Opioid modulation of taste hedonics within the ventral striatum.

There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity.

Acute stress-induced increases in thalamic CRH mRNA are blocked by repeated stress exposure.

Corticotropin-releasing hormone (CRH) coordinates multiple aspects of the stress response. Recently, CRH mRNA has been identified in two regions of the thalamus: the posterior nuclear group (Po), and a region located at the interface of the central medial and ventral posteromedial nucleus (parvicellular part) (CM-VPMpc). Previous studies demonstrated that in both regions CRH mRNA increases following 1 h of restraint stress, suggesting involvement of thalamic CRH in processing somatosensory and visceral information related to stress. The current study was proposed to further understand the effects of repeated and acute restraint stress on levels of thalamic CRH mRNA. Adult male rats were assigned to one of four groups in a 2 (repeated stress, no repeated) x2 (acute, no acute) design. Brain sections were processed for CRH mRNA in situ hybridization. ANOVA revealed no main effects of acute or repeated stress in either thalamic region. However, significant interactions between acute and repeated stress for levels of CRH mRNA were found for both regions of the thalamus. Compared to the no stress condition, acute restraint significantly increased CRH mRNA in the Po (39%) and the CM-VPMpc (32%). Repeated restraint did not alter baseline CRH mRNA levels, but blocked the acute restraint-induced effects. Thus, while acute stress increases levels of thalamic CRH mRNA, repeated exposure to the same stressor is without effect and prevents the acute response. These findings add to data establishing a role for thalamic CRH in the stress response and suggest a mechanism that may underlie habituation to repeated stress exposure.

Corticotropin-releasing hormone messenger RNA distribution and stress-induced activation in the thalamus.

Corticotropin-releasing hormone plays a critical role in mediating the stress response. Brain circuits hypothesized to mediate stress include the thalamus, which plays a pivotal role in distributing sensory information to cortical and subcortical structures. In situ hybridization revealed neurons containing corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group and the central medial nucleus of the thalamus, which interfaces with the ventral posteromedial nucleus (parvicellular part). These regions are of interest because they process somatosensory and visceral information. In the first experiment, the effect of acute stress on thalamic corticotropin-releasing hormone messenger RNA levels was assessed. Rats restrained for 1 h and killed 1 h later were found to have increased corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group. The time course of these changes was examined in a second experiment in which rats were killed immediately or 3 h after restraint. While no changes occurred in the thalamus immediately after restraint, 3 h after restraint, increases in corticotropin-releasing hormone messenger RNA occurred in both the posterior thalamic nuclear group and the central medial-ventral posteromedial nucleus (parvicellular part) of the thalamus. A different pattern of activation was observed in the paraventricular nucleus of the hypothalamus with increased corticotropin-releasing hormone messenger RNA immediately after restraint, but not 1 or 3 h later. In addition to the stress-induced changes, a prominent decrease in baseline thalamic corticotropin-releasing hormone messenger RNA was observed from 1000 to 1300 h. These results show that the thalamus contains corticotropin-releasing hormone messenger RNA that increases after restraint stress, indicating a role for thalamic corticotropin-releasing hormone systems in the stress response. Stress-induced changes in thalamic corticotropin-releasing hormone messenger RNA expression appears to be regulated differently than that in the paraventricular nucleus of the hypothalamus, and may be influenced by diurnal mechanisms.

Effects of acute and repeated restraint stress on corticotropin-releasing hormone binding protein mRNA in rat amygdala and dorsal hippocampus.

Corticotropin-releasing hormone (CRH) mediates endocrine, behavioral, and autonomic responses to stress. In addition to binding to two receptor subtypes, CRH binds to a CRH-binding protein (CRH-BP). While CRH-BP is hypothesized to play a role in regulating levels of free CRH and modulating the stress response, the effects of stressors on brain CRH-BP are relatively unexplored. The present study determined effects of acute and repeated restraint on CRH-BP mRNA in basolateral amygdala (BLA) and dorsal hippocampus (DH), brain regions involved in fear and motivation. Using in situ hybridization, we found that a single acute period of restraint significantly increased CRH-BP mRNA in BLA by 20% but had no effect in DH. Repeated restraint had no effect on basal levels of CRH-BP mRNA in BLA or DH. Importantly, repeated restraint blocked the effects of acute restraint in the BLA. These results demonstrate differential effects of acute and repeated restraint on CRH-BP mRNA.

A pharmacological analysis of the substrates underlying conditioned feeding induced by repeated opioid stimulation of the nucleus accumbens.

