Role of ghrelin in drug abuse and reward-relevant behaviors: a burgeoning field and gaps in the literature.

Ghrelin is a gut-brain hormone that regulates energy balance through food consumption. While ghrelin is well known for its role in hypothalamic activation and homeostatic feeding, more recent evidence suggests that ghrelin also is involved in hedonic feeding through the dopaminergic reward pathway. This paper investigated how ghrelin administration (intraperitoneal, intracerebroventricular, or directly into dopaminergic reward-relevant brain regions) activates the dopaminergic reward pathway and associated reward-relevant behavioral responses in rodents. A total of 19 empirical publications that examined one or more of these variables were included in this review. Overall, ghrelin administration increases dopamine levels in the nucleus accumbens, as well as reward-relevant behaviors such as food (both standard chow and palatable foods) and alcohol consumption. Ghrelin administration also increases operant responding for sucrose, and conditioned place preference. Following a review of the small body of literature examining the effects of ghrelin administration on the dopamine reward pathway, we present a model of the relationship between ghrelin and dopaminergic reward activation. Specifically, ghrelin acts on ghrelin receptors (GHS-R1A) in the ventral tegmental area (VTA) and lateral dorsal tegmental nucleus (LDTg) to stimulate the mesolimbic dopamine reward pathway, which results in increased rewarding behaviors in rodents. Results from this review suggest that selective antagonism of the ghrelin system may serve as potential treatment for addictive drug use. This review highlights gaps in the literature, including a lack of examination of sex- or age-related differences in the effects of ghrelin on dopamine reward processes. In light of vulnerability to drug abuse among female and adolescent populations, future studies should target these individual difference factors.

Effects of adolescent nicotine exposure on opioid consumption and neuroendocrine responses in adult male and female rats.

Effects of adolescent nicotine exposure on illicit drug consumption and neuroendocrine functioning were examined in adult rats. Nicotine (NIC; 2 doses) or saline (SAL) was administered via osmotic minipumps to 30 male and 30 female adolescent Wistar rats for 19 days. After NIC/SAL cessation, oral opioid consumption was assessed in the home cage for 4 weeks. Plasma corticosterone and ACTH were measured at the end of the experiment. Low-NIC male rats consumed more fentanyl than did high-NIC male rats; opioid consumption among adult female rats was not altered by NIC exposure. Females consumed more fentanyl than did males, regardless of NIC history. NIC exposure increased adult corticosterone and ACTH levels in a dose-dependent manner. Results suggest important effects of adolescent NIC exposure, including altered neuroendocrine status and opioid consumption.

Appraised control, coping, and stress in a community sample: a test of the goodness-of-fit hypothesis.

Lazarus and Folkman proposed one of the most comprehensive theories of stress and coping in the psychology literature, but many of their postulates have received little empirical attention, and some of the existing research hasyielded contradictory findings. This longitudinal study sought to clarify the associations among control appraisal, coping, and stress within this theoreticalframework. The theory postulates that coping strategies used tend to match the level of appraised controllability of the stressor (matching hypothesis). It further states that the effects of problem-focused versus emotion-focused coping are moderated by the appraised controllability of the stressor (goodness-of-fit hypothesis). An alternative to the latter is the main-effects hypothesis, which states that problem-focused coping is generally more effective in reducing distress regardless of appraisal. These hypotheses were tested on 72 adults who completed questionnaires on coping and control appraisal. Stress was assessed using self-report (Symptom Checklist-90-Revised) and a behavioral measure (proofreading task) at two times approximately 2 months apart. Appraised control significantly predicted type of coping such that greater control was associated with more problem-focused and less emotion-focused coping. Although the main-effects hypothesis was not supported, the goodness-of-fit hypothesis was partly confirmed by a significant control by emotion-focused coping interaction predicting both self-report and behavioral measures of stress.

Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight.

The human stress response has been characterized, both physiologically and behaviorally, as "fight-or-flight." Although fight-or-flight may characterize the primary physiological responses to stress for both males and females, we propose that, behaviorally, females' responses are more marked by a pattern of "tend-and-befriend." Tending involves nurturant activities designed to protect the self and offspring that promote safety and reduce distress; befriending is the creation and maintenance of social networks that may aid in this process. The biobehavioral mechanism that underlies the tend-and-befriend pattern appears to draw on the attachment-caregiving system, and neuroendocrine evidence from animal and human studies suggests that oxytocin, in conjunction with female reproductive hormones and endogenous opioid peptide mechanisms, may be at its core. This previously unexplored stress regulatory system has manifold implications for the study of stress.

Sex differences in effects of opioid blockade on stress-induced freezing behavior.

