ABSTRACT
Title
Behavioral and neurochemical characterization of the antianhedonic activity of lithium in rats
Authors
M.E. Secci
Doctorate School in Molecular Medicine
Dept. of Neuroscience, Section of Pharmacology
University of Siena, Italy
Doctorate School in Molecular Medicine
Dept. of Neuroscience, Section of Pharmacology
University of Siena, Italy
Abstract
Lithium is considered the gold standard medicament in the treatment of bipolar disorder, is effective as an adjunct treatment for depression and it reduces the risk of attempted or completed suicide, while other drugs routinely used as mood stabilizers, such as carbamazepine, and antidepressants lack substantial evidence of antisuicidal activity. One of the risk factors that has been associated with suicidal behavior is anhedonia. A strict relationship between anhedonia and suicidality seems to exist both in depressed, bipolar and schizophrenic subjects [1]. The aim of this study was to investigate the possible mechanisms underpinning lithium anti-suicidal activity by addressing the question of whether lithium is endowed with antianhedonic activity.
Anhedonia defines the inability to experience pleasure from normally pleasurable life events such as eating, exercise, and social or sexual interaction. Although the exact biological bases of anhedonia are not known, research suggests that it may result, in part from disruption of systems implicated in reward and motivation, which likely include the nucleus accumbens (NAc) and the fronto-striatal network [2]. The dopaminergic system plays a central role in the fronto-striatal network and a decreased dopaminergic transmission is likely involved in the observed functional PFC deficit. A widely accepted view on dopamine involvement in reward is that a phasic increase in mesolimbic dopamine output in response to a relevant stimulus is dependent on and quantifies the actual emotional value of its representation and confers incentive properties to it. In order to verify the hypothesis of an antianhedonic activity of lithium, I studied the effects of repeated lithium treatment in two experimental anhedonia-like models: a condition of cocaine sensitization and chronic unavoidable stress exposure. These two conditions are characterized by a blunted dopaminergic response to palatable food (Vanilla sugar, VS) consumption in the shell portion of the nucleus accumbens (NAcS), measured by microdialysis, and by the inability to acquire an instrumental behavior based on the reinforcing properties of VS pellets, the earning of which is made contingent on the choice of one of the two divergent arms of a Y-maze (VS sustained appetitive behavior, VAB).
Daily lithium administration (0.8 mEq/kg b.i.d.) for 10 days re-established a normal dopaminergic response in the NAcS; moreover, daily lithium administration 10 days before and during VAB training completely reinstated the competence to acquire VAB in cocaine-sensitized rats. In the anhedonia-like condition induced by unavoidable stress exposure lithium administered 10 days before and during VAB training reinstated the competence to acquire VAB in chronically stressed rats.
[1] Loas G. “Anhedonia and suicide: a 6.5-yr. follow-up study of patients hospitalised for a suicide attempt”. Psychol Rep. 2007 Feb;100(1):183-90.
[2] Scheggi S et al. “Cocaine sensitization models an anhedonia-like condition in rats”. Int J Neuropsychopharmacol. 2011 Apr;14(3):333-46
Anhedonia defines the inability to experience pleasure from normally pleasurable life events such as eating, exercise, and social or sexual interaction. Although the exact biological bases of anhedonia are not known, research suggests that it may result, in part from disruption of systems implicated in reward and motivation, which likely include the nucleus accumbens (NAc) and the fronto-striatal network [2]. The dopaminergic system plays a central role in the fronto-striatal network and a decreased dopaminergic transmission is likely involved in the observed functional PFC deficit. A widely accepted view on dopamine involvement in reward is that a phasic increase in mesolimbic dopamine output in response to a relevant stimulus is dependent on and quantifies the actual emotional value of its representation and confers incentive properties to it. In order to verify the hypothesis of an antianhedonic activity of lithium, I studied the effects of repeated lithium treatment in two experimental anhedonia-like models: a condition of cocaine sensitization and chronic unavoidable stress exposure. These two conditions are characterized by a blunted dopaminergic response to palatable food (Vanilla sugar, VS) consumption in the shell portion of the nucleus accumbens (NAcS), measured by microdialysis, and by the inability to acquire an instrumental behavior based on the reinforcing properties of VS pellets, the earning of which is made contingent on the choice of one of the two divergent arms of a Y-maze (VS sustained appetitive behavior, VAB).
Daily lithium administration (0.8 mEq/kg b.i.d.) for 10 days re-established a normal dopaminergic response in the NAcS; moreover, daily lithium administration 10 days before and during VAB training completely reinstated the competence to acquire VAB in cocaine-sensitized rats. In the anhedonia-like condition induced by unavoidable stress exposure lithium administered 10 days before and during VAB training reinstated the competence to acquire VAB in chronically stressed rats.
[1] Loas G. “Anhedonia and suicide: a 6.5-yr. follow-up study of patients hospitalised for a suicide attempt”. Psychol Rep. 2007 Feb;100(1):183-90.
[2] Scheggi S et al. “Cocaine sensitization models an anhedonia-like condition in rats”. Int J Neuropsychopharmacol. 2011 Apr;14(3):333-46