition by treatment with the higher dose of raclopride. The present results indicate an involvement of dopamine transmission in the allopregnanolone antidepressant-like effect in the forced swimming model of depression, and suggest that this effect depends mainly on stimulation of dopamine D2-like receptors.

Chronic mild stress increases alcohol intake in mice with low dopamine D2 receptor levels.

“…2009;, and DRD2 antagonists prevent the action of antidepressants (Binfaré, Mantovani, Budni, Santos, &. Rodriques, 2010;D'aquila et al, 2010). Our result is also in agreement with human studies that report depressive symptoms in patients with posttraumatic stress disorder (Lawford, Young, Noble, Kann, & Ritchie, 2006), in children who are reared in nonsupporting families and express the TaqAl alíele (Hayden et al, 2010), and in those that show a possible correlation between extrastriatal DRD2/3 levels and major depression (Lchto et al, 2008), but not with others (Hirvonen et al, 2008;Saijo et al, 2010).…”

In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis

“…Hence, the term “neurosteroid” is applied to those steroids that are specifically synthesized in the brain, where they reach physiological significant levels to modulate gene expression and neurotransmitter systems (Puia et al, 1990; 1991; 2003; Pinna et al, 2000; Lambert et al, 2003; 2009; Belelli et al, 2005; Majewska et al, 1992). Several pharmacological studies have indicated that allopregnanolone expresses anticonvulsant, anxiolytic, antidepressant, and even sedative-hypnotic actions (D’aquila et al, 2010; Nin et al, 2008; Rodriguez-Landa et al, 2009; Kita and Furukawa, 2008; Lonsdale and Burnham, 2007; Mares et al, 2006; Martin-Garcia and Pallares, 2005; Jain et al, 2005). These effects resemble those elicited by several positive allosteric modulators of GABA action at GABA A receptors, including barbiturates and benzodiazepines (Guidotti et al, 2001; Majewska et al, 1992), and thus, these effects define allopregnanolone as a “neuroactive steroid”.…”

Neurosteroids reduce social isolation-induced behavioral deficits: a proposed link with neurosteroid-mediated upregulation of BDNF expression

“…Impaired neurosteroid biosynthesis has been associated with numerous behavioral dysfunctions, which range from anxiety- and depressive-like behaviors to aggressive behavior and changes in responses to contextual fear conditioning in rodent models of emotional dysfunction (Pinna et al, 2003, 2004, 2006, 2008; Uzunova et al, 2004, 2006; Jain et al, 2005; Martin-Garcia and Pallares, 2005; Kita and Furukawa, 2008; D’Aquila et al, 2010; Pinna, 2010). In clinical studies, decreases in the serum, plasma, and cerebrospinal fluid (CSF) content of neuroactive steroids, including the progesterone metabolite, allopregnanolone, which is a potent positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABA A receptors (Puia et al, 1990, 2003; Lambert et al, 2003, 2009; Belelli and Lambert, 2005), are associated with several psychiatric disorders such as depression, anxiety spectrum disorders, posttraumatic stress disorders (PTSD), premenstrual dysphoric disorder, schizophrenia, and impulsive aggression (Rapkin et al, 1997; Romeo et al, 1998; Uzunova et al, 1998; Bloch et al, 2000; Nappi et al, 2001; Ströhle et al, 2002; Bäckström et al, 2003; Pinna et al, 2006; Rasmusson et al, 2006; Amin et al, 2007; Marx et al, 2009; Pearlstein, 2010).…”