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1.
J Neurosci ; 38(9): 2149-2162, 2018 02 28.
Article in English | MEDLINE | ID: mdl-29367407

ABSTRACT

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.


Subject(s)
Aminopyridines/pharmacology , Brain/drug effects , Dopamine/metabolism , Indoles/pharmacology , Receptor, Serotonin, 5-HT2C/drug effects , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Apathy/drug effects , Apathy/physiology , Brain/physiology , Female , Male , Mice , Mice, Inbred C57BL , Motivation/drug effects , Motivation/physiology , Reward , Signal Transduction/drug effects , Signal Transduction/physiology
2.
J Neurosci ; 33(13): 5834-42, 2013 Mar 27.
Article in English | MEDLINE | ID: mdl-23536095

ABSTRACT

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.


Subject(s)
Body Size/physiology , Growth Hormone/metabolism , Pituitary Gland/metabolism , Prolactin/metabolism , Receptors, Dopamine D2/metabolism , Analysis of Variance , Animals , Benzamides/pharmacokinetics , Body Size/drug effects , Body Size/genetics , Body Weight/drug effects , Body Weight/genetics , Case-Control Studies , Catatonia/chemically induced , Catatonia/metabolism , Dopamine Antagonists/pharmacology , Eating/drug effects , Eating/genetics , Eating/physiology , Female , Haloperidol/pharmacology , Insulin-Like Growth Factor I/metabolism , Intermediate Filament Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nestin , Oligodeoxyribonucleotides, Antisense/pharmacology , Pheromones/urine , Pituitary Gland/drug effects , Prolactin/genetics , Protein Binding/drug effects , Protein Binding/genetics , Proteins/metabolism , Radioimmunoassay , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/genetics , Social Dominance , Territoriality , Tritium/pharmacokinetics
3.
Nat Neurosci ; 14(8): 1033-8, 2011 Jul 10.
Article in English | MEDLINE | ID: mdl-21743470

ABSTRACT

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.


Subject(s)
Cocaine/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Motivation/physiology , Receptors, Dopamine D2/deficiency , Reward , Analysis of Variance , Animals , Autoradiography , Baclofen/pharmacology , Choice Behavior/physiology , Conditioning, Operant , Dihydroxyphenylalanine/metabolism , Dopamine/metabolism , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Drug Interactions , Enzyme Inhibitors/pharmacology , Exploratory Behavior/physiology , Food , GABA-B Receptor Agonists/pharmacology , Hydrazines/pharmacology , Hyperkinesis/drug therapy , Hyperkinesis/physiopathology , In Vitro Techniques , Maze Learning/physiology , Membrane Potentials/drug effects , Membrane Potentials/genetics , Mesencephalon/cytology , Mice , Mice, Knockout , Motor Activity/genetics , Neurons/physiology , Quinpirole/pharmacology , Reinforcement Schedule , Sulpiride/pharmacology
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