The present experiment examined the effects of naloxone on freezing behavior in male and female rats following stress and no-stress conditions. Twelve male and 12 female Wistar rats were exposed to 10 min of mild, unpredictable footshock stress and to a comparable no-stress condition. Immediately following stress or no-stress conditions, subjects were injected with naloxone or saline, and two independent observers measured freezing behavior. In male rats, naloxone potentiated freezing following stress but had no effect on freezing following no-stress. In females, naloxone did not affect freezing regardless of stress conditions. These results reveal a sex difference in effects of naloxone on freezing behavior and suggest that sex differences may exist with respect to the role of endogenous opioids under stress.

Posttranscriptional upregulation of Na(+)-K(+)-ATPase activity in newborn guinea pig renal cortex.

We measured Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity and subunit abundance in renal cortical homogenates and basolateral membranes (BLM) from fetal, newborn, and adult guinea pigs. Pump specific activity increased four- to fivefold in cortical homogenates and BLM during the transition from fetus to newborn. Immunoblots of BLM showed that alpha- and beta-subunit abundance increased four- to seven- and fourfold, respectively, during the transition from fetus to newborn. Immunoblots of cortical homogenates revealed similar developmental patterns, with newborns having 3.5-fold (alpha) and 2.3-fold (beta) greater subunit abundances than fetuses. Therefore, the bulk of the postnatal increase in BLM-Na(+)-K(+)-ATPase abundance resulted from increased pump production or decreased pump degradation, rather than from redistribution of pumps from intracellular pools. Despite the developmental increase in alpha- and beta-subunit protein levels, newborn guinea pig kidneys had only 1.4- to 2.1-fold greater alpha 1-subunit mRNA abundance and only a 1.5-fold greater beta 1-subunit mRNA abundance than fetal kidneys. These results demonstrate large increases in renal cortical Na(+)-K(+)-ATPase specific activity and protein abundance immediately after birth. These increases, which appear to result largely from posttranscriptional upregulation, may play an important role in mediating the rapid postnatal increase in tubular NaCl reabsorption.

Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats.

An operant conditioning paradigm was used to examine effects of predictable and unpredictable footshock on oral fentanyl (50 micrograms/ml self-administration (SA) in 12 female and 12 male Wistar rats (Rattus norvegicus). Rats were tested for drug SA under a progressive ratio schedule with and without repeated predictable or unpredictable footshock over 8 weeks. Female rats consumed greater amounts of fentanyl than did male rats. Male rats exhibited greater withdrawal behaviors following naloxone challenge. Predictable footshock with repeated exposure (i.e., chronic stress) was accompanied by greater fentanyl SA than was unpredictable footshock, particularly for female rats. Corticosterone levels were positively correlated with fentanyl SA. Predictability of the stressor also had a greater effect on maintenance of fentanyl SA than it did on relapse to fentanyl SA. Results suggest that sex plays an important role in drug-taking behavior by rats.

Effect of stress on oral fentanyl consumption in rats in an operant self-administration paradigm.

The effect of intermittent footshock stress (0.8 mA; 0.2 s on; 40 s off on the average; for 10 min/day) on oral fentanyl (50 or 75 micrograms/ml) self-administration (SA) in operant chambers was examined in male rats. In Experiment 1, after 1 month of initiation of the fentanyl SA by partial water deprivation, animals were tested for lever-pressing for fentanyl (75 micrograms/ml) under fixed-ratio-4 (FR-4) and progressive-ratio (PR) schedules of reinforcement for 30 min/day in operant chambers. Exposure to footshock stress increased fentanyl SA under the FR-4 and PR schedules compared with a nonstress condition. When water was substituted for the drug, the operant behavior persisted before extinction. In Experiment 2, different rats were tested for lever-pressing for fentanyl (50 micrograms/ml) under FR-6 and PR schedules. This experiment further assessed the role of taste in the stress-induced fentanyl SA and examined the effect of increasing the schedule requirements (i.e., FR-3, 6, and 12) on lever-pressing for fentanyl. Exposure to footshock stress increased lever-pressing for oral fentanyl SA under the FR schedules of reinforcement. When a quinine solution (30 micrograms/ml), matched for bitter taste with the fentanyl solution, was substituted for the drug solution, an extinction of the drug-reinforced behavior occurred, indicating that the stress-induced oral fentanyl SA is not related to stress-induced changes in taste sensitivity. In both experiments, no significant stress effects were observed for water consumption in home cage and lever-pressing on the nonoperative lever.

Urinary iodine excretion rates following intrathecal injections of iodinated organic carbonates.

Oily iodinated organic carbonates were investigated for use as myelographic media. The urinary excretion of total iodine was used to monitor the apparent elimination rate of these compounds from the subarachnoid space. Within the chain length series of C2-C6, the decrease of elimination rates and disposition rate constants with increasing chain length was demonstrated. This observation is consistent with a dissolution rate-limited elimination model. Such a model was derived and successfully NONLIN computer fitted to the observed elimination data. The model-derived parameter of clearance from the cerebrospinal fluid through the lipid "blood-brain barrier" correlated well with the compound's water solubilities and projected octanol-water partition coefficients. Additional compounds need to be tested to evaluate the postulated model system.