At What Stage of Neural Processing Does Cocaine Act to Boost Pursuit of Rewards?

Abstract

Dopamine-containing neurons have been implicated in reward and decision making. One element of the supporting evidence is that cocaine, like other drugs that increase dopaminergic neurotransmission, powerfully potentiates reward seeking. We analyze this phenomenon from a novel perspective, introducing a new conceptual framework and new methodology for determining the stage(s) of neural processing at which drugs, lesions and physiological manipulations act to influence reward-seeking behavior. Cocaine strongly boosts the proclivity of rats to work for rewarding electrical brain stimulation. We show that the conventional conceptual framework and methods do not distinguish between three conflicting accounts of how the drug produces this effect: increased sensitivity of brain reward circuitry, increased gain, or decreased subjective reward costs. Sensitivity determines the stimulation strength required to produce a reward of a given intensity (a measure analogous to the KM of an enzyme) whereas gain determines the maximum intensity attainable (a measure analogous to the vmax of an enzyme-catalyzed reaction). To distinguish sensitivity changes from the other determinants, we measured and modeled reward seeking as a function of both stimulation strength and opportunity cost. The principal effect of cocaine was a two-fourfold increase in willingness to pay for the electrical reward, an effect consistent with increased gain or decreased subjective cost. This finding challenges the long-standing view that cocaine increases the sensitivity of brain reward circuitry. We discuss the implications of the results and the analytic approach for theories of how dopaminergic neurons and other diffuse modulatory brain systems contribute to reward pursuit, and we explore the implications of the conceptual framework for the study of natural rewards, drug reward, and mood.

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

“…In support to this possibility, Yuan et al, (2013) recently identified GluN3A mediated current in VM DA neurons and showed that GluN3A-containing NMDARs mediate DA neurons plasticity induced by cocaine reward. Alternative hypotheses are that the reduction in GluN2A receptor was not sufficient to modify the excitatory drive of glutamate or that the behavioral change was not reliably detectable by the curve-shift paradigm and some other more sensitive paradigm, like the reward-mountain paradigm (Hernandez et al, 2010) would be necessary to detect such changes. The likelihood of these hypotheses, however, is very low given that a comparable downregulation in the GluN1 receptor produced a significant reduction in reward pursuit that was readily detectable by the behavioral paradigm that we used.…”

Action, time and the basal ganglia

“…As a neuromodulator, DA cannot produce significant synaptic currents directly to produce firing. But it can change the gain of other signals, in this case the reference signal for the rate of change, which is sent via the glutamatergic projections to the striatum [55]. Reduced DA may therefore result in a reduced velocity reference signal.…”

Role of Dopamine Tone in the Pursuit of Brain Stimulation Reward

“…ICSS is typically measured in the curve-shift (Edmonds and Gallistel, 1974;Edmonds and Gallistel, 1977;Miliaressis et al, 1986) or progressive-ratio (Hodos, 1961) paradigm. It has been demonstrated recently (Arvanitogiannis and Shizgal, 2008;Hernandez et al, 2010;Trujillo-Pisanty et al, 2011) that neither method provides sufficient isolation of the different processes underlying reward seeking to distinguish between competing hypotheses concerning the variables to which dopamine neurons contribute, which include the sensitivity and gain of brain reward circuitry (Hernandez et al, 2010) and subjective effort cost (Salamone et al, 2005;Niv et al, 2007).…”

“…The ambiguity inherent in curve-shift and progressive-ratio measures is reduced by measuring ICSS as a function of both the strength and cost of reward (Arvanitogiannis and Shizgal, 2008;Hernandez et al, 2010). This method, which produces a threedimensional (3D) structure called the "reward mountain," can distinguish between changes in the sensitivity of the reward circuitry and changes in a diverse set of variables that includes reward-circuit gain, subjective effort cost, and the value of alternate activities, such as grooming, exploring, and resting.…”

“…By measuring displacement of the reward mountain by cocaine, Hernandez et al (2010) showed that some combination of changes in gain, subjective effort costs, and the value of alternate activities is responsible for the drug-induced enhancement of ICSS performance. Although that experiment achieves greater specificity at the behavioral level than previous studies using twodimensional (2D) measurement methods, the results are ambiguous at the neurochemical level because cocaine blocks the transporters for dopamine, norepinephrine, and serotonin (Iversen, 2000).…”