Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats

ABSTRACTOxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin’s anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and postingestive reward value encoding (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of postingestive reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin’s effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA.HighlightsCentral oxytocin inhibits motivated responding for palatable food reinforcementCentral oxytocin does not play a role in encoding postingestive reward valueCentral oxytocin blunts VTA dopamine neuron activity in response to food cues

Schizophrenia, Parkinson’s disease, and attention deficit hyperactivity disorder

Schizophrenia, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD) discusses how hyperactive dopaminergic neurotransmission appears to underlie schizophrenia’s positive symptoms, loss of dopaminergic neurons in adulthood leads to Parkinson’s disease, and dopamine neuron hypofunction in childhood and adolescence may underlie ADHD. Positive schizophrenia symptoms may arise from excessive incentive learning that is gradually lost with antipsychotic treatment. Declarative learning and memory may contribute to delusions based on excessive incentive learning. Loss of responsiveness to environmental stimuli in Parkinson’s may result from a decrease of their conditioned incentive value and inverse incentive learning. Conditioned incentive stimuli not encountered while in a state of decreased dopaminergic neurotransmission may retain their incentive value, producing apparent kinesia paradoxa. Dopamine hypofunction in juveniles does not lead to hypokinesia but may result in loss of incentive learning that focuses attention. Pro-dopaminergic drugs have a calming effect in ADHD, presumably because they reinstate normal incentive learning.

Dopamine and inverse incentive learning

Dopamine and inverse incentive learning explains that dopamine determines an incentive–value continuum. Novel and intense stimuli innately produce rapid dopamine neurons activation followed by inhibition. The repeated presentation of novel stimuli leads to a loss of this effect. Aversive stimuli, biologically important by definition, often deactivate dopamine neurons and may produce inverse incentive learning, leading to conditioned inverse incentive stimuli with decreased ability to elicit approach and other responses. The offset of aversion may increase the firing of dopamine neurons producing incentive learning about safety-related stimuli. Habituation to stimuli enhances their ability to produce inverse incentive learning, suggesting that inverse incentive learning may occur during habituation. In the end, there may be no “neutral” stimuli, only stimuli that lie on a continuum of incentive value from strong conditioned incentive stimuli to strong conditioned inverse incentive stimuli with most of the things we encounter in day-to-day life falling in between.

Mechanisms of dopamine-mediated incentive learning

Mechanisms of dopamine-mediated incentive learning explains how sensory events, resulting from an animal’s movement and the environment, activate cortical glutamatergic projections to dendritic spines of striatal medium spiny neurons to initiate a wave of phosphorylation. If no rewarding stimulus is encountered, a subsequent wave of phosphatase activity undoes the phosphorylation. If a rewarding stimulus is encountered, dopamine initiates a cascade of events in D1 receptor-expressing medium spiny neurons that may prevent the phosphatase effects and work synergistically with signaling events produced by glutamate. As a result, corticostriatal synapses have a greater impact on response systems; this may be part of the mechanism of incentive learning. Dopamine acting on dendritic spines of D2 receptor-expressing medium spiny neurons may prevent synaptic strengthening by inhibiting adenosine signaling; these synapses may be weakened through mechanisms involving endocannabinoids. When dopamine concentrations drop, e.g. during negative prediction errors, the opposite may occur, producing inverse incentive learning.

Dopamine as the dependent variable

Dopamine as the dependent variable discusses how postmortem biochemistry, intracerebral microdialysis, electrophysiological recording, in vivo electrochemistry, and positron emission tomography studies provide compelling evidence that dopaminergic neurons are activated by primary rewarding stimuli including food and water and by numerous conditioned incentives, including money. Early in training, primary rewarding stimuli activate dopaminergic neurons. When a cue is reliably paired with a primary rewarding stimulus over trials, the dopamine response begins to be seen upon presentation of the cue and eventually is not seen upon presentation of the primary rewarding stimulus when it follows the cue. These conditioned cues acquire the ability to act as rewarding stimuli that can produce incentive learning. If conditioned incentive stimuli are repeatedly presented in the absence of primary incentive stimuli, they gradually lose their ability to elicit approach and other responses and to act as rewarding stimuli by producing incentive learning in their own right.

Life's rewards

Life’s Rewards: Linking Dopamine, Incentive Learning, Schizophrenia, and the Mind explains how increased brain dopamine produces reward-related incentive learning, the acquisition by neutral stimuli of increased ability to elicit approach and other responses. Dopamine decreases may produce inverse incentive learning, the loss by stimuli of the ability to elicit approach and other responses. Incentive learning is gradually lost when dopamine receptors are blocked. The brain has multiple memory systems defined as “declarative” and “non-declarative;” incentive learning produces one form of non-declarative memory. People with schizophrenia have hyperdopaminergia, possibly producing excessive incentive learning. Delusions may rely on declarative memory to interpret the world as it appears with excessive incentive learning. Parkinson’s disease, associated with dopamine loss, may involve a loss of incentive learning and increased inverse incentive learning. Drugs of abuse activate dopaminergic neurotransmission, leading to incentive learning about drug-associated stimuli. After withdrawal symptoms have been alleviated by detoxification treatment, drug-associated conditioned incentive stimuli will retain their ability to elicit responses until they are repeatedly experienced in the absence of primary drug rewards. Incentive learning may involve the action of dopamine at dendritic spines of striatal medium spiny neurons that have recently had glutamatergic input from assemblies of cortical neurons activated by environmental and proprioceptive stimuli. Glutamate initiates a wave of phosphorylation normally followed by a wave of phosphatase activity. If dopaminergic neurons fire, stimulation of D1 receptors prolongs the wave of phosphorylation, allowing glutamate synaptic strengthening. Activity in dopaminergic neurons in humans appears to affect mental experience.

Drug abuse and incentive learning

Drug abuse and incentive learning explains how abused drugs, including nicotine, ethanol, marijuana, amphetamine, cocaine, morphine, and heroin, produce conditioned place preference and are self-administered; dopamine receptor antagonists block these effects. Stimuli that become reliable predictors of drug reward produce burst firing in dopaminergic neurons, but the drug retains its ability to activate dopaminergic neurons. Thus, repeated drug users experience two activations of dopaminergic neurotransmission, one upon exposure to the conditioned stimuli signaling the drug and another upon taking the drug. This may lead to long-term neurobiological changes that contribute to withdrawal and addiction. Withdrawal can be remediated by abstinence but this does not reduce the conditioned incentive value of cues associated with drug taking; those cues can lead to relapse. Effective treatment will include detoxification and systematic exposure to drug taking-associated conditioned incentive stimuli in the absence of drug so that those stimuli lose their ability to control responses.

Dopamine receptor subtypes and incentive learning

Dopamine receptor subtypes and incentive learning explains that dopamine receptors are G protein-coupled and form two families: D1-like receptors, including D1 and D5, stimulate adenylyl cyclase and cyclic adenosine monophosphate (cAMP); D2-like receptors, including D2, D3, and D4, inhibit cAMP. Antipsychotic medications are dopamine receptor antagonists and their clinical potency is strongly correlated with blockade of D2 receptors, implicating overactivity of D2 receptors in psychosis in schizophrenia. D1- and D2-like receptors appear to be involved in unconditioned locomotor activity and incentive learning. D1-like receptors are implicated more strongly in incentive learning and D2-like receptors more strongly in locomotion. D3 receptors may play a relatively greater role in expression than acquisition of incentive learning. Dopamine receptor subtypes form heteromers with each other and with the receptors of other neurotransmitters (e.g., glutamate, adenosine, ghrelin) and the signaling properties of these heteromers can differ from those of either receptor in isolation.