Research reportAn examination of the effects of subthalamic nucleus inhibition or μ-opioid receptor stimulation on food-directed motivation in the non-deprived rat
Highlights
► The subthalamic nucleus (STN) regulates movement, cognition, and motivation. ► We tested STN inhibition or μ-opioid stimulation on food motivation in free-fed rats. ► STN inhibition did not affect palatable feeding, progressive ratio, or DRL responding. ► STN μ-opioid receptor stimulation increased food intake and impaired DRL performance.
Introduction
The subthalamic nucleus (STN) is a central node of basal ganglia circuitry that has garnered much attention for its role in Parkinson's disease. Neural activity within the STN increases following the death of the midbrain dopaminergic neurons that causes the movement disorder (for reviews of STN function in human and animal models of Parkinson's disease, see [1], [2]). Deep brain stimulation of the STN (which is thought to functionally inhibit STN output) reduces the motor symptoms of Parkinson's disease patients, often substantially improving function for as long as five years [3]. Although initially viewed as an exclusively motor-related structure, converging evidence from both animal and human studies suggests that the STN also regulates cognitive and motivational functions. Recordings from the rat, cat, and monkey demonstrate that STN neurons encode movements, task-relevant stimuli, and reward presentation [4], [5], [6], [7]. In humans, deep brain stimulation of the STN improves motor function in Parkinson's disease patients, but has also been shown to cause mild to moderate impairments of performance on cognitive tasks such as verbal fluency, attention, and working memory [2], [8], [9], [10], [11]. Other reported side effects of STN stimulation include depression and weight gain [2], [12]. Likewise, STN lesions or inactivation in rodents reverses spontaneous striatal glutamate output [13] and improves motor dysfunction that is caused by 6-hydroxydopamine-induced lesions of the dopamine inputs into striatum [14], [15], [16]. However, despite improved locomotor function in this rodent model of Parkinsonism, dopamine-depleted rats treated with lesions or inactivation of the STN also show alterations in goal-directed behavior, such as premature responding in tasks that require the animals to withhold responding or attend to a delay prior to the initiation of a response [14], [15], [16], [17].
That manipulations of the STN affect mood, motivation, and/or reward processes is consistent with its anatomical connections with the limbic components of basal ganglia circuitry. The STN has been traditionally viewed as an important node within the “indirect” motor pathway of the basal ganglia (which regulates motor and limbic function), and its firing properties and functional output is influenced by mesolimbic dopamine afferents [18], [19], [20]. Recent evidence suggests that the STN may also affect basal ganglia function via a “hyperdirect” pathway, in which the STN receives input from frontal cortices and subsequently projects to the functional output of the striatum, the globus pallidus [21], [22]. Thus, the STN influences neural processing across basal ganglia dopaminergic-ventral striatum-pallidal circuits, all of which have been identified as critical regions for learning about and directing behavior toward motivationally-relevant stimuli, such as natural rewards or drugs of abuse [23], [24], [25], [26].
Recent research has begun to examine the behavioral role that the STN plays in regulating motivated behavior. Consistent with the effects of lesions in Parkisonian rat models, STN lesion or inactivation in otherwise intact rats reduces response inhibition and increases impulsive behavior in hungry animals trained to nose-poke or lever-press for food reinforcement. Specifically, STN lesions have been argued to cause deficits in response inhibition and attentional processing [27], [28], and may additionally affect the motivational salience of food rewards and/or the cues that predict reward [8], [29], [30], [31]. Previous research has demonstrated that lesions, pharmacological inhibition, or deep brain stimulation of the rat STN increases the effort that food-deprived rats will expend to earn food reinforcement [8], [29], [30], [31]. This pattern of data suggests that the STN may play an important role in regulating the incentive salience of food rewards. Interestingly, similar treatments appear to reduce the effort that rats will expend to self-administer cocaine [32], [33], suggesting that STN manipulations may differentially regulate the salience of natural versus drug rewards.
