Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit 1 to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MD compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stem fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences.

Objectives: To identify salient dimensions and outcomes of the peer-mentoring relationship among individuals with spinal cord injury (SCI). To understand from the perspective of the mentee how the mentoring relationship differs from other supportive relationships. Study Design: Qualitative. Participants: Convenience sample of 7 mentees from a hospital-based SCI peer-mentoring project. Method. Telephone inter-views with mentees were conducted 1-4 months postdischarge, and results were coanalyzed with grounded theory methodology. Results: Mentees emphasized the impact of the mentor in terms of his or her practical, emotional, and identity-changing influence. Relationship quality was influenced by multiple factors (e.g., age, friendliness). Five components of the relationship (credibility, equitability, mutuality, acceptance, normalization) differentiated mentoring from other supportive relationships. Conclusions: Peer mentors provide a unique combination of supportive elements not replicated by other relationships. Mentoring programs are useful interventions for facilitating adjustment after SCL Recommendations for implementing a mentoring program are provided on the basis of participant suggestions.

In 2 experiments we investigated the effects of withdrawal and stress on the affective correlates of urges to smoke. In both, habitual cigarette smokers were divided into continuing and withdrawing smoker groups. In the 1st study, 44 adults reported current mood, urge, and expectations over a 24-hr period. In the 2nd, a controlled laboratory study, urge, affect, and physiological data were obtained from continuing and withdrawing groups (N = 64) exposed to high- or low-stress conditions. Urges among withdrawing smokers were positively associated with negative affect and negatively associated with positive affect; continuing smokers reported urges that were directly associated with positive affect and unrelated to negative affect. Stress and withdrawal produced urge self-reports that were related to negative affect. Moreover. subjects who smoked after exposure to withdrawal and stress reported greater pleasure and arousal than did other subjects.

Although nicotine is a drug of abuse for millions of smokers, it has been difficult to demonstrate clearly the motivational properties of nicotine with rats using the conditioned place preference (CPP) paradigm. The first experiment attempted to replicate CPPs reported by other researchers using nicotine doses of 0.4, 0.8, and 1.2 mg/kg. There was a trend for all three doses to produce aversions, but it was significant only for the 0.8 mg/kg dose. Exposures to the CS alone extinguished aversions, but a "priming" dose (0.2 mg/kg) of nicotine given after extinction produced aversions only in animals exposed to 1.2 mg/kg. Experiment 2 tested whether preexposure to morphine or nicotine would sensitize animals to nicotine's reinforcing effects. In this experiment, rats were exposed to either six nicotine (0.6 mg/kg) or morphine (1.0 mg/kg) dosings prior to preference conditioning. Neither preferences nor aversions were observed in any group following subsequent conditioning with 0.6 mg/kg nicotine. The results suggest that previous observations of preference effects may have been due to specific procedural factors or may have depended on negative reinforcement due to stress reduction.

Thirty-five male drug-free heroin addicts rated their affect, craving, and withdrawal in response to boring, anxiety-eliciting, and heroin stimuli. Results revealed that: (a) heroin cues were more effective than boring or anxiety-eliciting cues in prompting self-reports of craving or withdrawal; (b) heroin cues produced an affective state characterized by self-reported low-pleasure and high anxiety/tension; (c) craving was not correlated with any particular affective state, but rather was associated with a variety of negative affects — anxiety, depression, fatigue, anger; (d) the coherence (intercorrelations) of affective, craving, and withdrawal measures was greatest when addicts made their self-ratings immediately after exposure to drug stimuli; and (e) while addicts routinely reported craving without withdrawal sickness, they virtually never reported withdrawal sickness without reporting craving. These results suggested that the potential for negative reinforcement subserved stimulus elicited craving and that craving involved cognitive appraisal processes (attributions, expectations).

The role of corticotropin-releasing factor (CRF), an endogenous neuropeptide, in modulating species-typical responses was examined in an unfamiliar open field containing a small chamber. Rats placed in this small chamber spent most of their time withdrawn in it. However, rats given an intracerebroventricular injection (20 micrograms) of alpha-helical CRF(9-41), a CRF receptor antagonist, emerged from the chamber and explored the unfamiliar open field. Additional studies showed that after 1 exposure to the test environment, vehicle-treated rats increased their time spent in the open field and returned intermittently to the chamber. This result suggests that reexposure reduces the threatening impact of an unfamiliar open field. Importantly, CRF (300 ng) injected centrally, but not peripherally, before reexposure to the test environment significantly reduced exploration in the open field and increased a pattern of defensive-withdrawal into the chamber. Data suggest that whether defensive-withdrawal or exploratory behavior is exhibited may depend on CRF actions in brain systems that mediate the perception of threat in the environment.

