Dissecting the role of dopamine in brain stimulation reward: neuroeconomic, pharmacological, and optogenetic studies

Dopamine (DA) is critical for reward-seeking. However, its specific role in reward has remained elusive. In the Intracranial Self-Stimulation (ICSS) paradigms, animals are trained to perform operant tasks to deliver trains of electrical or optical pulses to reward-related brain regions. The tight experimental control attainable by these paradigms makes them suitable for psychophysical and computational studies aiming at understanding how specific neural circuits and signals mediate reward seeking. However, common measurement methods in ICSS studies fail to distinguish between effects arising at different stages of reward processing. The reward-mountain model links the effects of experimental manipulations to specific stages of neural processing. I used the reward-mountain model to distinguish between variables affecting the integration of reward intensity and other factors that influence ICSS. I administered a DA reuptake blocker or a DA receptor antagonist to animals working for electrical stimulation of the Medial Forebrain Bundle (MFB). The results show that DA signaling affects ICSS at a stage beyond the computation of reward intensity by modulating reward gain, costs, or the value of competing activities. Optogenetics allows for direct optical stimulation of specific neural subtypes with tight temporal control. I present a technical development that proved critical in running long experimental sessions with rats. I used optogenetics to bypass the inputs to midbrain-DA neurons. I adapted the reward-mountain paradigm to rats working for optical stimulation of midbrain-DA neurons, allowing me to further dissect the role of DA in reward seeking. In these animals, DA reuptake blockade affected the integration of reward intensity. This contrasts with the effects produced by the same drug in rats working for electrical ICSS (eICSS). The drug also affected reward gain, cost, or the value of competing activities. Overall, the results show that eICSS and optical ICSS (oICSS) recruit the reward system at different stages of neural processing. In eICSS, DA signaling affects reward-seeking at a stage beyond the computation of reward intensity, whereas in oICSS of midbrain-DA neurons, reward intensity is determined by a second reward-integrator downstream from the one that determines the reward intensity in eICSS

Uncovering the attenuating effects of cannabinoid receptor blockade on the persuit of brain stimulation reward

Multiple lines of evidence suggest that blockade of CBI receptors reduces reward-seeking. However, the reported effects of CBI blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we provide evidence consistent with reward-attenuating effects of cannabinoid receptor blockade: AM-2SI, a CBI receptor antagonist, decreases the willingness of rats to pay for medial forebrain bundle stimulation. This analysis clarifies inconsistencies between prior reports, which likely arose from: a) the averaging of data across subjects showing heterogeneous effects and b) the use of methods that cannot distinguish changes in the sensitivity of the reward substrate from changes in reward-substrate gain, reward costs and the value of competing activities such as grooming, resting, and exploring. The results link endocannabinoids to the roles of the latter three factors in reward seeking rather than to the modulation of reward sensitivity

Video illustrating the reward-mountain model

This video reveals a fundamental source of ambiguity in two-dimensional measurements of operant performance for reward, such as those obtained in the curve-shift and progressive-ratio paradigms. We show how the three-dimensional portrayal provided by the reward-mountain model resolves this ambiguity

A new view of the effect of dopamine receptor antagonism on operant performance for rewarding brain stimulation in the rat

RATIONALE:Previous studies of neuroleptic challenges to intracranial self-stimulation (ICSS) employed two-dimensional (2D) measurements (curve shifts). Results so obtained are ambiguous with regard to the stage of neural processing at which the drug produces its performance-altering effect. We substituted a three-dimensional (3D) method that measures reward-seeking as a function of both the strength and cost of reward. This method reveals whether changes in reward seeking are due to drug action prior to the output of the circuitry that performs spatiotemporal integration of the stimulation-induced neural activity. OBJECTIVES:The aim of this study was to obtain new information about the stage of neural processing at which pimozide acts to alter pursuit of brain stimulation reward (BSR). METHODS:Following treatment with pimozide (0.1 mg/kg) or its vehicle, the proportion of trial time allocated to working for BSR was measured as a function of pulse frequency and opportunity cost. A surface defined by Shizgal's reward-mountain model was fitted to the drug and vehicle data. RESULTS:Pimozide lowered the cost required to decrease performance for a maximal BSR to half its maximal level but did not alter the pulse-frequency required to produce a reward of half-maximal intensity. CONCLUSIONS:Like indirect dopamine agonists, pimozide does not alter the sensitivity of brain reward circuity but changes reward-syste