It has previously been demonstrated that stimulation of opiate receptors within the nucleus accumbens results in marked hyperphagia, perhaps reflecting enhancement of taste palatability. Rats that have received multiple morphine treatments also increase feeding in response to environmental stimuli that have been associated with the morphine injections. The present investigation further examined this phenomenon. In Experiment 1, it was shown that induction of conditioned feeding was dose-dependent; significant conditioned feeding was obtained with repeated (n = 5) intra-accumbens injections of 5 or 10 microg/microl morphine but not with saline or 1 microg. The conditioned feeding response was blocked by systemic naltrexone (5 mg/kg). In the second experiment, co-treatment with either a D-1 (SCH 23390, 0.1 mg/kg) or D-2 (haloperidol, 0.25 mg/kg) antagonist did not block the development of conditioned feeding, nor did these drugs block morphine-induced feeding. In Experiment 3, it was found that systemic naltrexone blocked the expression of conditioned feeding (confirming Experiment 1), as did SCH-23390, whereas haloperidol did not affect expression of conditioned feeding. In the fourth experiment, we observed that significant conditioned feeding was induced with repeated treatment with the selective mu agonist D-Ala2, NMe-phe4, Glyol5-enkephalin (DAMGO, 2.5 microg), but not with the delta agonist D-Pen2,5-enkephalin (DPEN, 3.1 microg). The final experiment tested the diurnal variability of the expression of conditioned feeding, and it was found that the magnitude of the effect depended on time of day. In summary, the development of opioid-induced conditioned feeding depends on mu opiate receptor stimulation, but not dopamine receptor stimulation. Its expression, however, involves both opiate and D-1 receptor activation. These findings are considered in terms of putative neural mechanisms governing conditioned meal initiation, and implications for compulsive eating and bulimia are also discussed.

Corticotropin-releasing hormone and animal models of anxiety: gene-environment interactions.

The study of the neural substrates underlying stress and anxiety has in recent years been enriched by a burgeoning pool of genetic information gathered from rodent studies. Two general approaches have been used to characterize the interaction of genetic and environmental factors in stress regulation: the evaluation of stress-related behavioral and endocrine responses in animals with targeted deletion or overexpression of specific genes and the evaluation of changes in central nervous system gene expression in response to environmental perturbations. We review recent studies that have used molecular biology and genetic engineering techniques such as in situ hybridization, transgenic animal, and antisense oligonucleotide gene-targeting methodologies to characterize the function of corticotropin-releasing hormone (CRH) system genes in stress. The effects of genetic manipulations of each element of the CRH system (CRH, its two receptors, and its binding protein) on stress-related responses are summarized. In addition, the effects of stress (acute, repeated, or developmental) on CRH system gene expression are described. The results from these studies indicate that experimentally engineered or stress-induced dysregulation of gene expression within the CRH system is associated with aberrant responses to environmental contingencies. These results are discussed in the context of how CRH system dysfunction might contribute to stress-related psychopathology and are presented in conjunction with clinical findings of CRH system dysregulation in psychiatric illness. Finally, future research strategies (i.e., high-throughput gene screening and novel gene-targeting methodologies) that may be used to gain a fuller understanding of how CRH system gene expression affects stress-related functioning are discussed.

Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats.

Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response. This phenomenon, termed prepulse inhibition (PPI), provides an operational measure of sensorimotor gating, and is deficient in schizophrenia patients. Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood. The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning). PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point. Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning). Therefore, ISO produces dissociable effects on PPI and locomotor activity, with PPI deficits emerging only during or after puberty. ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.

Alpha-1-adrenergic receptors mediate sensorimotor gating deficits produced by intracerebral dizocilpine administration in rats.

Prepulse inhibition refers to the inhibition by a weak prepulse of the startle response to an intense stimulus. Prepulse inhibition is thought to provide an operational measure of sensorimotor gating, a putative central inhibitory process by which an organism filters information from its environment. Prepulse inhibition deficits are observed in schizophrenia patients and in rats treated with psychotomimetic compounds, such as the non-competitive N-methyl-D-aspartate antagonists phencyclidine or dizocilpine maleate. In rats, phencyclidine-induced prepulse inhibition deficits are blocked by clozapine, olanzapine and quetiapine, which are multireceptor antagonists and atypical antipsychotics, or by prazosin, which is a selective alpha1-adrenergic antagonist. The dorsal hippocampus and amygdala are two of the brain regions shown to contribute to the disruption of prepulse inhibition produced by non-competitive N-methyl-D-aspartate antagonists. The present study tested the hypotheses that quetiapine or prazosin would prevent deficits in prepulse inhibition produced by dizocilpine infusion into the dorsal hippocampus or amygdala. In separate groups of rats, either quetiapine (0 or 5.0 mg/kg, s.c.) or prazosin (0 or 1.0 mg/kg, i.p.) was administered 15 min prior to bilateral infusion of dizocilpine (0 or 6.25 microg/0.5 microl/side) into either the dorsal hippocampus or amygdala. Rats were placed into startle chambers immediately after intracerebral drug infusion and prepulse inhibition was assessed. Confirming previous studies, prepulse inhibition was decreased after either intra-dorsal hippocampus or intra-amygdala infusions of dizocilpine. Both quetiapine and prazosin blocked the prepulse inhibition deficits produced by intracranial dizocilpine administration. Startle reactivity was increased by dizocilpine infusion into either region; these effects were not blocked by either quetiapine or prazosin. These results indicate that non-competitive N-methyl-D-aspartate antagonists may disrupt sensorimotor gating via actions within the dorsal hippocampus or amygdala, and that alpha1-adrenergic receptors distal to these sites might mediate this effect.

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats.

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.