Three experiments were conducted to test the hypothesis that brain corticotropin-releasing hormone (CRH) systems mediate stress-induced freezing behavior, an index of a rat's level of fear. We administered i.c.v. 0-50 micrograms of alpha-helical CRH9-41 (a specific CRH antagonist) before foot shock and showed that this peptide had little effect on baseline preshock behavior but significantly attenuated the occurrence of shock-induced freezing. We concluded that this attenuation of freezing behavior was not related to the effects of alpha-helical CRH9-41 on the animals' sensitivity to pain, because no significant effects on latency to respond on a hot-plate test of pain sensitivity were found. We also showed that alpha-helical CRH9-41 has a relatively rapid time course of action when administered i.c.v., since it blocked shock-induced freezing when given 20 min but not 40 min before foot shock. Our findings suggest that endogenous CRH systems mediate stress-induced, fear-related behavior through mechanisms other than alteration of nociceptive systems.

Freezing is an adaptive response often induced by stressful, fear-eliciting stimuli. Three experiments with rats investigated the effects of intracerebroventricular (ICV) administration of corticotropin-releasing hormone (CRH) on freezing behavior and pain sensitivity. Experiments 1 and 3 demonstrated that ICV-CRH (300 ng) enhanced shock-elicited freezing. In Experiment 1, ICV-CRH also enhanced recovery from shock-elicited freezing, suggesting that the peptide has a biphasic effect. Experiments 2 and 3 established that CRH-induced freezing was not caused by heightened pain sensitivity. Interestingly, in Experiment 2, hot-plate exposure produced increased freezing that was attenuated by ICV-CRH. Thus, the direction of the ICV-CRH effect on freezing was found to depend on the nature of the stressor. These results suggest that endogenous CRH systems modulate stress-induced freezing.

Traditionally, theories of addiction have stressed that drug urges are characterized by dysphoria, occur in response to decreasing levels of drug or drug effect, and are associated with withdrawal symptoms/signs or drug-antagonistic responses arising from a homeostatic mechanism. However, recent research has shown that urges, drug self-administration, and relapse all occur concomitant with both positive and negative affect, rising and falling levels of drug, and with drug-agonistic responses, as well as antagonistic/withdrawal responses. In keeping with recent theorizing about motivation and emotions, we believe that affective responding provides a readout of the motivational status of an organism (e.g., Buck, 1985). We conceive of urges as affects, whose activation mediates drug pursuit and self-administration. Moreover, we believe that affects are represented in neural networks comprising information on affect-relevant stimuli, responses, and meaning/expectancy. We believe that there are two types of urge networks. One, a "positive-affect" network, is activated, associatively and nonassociatively, by appetitive stimuli, especially appetitive drug actions that activate "GO" motivational incentive systems. Activation of this network is characterized by positive affect, drug isodirectional responding, attentional focus on a dominant response, and enhanced pursuit of appetitive stimuli--especially the drug. The operating characteristics of the positive-affect network, and the associated motivational systems, result in a drug's instating a positive feedback loop. Appetitive drug actions increase the likelihood of the pursuit of appetitive stimuli, and additional drug constitutes a prepotent candidate from among the available appetitive stimuli. This positive feedback loop may account in part for cardinal features of addiction: for example, the great relapse likelihood once any drug is sampled, the attainment of very high blood levels of a drug, and the pursuit of adjunctive appetitive stimuli while using a drug. The second type of urge network we have labeled a "negative-affect" network, and we believe it is activated, associatively and nonassociatively, by inappetitive stimuli or consequences (punishment, signals of punishment, frustrating lack of reward, etc.) and by withdrawal and signals of withdrawal (e.g., drug cues, which during the course of addiction are associated with both direct drug effects and withdrawal). Activation of the network is characterized by withdrawal symptoms and signs, negative affect, and drug seeking.(ABSTRACT TRUNCATED AT 400 WORDS)

To assess whether centrally administered corticotropin-releasing hormone (CRH) modulates behavioral and antinociceptive effects of exposure to a novel environment, vehicle or 0.03, 0.3, or 3.0 μg of CRH was administered intracerebroventricularly (ICV) to rats, which were then tested under novel or familiar conditions. Novelty decreased sleeping and grooming and increased rearing, walking, and latency to respond on the hot-plate test of analgesia. CRH increased grooming and walking, decreased rearing and sleeping, and had no effect in the hot-plate test. The lowest dose was without effect on any measure; otherwise, CRH effects generally were dose-dependent. There was no evidence that CRH selectively enhanced or interfered with novelty-induced behavioral changes; it influenced behavior to the same degree in both test conditions. However, test condition selectively modulated the degree of peptide-induced self-gnawing and burrowing.

