Regular PapersNeuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze
Introduction
Neuropeptide Y (NPY) seems to play a role in mediating the adaptive response of animals to fear-provoking stimuli. NPY has been shown to produce changes in emotional responsiveness to stressful stimuli similar to those observed with benzodiazepines and ethanol. Central administration of NPY produces anxiolytic-like behavioral responses in the conflict test [23], [24], elevated plus maze [7], [25] and fear-potentiated startle paradigm [7], [50]. Like benzodiazepines, NPY produces sedation at high doses [14], [47] and diminishes central nervous system excitability consistent with an anticonvulsant action [10], [13], [42], [54]. Exogenously administered NPY also protects against corticotropin-releasing factor (CRF)- and stress-induced colonic motility disturbances [18], [31] and gastric erosions induced by stress [22]. NPY has a role in the regulation of several hypothalamic functions including food intake and energy balance, glucose regulation, and control of pituitary hormone secretion (e.g. [51]). Increased plasma levels of immunoreactive NPY are found after exposure to a variety of aversive stimuli [8], [9], [34], [39], [52]. Conversely, animals depleted of NPY display behavior consistent with increased fear or stress [49]. The mechanism of action for the benzodiazepine-like behavioral effects of NPY in animal models of anxiety is unknown.
Previous work has established that CRF plays an important role in behavioral responsiveness to stressful stimuli, producing behavioral and physiological states resembling fear or stress. Central administration of CRF produces behavioral changes consistent with enhanced emotionality in a number of behavioral paradigms including the conflict test [3], elevated plus maze [2], and acoustic startle paradigm [43], [44]. Central administration of CRF antagonists blocks many of the behavioral effects of stress [32], [33], [37], [44]. These behavioral effects of CRF, in conjunction with its physiological, endocrine and sympathoadrenomedullary activating effects, have led to the hypothesis that CRF may have a causal role in behavioral responses to stressful stimuli.
A potential interplay of NPY and CRF has been suggested by several investigators [19], [26], [29], [38], [47]. The purpose of the current investigation was to investigate whether CRF and NPY exert a reciprocal regulation on responsiveness to stressful stimuli, addressing the hypothesis that endogenous NPY systems are important neurochemical modulators of the ‘stress-like’ and proconflict actions of CRF observed in two animal models of anxiety, an operant conflict test and the elevated plus maze.
Section snippets
Subjects
All animal care was conducted in accord with IACUC guidelines. Male Wistar rats (Charles River) weighing 300–400g at the start of the experiment were housed three per cage in a temperature- and light-controlled environment on a 12-h light : dark cycle with free access to water. For operant training, rats were maintained on 15 to 18 g of food per day in addition to that obtained during testing. Under this regimen, the rats were effectively meal-deprived, but gained weight steadily during the
Dose-response of NPY and CRF in the conflict test
The effect of NPY (veh, 1.0, 2.0, 4.0, and 8.0 μg/rat, i.c.v.) on responding in the conflict test is shown in Fig. 1A. A 15-min pretreatment with NPY significantly increased responding in the conflict (punished) component of the operant conflict paradigm (F4,30 = 6.72, P < 0.05). No significant effects were observed in the random interval (unpunished) reinforcement component of the conflict test (F4,30 = 2.41, n.s.).
Consistent with our previous results [3], [4], [5], CRF (veh, 0.25, 0.50, 0.75
Discussion
The results of this study confirm our previous findings [24], [25] that NPY produces an anxiolytic-like action, and CRF an anxiogenic-like action [3], [4], [5], in both the operant incremental shock conflict and elevated plus maze paradigms. NPY antagonized the response suppressant action of CRF in the conflict test at doses as low as 2 μg of NPY, i.c.v., a threshold dose for intrinsic behavioral activity in this conflict paradigm. The CRF antagonist D-Phe12–41 produced no discernible intrinsic
Acknowledgements
This work was supported by a VA Merit Review (KTB).
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2018, NeuroscienceCitation Excerpt :The present study suggests that NPY is an additional component involved in the pre-synaptic regulation of CRF afferents in the LC. It has been previously proposed that NPY can counteract the stress promoting effects of CRF (Heilig et al., 1994; Heilig, 2004; Sajdyk et al., 2004; Palkovits, 2008; Thorsell, 2010), and administration of NPY in the BLA reduces anxiety and blocks the anxiogenic effect of CRFr1/r2 activation (Britton et al., 2000; Sajdyk et al., 2006). Furthermore, the LC is known to receive NPY afferents from the arcuate nucleus and from other regions, but importantly also synthesizes NPY and directs it to terminal regions (Everitt et al., 1984; Smialowska, 1988; Yoon et al., 2013).
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2015, Neurobiology of StressCitation Excerpt :For example, central administration of exogenous NPY has demonstrated anxiolytic properties in rodents and is capable of inhibiting the anxiogenic effects of CRF (Primeaux et al., 2005; Ehlers et al., 1997; Britton et al., 1997). In addition, stress-sensitive brain regions such as the locus coeruleus (LC) (Makino et al., 2000), the amygdala (Adrian et al., 1983), and the paraventricular nucleus (Baker and Herkenham, 1995) all highly express both neuropeptides and NPY is reported to oppose the effects of CRF in these regions (Britton et al., 2000; Heilig et al., 1994). One example occurs in the LC, where CRF serves as an excitatory neurotransmitter (Valentino et al., 1983) and NPY decreases the LC-noradrenergic neuronal firing (Illes et al., 1993).