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Principal Investigator: Nicholas W Simon
Organization: UNIVERSITY OF MEMPHIS
Fiscal Year: 2024
Award: $173,417
Funding agency: National Institute on Drug Abuse
Abstract
A fundamental characteristic of substance use disorder (SUD) is ongoing drug seeking and misuse despite
physical, financial, and legal consequences. Critically, aversive consequences following a substantial delay,
such as withdrawal after substance use, are often underestimated. Despite the common occurrence of delayed
punishment, cost/benefit decision-making research has focused almost entirely on punishment occurring
immediately after a choice. To address this gap, we developed the Delayed Punishment Decision-making Task
(DPDT), which reveals that rats, like humans, underestimate or “discount” the negative value of delayed
punishment during decision-making. Preliminary data obtained using DPDT reveal that orbitofrontal cortex
(OFC) inactivation increases sensitivity to delayed punishment, and OFC encodes information about
punishment delay prior to choice. While these data suggest a role of OFC in the assessment of delayed
punishment, the mechanism underlying this process remains unclear. OFC activity is sculpted by
catecholaminergic projections from distinct midbrain nuclei, specifically dopaminergic projections from the
ventral tegmental area (VTA) and noradrenergic projections from the locus coeruleus (LC). Our central
hypothesis is that sensitivity to delayed punishment is modulated by dopamine and norepinephrine projections
to OFC, with dopamine release from neurons arising from VTA affecting the discounting of delayed
punishment, and noradrenergic neurons from LC regulating sensitivity to punishment regardless of delay. We
will evaluate this using DREADDS for both circuit and cell-type specific manipulation of neural activity in LC or
VTA neurons projecting to OFC during DPDT. In Aim 1, we will use infuse inhibitory or excitatory DREADDS
into the VTA of TH-Cre rats, then directly stimulate these receptors in the OFC terminals prior to DPDT. This
will enable selective modulation of dopamine release in OFC. For Aim 2, we will infuse excitatory or inhibitory
DREADDS into LC, then stimulate these receptors in OFC prior to DPDT. For all manipulations in both Aims,
we will perform control experiments to confirm that manipulations are affecting sensitivity to immediate or
delayed punishment rather than pain tolerance, reward discrimination, or behavioral flexibility. Collectively,
these studies will determine a potential mechanism for how the OFC regulates sensitivity to both delayed and
immediate punishment. Moreover, these experiments will determine if direct manipulation of two understudied
neuronal circuits has efficacy as a potential treatment to improve sensitivity to delayed consequences in SUD.
Terms: <Address><Affect><Agonist><Aversive Stimulus><Behavioral><Biological><Brain><Brain Nervous System><Catecholamines><Cell Nucleus><Characteristics><Clozapine><Cognition><Cognitive Discrimination><Common Rat Strains><Costs and Benefits><DA Neuron><DREADDs><Data><Decision Making><Discrimination><Dopamine><Dopamine Receptor><Dopamine neuron><Drugs><Economics><Encephalon><Evaluation><Goals><Human><Hydroxytyramine><Infusion><Infusion procedures><Intervention><Intervention Strategies><Investigation><Legal><Levarterenol><Levonorepinephrine><Locus Coeruleus><Mediating><Medication><Mesencephalon><Mid-brain><Midbrain><Midbrain structure><Modern Man><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Neurotransmitters><Noradrenaline><Norepinephrine><Nucleus><Nucleus Pigmentosus Pontis><Outcome><Oxides><Pain Threshold><Pain Tolerance Level><Pharmaceutical Preparations><Prevalence><Process><Punishment><Rat><Rats Mammals><Rattus><Receptor Activation><Receptor Protein><Regulation><Research><Rewards><Role><Substance Use Disorder><Sympathins><System><Time><Training><Tyrosine 3-Monooxygenase><Tyrosine Hydroxylase><Ventral Tegmental Area><Withdrawal><addiction><addictive disorder><biologic><blue nucleus><cell type><designer receptors exclusively activated by designer drugs><discount><discounting><dopaminergic neuron><drug/agent><economic><experiment><experimental research><experimental study><experiments><flexibility><flexible><genetic approach><genetic strategy><improved><infusions><insight><interventional strategy><locus ceruleus structure><neural><neural mechanism><neurobiological><neuromechanism><neuronal><neuronal circuit><neuronal circuitry><noradrenergic><novel><pain tolerance><pharmacologic><receptor><social role><substance use><substance use and disorder><substance using><ventral tegmentum>