Also consistent with a potential role for the STN in regulating incentive motivation for food is the presence of μ-opioid receptors within the nucleus [34], [35], which have been implicated in motivational processes within other brain regions. In the interconnected basal ganglia pathways that the STN regulates, enhancement of both “wanting” of palatable foods (as measured by food intake) and the “liking” of palatable solutions (as measured by orofacial hedonic responses) result from the stimulation of local μ-opioid receptors. Specifically, μ-opioid receptor stimulation of the ventral tegmentum [36], [37], [38], nucleus accumbens [39], and ventral pallidum [40] all increase feeding, and specific zones within the nucleus accumbens and ventral pallidum appear to modulate the “liking” of palatable solutions [40], [41]. To our knowledge, there have been no studies examining whether opioid receptors of the STN might serve a similar function.
The purpose of the current experiments was two-fold. First, in most prior reports in which rats were shown to have increased incentive motivation for food following STN lesions or inhibition, the animals were tested in a food deprived state. This makes it difficult to determine if the resulting behavioral patterns were due to a general increase of motivational processes caused directly by STN manipulation (which should be evident even in ad libitum fed animals), or were rather due to an effect of STN manipulation exaggerating the normal increase in incentive processes when the animal is in a state of caloric need. Thus, these experiments examined the effects of STN manipulations in non-deprived rats. The first aim was to determine if appetitive or consummatory motivation toward palatable food was enhanced by pharmacological inhibition of the STN in rats that were not food deprived. Secondly, as μ-opioid receptors are heavily expressed in the STN, and are furthermore found throughout ascending pathways that sense and regulate food intake, it was of interest to determine whether μ-opioid receptors within the STN might regulate food intake and appetitive motivation similar to that seen in other nodes of basal ganglia circuitry. Individual groups of rats were given 2-h daily exposure to a palatable sweetened fat diet (Experiments 1 and 2), were trained to lever press on a progressive ratio 2 (PR-2) schedule of reinforcement for sugar reward (Experiment 3), or were trained on a differential reinforcement of low rate of responding task (DRL-20 s; Experiment 4). Once non-deprived rats stabilized their consumption or performance of the operant task, they were tested following STN infusions of the GABAA receptor agonist muscimol or with the μ-opioid receptor agonist DAMGO.
Section snippets
Subjects and housing
Adult male Sprague-Dawley rats (approximately 300 g at experiment onset; Harlan, Madison, WI) were acclimated to dual housing in a colony room maintained at ∼21 °C with a 12-h light–dark cycle. Standard rat chow and water were available ad libitum except as noted below during operant training. All procedures were conducted in accordance to NIH animal care guidelines and approved by the Wake Forest University Animal Care and Use Committee.
Surgery
Following approximately 1-wk acclimation to the housing
Experiment 1
Food intake was analyzed utilizing two-way repeated measures analysis of variance (ANOVA) comparing the amount of palatable diet consumed (in grams) as a function of drug dose and time within each 2 h session (with intake quantified at 5 min intervals). Total ambulation, rearing, water intake, and head entry measures were summed across the entire feeding session and analyzed using repeated measures ANOVAs with drug dose as the independent variable.
As can be seen in the top panels of Fig. 2,
Discussion
The goal of these experiments was to examine the effects of STN inactivation or μ-opioid receptor stimulation upon palatable feeding, progressive ratio performance, and impulsive-like behavior as measured in the DRL-20 s schedule of reinforcement in rats that were not food restricted. Although muscimol injections into the STN increased locomotor activity at the highest dose tested, there were no effects of STN inhibition on the amount of palatable diet consumed in a 2-h feeding session, the
Acknowledgments
This work was supported by the Wake Forest University Department of Psychology and by the National Institute of Drug Abuse (R15 DA030618). We would like to thank Dr. Matthew E. Andrzejewski for graciously providing the Med PC script for the operant behavioral paradigms. Emilia Brown and Brianna Lukasevics provided technical support for some aspects of these experiments. The examination of cannula placements and the taking of photomicrographs was supported by the Wake Forest University
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