Role of dopamine tone in the pursuit of brain stimulation reward

Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but it is not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909, a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be due to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain. Video: The video reveals a fundamental source of ambiguity in two-dimensional measurements of operant performance for reward, such as those obtained in the curveshift and progressive-ratio paradigms. We show how the three-dimensional portrayal provided by the reward-mountain model resolves this ambiguity. The reward-mountain model is derived, described, discussed, and applied in the following papers: • Arvanitogiannis A, & Shizgal P (2008). The reinforcement mountain: allocation of behavior as a function of the rate and intensity of rewarding brain stimulation. Behav Neurosci 122:1126-1138. doi: 10.1037/a0012679 http://psycnet.apa.org/journals/bne/122/5/1126/ • Hernandez G, Breton YA, Conover K, & Shizgal P (2010). At what stage of neural processing does cocaine act to boost pursuit of rewards? PLoS One 5:e15081. doi: 10.1371/journal.pone.0015081 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015081 • Shizgal, P, & Hernandez, G (2010). Intracranial Self-Stimulation. Encyclopedia of Psychopharmacology, 653–660. doi:10.1007/978-3-540-68706-1_66 http://www.springerlink.com/content/w37074k2586301j6/?MUD=MP • Trujillo-Pisanty I, Hernandez G, Moreau-Debord I, Cossette MP, Conover K, Cheer JF, & Shizgal P (2011). Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation. J Neurosci 31:5426-5435. http://www.jneurosci.org/content/31/14/5426.long • Shizgal, P. (2012). Scarce means with alternative uses: Robbins' definition of economics and its extension to the behavioral and neurobiological study of animal decision making. Frontiers in Neuroscience, 6, 20. doi:10.3389/fnins.2012.00020 http://www.frontiersin.org/Decision_Neuroscience/10.3389/fnins.2012.00020/abstract • Hernandez, G., Trujillo-Pisanty, I., Cossette, M-P., Conover, K., & Shizgal, P. (2012). Role of dopamine tone in the pursuit of brain stimulation reward. Journal of Neuroscience, 2012, in press

Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation

There is ample evidence that blockade of CB1 receptors reduces reward seeking. However, the reported effects of CB1 blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB1 receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward-seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB1 receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from: a) the averaging of data across subjects showing heterogeneous effects and b) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB1 receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward

Robust optical fiber patch-cords for in vivo optogenetic experiments in rats

In vivo optogenetic experiments commonly employ long lengths of optical fiber to connect the light source (commonly a laser) to the optical fiber implants in the brain. Commercially available patch cords are expensive and break easily. Researchers have developed methods to build these cables in house for in vivo experiments with rodents [1–4]. However, the half-life of those patch cords is greatly reduced when they are used with behaving rats, which are strong enough to break the delicate cable tip and to bite through the optical fiber and furcation tubing. Based on [3] we have strengthened the patch-cord tip that connects to the optical implant, and we have incorporated multiple layers of shielding to produce more robust and resistant cladding. Here, we illustrate how to build these patch cords with FC or M3 connectors. However, the design can be adapted for use with other common optical-fiber connectors. We have saved time and money by using this design in our optical self-stimulation experiments with rats, which are commonly several months long and last four to eleven hours per session. The main advantages are: • Long half-life. • Resistant to moderate rodent bites. • Suitable for long in vivo optogenetic experiments with large rodents

Raw data for Trujillo-Pisanty, I., Conover, K., Solis, P., Palacios, D., & Shizgal, P. Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward. PLOS ONE, 2020, in press

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards

Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward.

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards