Kent Conover

Prolonged rewarding stimulation of the rat medial forebrain bundle: Neurochemical and behavioral consequences.

Extracellular dopamine levels were measured in the rat nucleus accumbens by means of in vivo microdialysis. Delivery of rewarding medial forebrain bundle stimulation at a low rate (5 trains/min) produced a sustained elevation of dopamine levels, regardless of whether train onset was predictable. When the rate of train delivery was increased to 40 trains/min, dopamine levels rose rapidly during the first 40 min but then declined toward the baseline range. The rewarding impact of the stimulation was reduced following prior delivery of stimulation at the high, but not the low, rate. These results support the idea that dopamine tone plays an enabling role in brain stimulation reward and is elevated similarly by predictable and unpredictable stimulation.

Competition and summation between rewarding effects of sucrose and lateral hypothalamic stimulation in the rat.

Rats were offered a forced choice between a train of brain stimulation that varied in strength from trial to trial and a fixed standard reward. This standard reward consisted of an intraoral sucrose infusion presented either alone or paired with an equipreferred train of brain stimulation. Postingestional effects were minimized by opening a gastric cannula. The presence of a sucrose standard led the subjects to forgo trains of brain stimulation for which they had responded when the sucrose was absent. The strength of the brain stimulation required to balance the compound reward exceeded the stimulation strength required to balance a reward consisting of sucrose alone. These results imply that the rewarding effects of brain stimulation and intraoral sucrose can be evaluated in a common system of measurement and combined.

Effects of sodium depletion on competition and summation between rewarding effects of salt and lateral hypothalamic stimulation in the rat.

The effect of sodium depletion on the value of lateral hypothalamic (LH) stimulation and on competition and summation between saline reward and LH reward was assessed. Sodium depletion did not alter curves relating the number of LH rewards earned per trial to the number of stimulation pulses per train, suggesting that negative sodium balance does not alter the reward value of the stimulation. In contrast, sodium depletion increased the ability of saline (0.9% NaCl) to compete with LH stimulation in a forced-choice preference test. Summation between the effects of the 2 rewards was also seen under sodium depletion. These findings imply that the rewarding effects of saline and LH stimulation are evaluated within a common system of measurement and that negative sodium balance modulates the value of the saline reward upstream from the point where the rewarding effects of saline and LH stimulation are combined.

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

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.

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 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3- phenylpropyl]piperazine), 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-12909-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 attributable to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain.

Growth of brain stimulation reward as a function of duration and stimulation strength

The strength of a train of rewarding brain stimulation required to support a criterion level of operant performance declines hyperbolically as the duration is increased. This finding has been attributed to a process of leaky integration. However, the rate at which integration approaches asymptote has been shown to depend on stimulation strength, a finding that differs from the behavior of a simple leaky integrator. The authors replicate both findings and show that they are both well described by a new model that incorporates a hyperbolic strength-duration function, a logistic function mapping stimulation frequency onto reward intensity, and another logistic function mapping reward intensity onto performance.

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 the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) 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.

Differential effects of postingestive feedback on the reward value of sucrose and lateral hypothalamic stimulation in rats

The effects of postingestive feedback on the value of intraoral sucrose and lateral hypothalamic (LH) stimulation were compared. Rats chose between a fixed LH stimulation train or a compound reward composed of the same stimulation train and an oral infusion of 1 M sucrose. The rats preferred the compound reward when postingestive feedback was reduced by opening a gastric cannula. However, when the cannula was closed, the compound was preferred only at the beginning of each session, and preference declined or reversed as consumption continued. A second experiment showed that the reduction in preference caused by closing the gastric cannula was not due to a punishing effect of the gastrointestinal load. This study suggests that postingestive signals modulate gustatory reward at a stage of processing before gustatory and brain stimulation rewards are combined.

Employing labor-supply theory to measure the reward value of electrical brain stimulation

A model drawn from labor-supply theory is shown to provide a good account of time-allocation decisions taken by rats working for rewarding brain stimulation. The model makes it possible to infer, from behavioral data, the growth of the rewarding effect as a function of stimulation strength. Measurement of this function provides information about the stage of the reward circuitry where drugs or lesions alter the rewarding effect. The labor-supply model is used to illustrate how approaches drawn from economics, psychology, and neuroscience can inform each other. The model is linked to a set of psychological processes, including those responsible for transformation of the transient neural signal produced by the rewarding stimulation into an enduring record of payoff, estimation of a mean effort price, delay discounting, and estimation of the substitutability of work and leisure goods. All of these

The Effects of Electrical and Optical Stimulation of Midbrain Dopaminergic Neurons on Rat 50-kHz Ultrasonic Vocalizations

Rationale: Adult rats emit ultrasonic vocalizations (USVs) at around 50-kHz; these commonly occur in contexts that putatively engender positive affect. While several reports indicate that dopaminergic (DAergic) transmission plays a role in the emission of 50-kHz calls, the pharmacological evidence is mixed. Different modes of dopamine (DA) release (i.e., tonic and phasic) could potentially explain this discrepancy. Objective: To investigate the potential role of phasic DA release in 50-kHz call emission. Methods: In Experiment 1, USVs were recorded in adult male rats following unexpected electrical stimulation of the medial forebrain bundle (MFB). In parallel, phasic DA release in the nucleus accumbens (NAcc) was recorded using fast-scan cyclic voltammetry. In Experiment 2, USVs were recorded following response-contingent or non-contingent optogenetic stimulation of midbrain DAergic neurons. Four 20-s schedules of optogenetic stimulation were used: fixed-interval, fixed-time, variable-interval, and variable-time. Results: Brief electrical stimulation of the MFB increased both 50-kHz call rate and phasic DA release in the NAcc. During optogenetic stimulation sessions, rats initially called at a high rate comparable to that observed following reinforcers such as psychostimulants. Although optogenetic stimulation maintained reinforced responding throughout the 2-h session, the call rate declined to near zero within the first 30 min. The trill call subtype predominated following both electrical and optical stimulation. Conclusion: The occurrence of electrically-evoked 50-kHz calls, time-locked to phasic DA (Experiment 1), provides correlational evidence supporting a role for phasic DA in USV production. However, in Experiment 2, the temporal dissociation between calling and optogenetic stimulation of midbrain DAergic neurons suggests that phasic mesolimbic DA release is not sufficient to produce 50-kHz calls. The emission of the trill subtype of 50-kHz calls potentially provides a marker distinguishing positive affect from positive reinforcement.