Urges/craving to use drugs may be conceptualized as affective states indexing appetite motivation for drug use. To explore urges/cravings among cigarette smokers, we measured attitudinal/verbal, physiological and behavioral responses of withdrawing, continuing and non-smokers under experimental conditions theoretically or empirically related to enhanced urges/craving to smoke, i.e. drug-associated stimuli, drug-availability and noxious stimulation. Preliminary results suggested that urges/craving to smoke might be subserved by different processes in withdrawing and continuing smokers. They differed in phasic heart rate responses, self-reported mood, arousal and drug craving. Of particular interest, for withdrawing smokers self-reported craving was associated with negative affect, whereas for continuing smokers craving was associated with positive affect or low levels of negative affect. These findings are discussed in the context of current theory.

To explore the hypothesized integrative function of corticotropin releasing hormone (CRH) in the stress response, stress-related behaviors including antinociception were studied in rats after either intracerebroventricular (ICV) or peripheral administration of CRH. The effects of low-dose (0.3 ωg) and high-dose (3.0 ωg) ICVCRH were compared to those of vehicle, employing a within-S design. The two doses yielded comparable behavioral changes suggestive of increased arousal and stress. These changes were characterized by significant increases in grooming, walking, burrowing, self-gnawing, and pica, and decreases in rearing and sleeping. None of these effects of ICVCRH were obtained with peripheral administration of the same doses. The hot-plate test of analgesia failed to show a significant effect of ICVCRH or peripherally administered CRH. A between-S experiment incorporating both the tail-flick and the hot-plate tests of analgesia compared ICVCRH (3.0 ωg) with vehicle. ICVCRH did not affect antinociceptive responding in either of these tests. In contrast, ICV morphine (10 ωg) yielded potent analgesia in both tests. Thus, with doses of ICVCRH yielding clear evidence of stress-related behavior, no evidence of analgesia was obtained. These findings question the possible role of central CRH systems in antinociceptive processes.

The present experiments examined the reinforcing effects of an ethanol (EtOH) unconditioned stimulus (UCS) on conditioned flavor preferences in food-deprived rats and in water-deprived rats. In Experiment 1A food and water deprived animals received distinct conditioning treatments. One half of the animals were intragastrically intubated with EtOH (0.5 g/kg), and thereafter allowed 20 min free access to similar flavored drinking solutions. Remaining animals were intubated with distilled water. All animals received 15 presentations of an EtOH-paired flavor. A two-bottle preference test was subsequently used to evaluate preferences or aversions to flavors paired with EtOH in food-deprived and water-deprived animals. Results of Experiment 1A showed that food-deprived animals preferred the flavor associated with EtOH. Conversely, preferences for EtOH-paired flavors were not established in water-deprived animals. In Experiment 1B deprivational states of animals used in Experiment 1A were reversed without further drug training. Following a two week habituation period to deprivation state animals again received a two-bottle preference test to re-evaluate preferences or aversions to the EtOH-paired flavors. Results of those manipulations indicated that an ethanol aversion was established in the water-deprived animals. Those results indicated that water-deprived animals of Experiment 1B reversed their EtOH-paired flavor preference when the caloric need associated with food deprivation conditions was eliminated. Since deprivational state determined the development of EtOH preferences, the present results indicate that caloric need may play an initial role in establishing conditioned preferences for EtOH.

Recent research has shown that rats exposed to repeated stress display enhanced morphine analgesia. This study examined the possible contribution of classically conditioned analgesia to this effect. First, drug-naive rats exposed to nine daily sessions of stress, each consisting of a single 45-s exposure to footshock, subsequently displayed enhanced analgesic responsiveness to morphine 1 and 10 days after stress (Experiments 1, 2, and 5). This enhancement was also observed in morphine-experienced rats 1 and 8 days after stress (Experiment 1). Second, the effect of footshock stress on morphine analgesia was found to be specific to the environment in which stress was administered (Experiments 2 and 3). Rats tested in the same distinctive environment in which stress was administered displayed enhanced morphine analgesia; rats shocked elsewhere did not differ from nonshocked controls (Experiment 2). Third, conditioned analgesia was found under the same conditions that yielded enhanced morphine analgesia (Experiments 2 and 4). Lastly, both this conditioned analgesia and the acute analgesia elicited by the footshock stressor were found to be attenuated by naloxone (Experiments 5 and 6). These data are consistent with the hypothesis that the enhanced morphine analgesia observed after repeated footshock stress reflects the contribution of an opioid mediated , conditioned analgesia elicited by cues formerly paired with the stressor.

Two experiments explored the reinforcing effect of ethanol on conditioned location and flavor preferences in hungry rats. In Experiment 1, rats were administered ethanol (.5, 1.0, or 2.0 g/kg, ig) prior to confinement in one side of a shuttlebox with access to a flavored solution. On control trials, H2O was administered prior to confinement to the opposite side with a different flavored solution. Location choice tests revealed an overall aversion for the ethanol-associated side that was largest at the 2.0-g/kg dose. Flavor choice tests revealed an aversion for the ethanol-associated flavor at the 2.0-g/kg dose, no reliable difference at the 1.0-g/kg dose, and, of particular interest, a preference at the .5-g/kg dose. The results of Experiment 2 suggest that caloric restoration served as the reinforcing mechanism for the conditioned flavor preference. An isocaloric glucose solution conditioned a flavor preference of the same magnitude as that obtained with ethanol. Moreover, when ethanol provided no caloric advantage, the associated flavor was less preferred than a flavor associated with an isocaloric glucose solution.

Exposure to a variety of stressors produces a subsequent analgesic reaction. This stress-induced analgesia (SIA) is sometimes opioid in nature (reversed by opiate antagonists and cross-tolerant with morphine) and sometimes nonopioid. Both 30 min of intermittent footshock and 60-80 five-sec tailshocks have been shown to produce opioid SIA, whereas 3 min of continuous footshock and 5-40 tailshocks produce nonopioid SIA. We report that both of the opioid SIA procedures produce a learned helplessness effect as assessed by shuttlebox escape acquisition and an analgesia that is reinstatable 24 hr. later. The nonopioid procedures produce neither a learned helplessness effect nor a reinstatable analgesia. It is argued that these data implicate the learning of uncontrollability in the activation of opioid systems.

The associative model of morphine tolerance predicts that established tolerance should be attenuated, i.e., extinguished, by placebo injections in the former morphine injection environment. The present study examined the effect of placebo sessions, with and without accompanying nociceptive stimulation, on the extinction of analgesic tolerance. In Experiment 1, rats rendered tolerant to morphine displayed recovery of morphine's analgesic action only following placebo sessions including exposure to a painful hot plate surface (52.5°C); placebo sessions on a cool plate (23–24°C) failed to attenuate tolerance even though these placebo sessions more closely matched the stimulus conditions of tolerance acquisition. In Experiment 2, repeated hot plate exposures were similarly found to enhance morphine analgesia in drug-naive rats. These results question an extinction account of the effect of hot plate placebo sessions observed in Experiment 1. Instead, they suggest that nociceptive hot plate exposures, per se, are sufficient to enhance subsequent morphine analgesia.

Different patterns of foot shock activate opioid and nonopioid mechanisms of stress analgesia in the rat. Opioid, but not nonopioid, stress analgesia is reduced by adrenal demedullation and denervation and is potentiated by reserpine, a drug known to increase concentrations of adrenal medullary enkephalin-like peptides. It is suggested that adrenal enkephalins mediate opioid stress analgesia.

Opioid and non-opioid mechanisms of analgesia elicited by two kinds of footshock stress that differ only in temporal characteristics previously have been inferred on the basis of susceptibility to naloxone blockade. The present study sought further evidence on this point by comparing these two kinds of footshock analgesia for possible tolerance development and cross-tolerance with morphine. It was found that, with repeated exposure to stress, tolerance developed to naloxone- sensitive, but not naloxone-insensitive, stress analgesia. Furthermore, morphine-tolerant rats displayed cross-tolerance to only the naloxone- sensitive form of footshock analgesia. Although prior exposure to both footshock paradigms potentiated morphine analgesia, less potentiation occurred in rats tolerant to the naloxone-sensitive footshock stress. Thus, cross-tolerance between morphine and this type of stress analgesia appears to occur in both directions. These findings are consistent with those using naloxone antagonism as a criterion for opioid mediation and support the conclusion that separate opioid and non-opioid mechanisms of stress analgesia exist.