Anxious depression as a clinically relevant subtype of pediatric major depressive disorder.

In adults, anxious depression has been identified as a more severe form of major depressive disorder (MDD), associated with higher depression severity, more suicidal ideation and worse treatment outcome. Research in pediatric depression, however, has been sparse. 126 children and adolescents aged 8-18 years with a primary diagnosis of MDD were categorized into a MDD-only group and an anxious depression group based on clinically elevated scores on the Beck Anxiety Inventory. One-third of the sample was classified as having anxious depression with females being overrepresented in the anxious depressed compared to the MDD-only group. 42.2% of the anxious depressed youth met diagnostic criteria for a comorbid anxiety disorder. Anxious depressed youth were more likely to suffer recurrent depressive episodes, showed higher depression severity and a unique pattern of depressive symptoms characterized by more severe sleep problems, more somatic complaints, more severely depressed mood and more frequent suicidal ideations. Scores on a suicidal ideation scale were increased even when controlling for overall depression severity. However, when comparing depressed patients with and without comorbid anxiety disorders, no differences in depression severity, symptom patterns or suicidal ideations were observed. The results indicate that high anxiety levels in depressed youth are clinically relevant, and given the increase in suicidal ideation, anxiety symptoms during depressive episodes should routinely be screened in clinical practice even in the absence of a fully formed comorbid anxiety disorder.

Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents.

STUDY OBJECTIVES: We aimed to examine the association between self-rated and clinician-rated sleep disturbances and C-reactive protein (CRP), an objective marker of inflammation, in pediatric depression. METHODS: Two hundred fifty-six children and adolescents (15.2 ± 1.6 y, 72.3% female) with moderate to severe symptoms of depression participated in the study. Sleep disturbances were assessed by self-reports (Insomnia Severity Index) and clinician ratings (Kiddie-Schedule for Affective Disorder and Schizophrenia), inflammation by plasma CRP levels. RESULTS: Higher levels of CRP correlated positively with clinician-rated middle insomnia and hypersomnia. After adjusting for control variables (body mass index, tobacco, alcohol, stress, age, sex, antidepressants, sleep medication, depression severity), regression models confirmed the significant association of clinician-rated hypersomnia and middle insomnia symptoms with elevated CRP levels. In the adjusted regression models, other clinician-rated manifestations of sleep disturbance (eg, initial insomnia) and insomnia self-ratings were not significantly associated with CRP. Body mass index correlated positively with CRP, but body mass index had no mediating effect on the associations between sleep disturbances and CRP. We did not find an association between depression severity, assessed by the Children's Depression Rating Scale-Revised, and CRP. CONCLUSIONS: Results of the present study indicate a significant association of hypersomnia and middle insomnia symptoms with CRP in pediatric depression, not linked to alterations in the body mass index. CITATION: Strumberger MA, Häberling I, Emery S, et al. Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents. J Clin Sleep Med. 2023;19(10):1775-1784.

Executive functions and borderline personality features in adolescents with major depressive disorder.

Background: Executive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF). Methods: We examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child's EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity. Results: Over the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries. Conclusion: On average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03167307.

When parents and children disagree: Informant discrepancies in reports of depressive symptoms in clinical interviews.

BACKGROUND: Parents and their children often disagree on the existence and severity of psychopathological symptoms, especially in major depressive disorder (MDD). Discrepant estimations pose a problem for the validity of diagnoses and illness severity with major implications for treatment evaluation. METHODS: 118 adolescents aged 13-18 years and their parents were interviewed and their reports were compared regarding the presence of a MDD diagnosis. In addition, severity ratings of depression symptoms reported in the Children's Depression Rating Scale-Revised (CDRS-R) were compared between parents and their offspring using multivariate analyses and polynomial regressions. The association between borderline features, functional impairment, and treatment history variables with parent-child agreement was assessed. RESULTS: In 38% of the cases, parents and adolescents agreed on DSM-IV diagnostic MDD criteria, while in 53%, only the adolescent endorsed criteria for a MDD. A MDD that was endorsed by parents and adolescents was characterized by higher depression severity, higher number of previous treatments, and higher functional impairment. Using a polynomial approach, neither age nor borderline tendencies were associated with agreement. LIMITATIONS: We did not differentiate between mother's versus father's reports and borderline features were assessed by self-report only. CONCLUSIONS: Adolescents and their parents gave differing reports of the existence and severity of depressive symptoms. The high discrepancy levels combined with the uncertainty of previously published findings due to methodological challenges are concerning. Clinicians and researchers need to consider discrepancies in agreement in relation to diagnosis and illness severity in the context of their clinical and research decisions.

Verbal Memory Performance in Depressed Children and Adolescents: Associations with EPA but Not DHA and Depression Severity.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been described as positively associated with cognitive functioning. Current meta-analyses have identified eicosapentaenoic acid (EPA) as potentially more effective than docosahexaenoic acid (DHA). An especially vulnerable subgroup that might benefit from these beneficial effects are depressed youths. In this study, we examined associations between red blood cell (RBC) DHA and EPA levels and depression severity and verbal memory performance in a sample of 107 moderately (n = 63) and severely (n = 44) depressed youths. The findings showed that youths with high RBC EPA levels had steeper learning curves compared to those with moderate or low RBC EPA levels (Pillai's Trace = 0.195, p = 0.027, ηp2 = 0.097). No associations between RBC DHA levels or depression severity and verbal memory performance were observed. Our results further confirm previous findings indicating a more important role of EPA compared to DHA in relation to cognitive functioning. Future research should further investigate the differential role of EPA and DHA concerning cognitive functioning in depressed youths. Evidence supporting beneficial supplementation effects could potentially establish a recommendation for a natural and easily accessible intervention for cognitive improvement or remission.

Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat.

RATIONALE: Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been demonstrated. OBJECTIVES: The objectives of this study were to determine whether CRF and NA systems can interact to influence reinstatement responding and, if so, in what direction the interaction occurs. MATERIALS AND METHODS: Rats were trained to self-administer cocaine (0.23 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished, and tests for reinstatement were conducted following: (1) pretreatment with the CRF receptor antagonist, D: -Phe CRF(12-41) [1 microg, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 microg; Experiment 1); (2) pretreatment with the alpha(2) adrenoceptor agonist, clonidine (40 microg/kg, i.p.), prior to i.c.v. injections of CRF (0.5 microg; Experiment 2); (3) pretreatment with D: -Phe (1, 5 microg, i.c.v.), prior to systemic injections of the alpha(2) adrenoceptor antagonist, yohimbine (1.25 mg/kg; Experiment 3A); or (4) pretreatment with clonidine (40 microg/kg, i.p.) prior to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B). RESULTS: NA reliably induced reinstatement, an effect that was blocked by pretreatment with D: -Phe. In contrast, CRF-induced reinstatement was not attenuated by pretreatment with clonidine. Pretreatment with neither D: -Phe nor clonidine was effective in blocking yohimbine-induced reinstatement. CONCLUSION: Together, the present findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA.

Effects of repeated yohimbine on the extinction and reinstatement of cocaine seeking.

Acute exposure to the pharmacological stressor yohimbine (YOH) reinstates drug seeking in rats. The present experiments investigated whether repeated exposure to YOH during extinction training affects the time-course of extinction and the magnitude of subsequent YOH- or footshock-induced reinstatement of cocaine seeking. Rats trained to self-administer cocaine were given five days of extinction training, during which they were injected with YOH (1.25 mg/kg, i.p.) either before or after daily extinction sessions. Following additional extinction training in the absence of YOH, animals were tested for reinstatement to a YOH (1.25 mg/kg, i.p.) or footshock (20 min, intermittent, 0.9 mA per 0.5 s shock) challenge. Animals injected with YOH before daily extinction sessions showed an attenuated rate of extinction, relative to control animals. Following additional extinction training in the absence of YOH treatment, these same animals showed a marked attenuation of YOH-induced reinstatement of cocaine seeking. YOH treatment during extinction did not, however, affect the magnitude of reinstatement induced by footshock. These findings demonstrate that repeated exposure to a stressor during extinction training can modulate the processes governing extinction learning and the subsequent reinstatement of drug seeking induced by that stressor.

Positive urgency partially mediates the relationship between childhood adversity and problems associated with substance use in an undergraduate population.

BACKGROUND: Childhood adversity predicts the development of substance use problems in young adulthood. Building on past work examining the mediating role of impulsivity in the relationship between childhood maltreatment and substance use in alcohol and nicotine users, this study examined the relationship with other substances in a representative undergraduate sample. In addition, the study aimed to determine whether there was convergence in findings between different measures of childhood adversity and impulsivity. METHOD: 309 undergraduate students completed self-report questionnaires assessing childhood adversity (Childhood Trauma Questionnaire - CTQ; Adverse Childhood Experience Scale - ACE), impulsivity (Short UPPS-P; Barratt Impulsivity Scale - BIS-11) and problems associated with substance use (Drug Abuse Screening Test - DAST-10). RESULTS: The SUPPS-P positive urgency facet partially mediated the relationship between CTQ and DAST-10 (b = 0.0039, 95% CI [0.0008, 0.0086]), as well as between ACE and DAST-10 (b = 0.015, 95% CI [0.0014, 0.0446]). The BIS-11 motor facet partially mediated the effect of CTQ on DAST-10 (b = 0.0017, 95% CI [0.0002, 0.0054]). CONCLUSION: Positive urgency partially mediated the relationship between childhood maltreatment and substance use problems for both the CTQ and ACE. While these results are consistent with past studies showing a selective mediation effect of positive urgency in a sample of young adults, they are inconsistent with those showing a selective mediation effect of negative urgency in a sample of heavy drinkers. Together, these findings suggest that the relationship between childhood adversity, impulsivity, and substance use-related problems may be influenced by experience.

Dissociative effects of dorsomedial striatum D1 and D2 receptor antagonism in the regulation of anxiety and learned approach-avoidance conflict decision-making.

The dorsal striatum is traditionally known for its role in sensorimotor integration. However, the dorsomedial striatum (DMS) has also been implicated in cost-benefit conflict processing, a role more readily attributed to the ventral striatum (VS), as a site of limbic-motor integration. We recently showed that dopaminergic D1 (D1R) and D2 receptors (D2R) in the VS exert dissociable control over cue-elicited approach-avoidance decision-making, in the presence of conflicting motivational stimuli. We therefore sought to investigate the contribution of DMS dopaminergic receptors in the regulation of cue-elicited and innate approach-avoidance decision-making. Using a conditioned mixed-valence conflict paradigm, we trained rats in a three-arm radial maze to associate visuotactile cues with appetitive, aversive, and neutral outcomes. Rats then received an intra-DMS or intra-dorsolateral striatum (DLS) microinfusion of D1-like antagonist (SCH23390) or D2-like antagonist (sulpiride), and were then tested for the expression of approach-avoidance behavior in a conflict scenario, wherein the appetitive and aversive cues were superimposed within a single maze arm. The results revealed that DMS (but not DLS) D1R antagonism, suppressed approach towards the conflict arm while DMS (but not DLS) D2R antagonism enhanced approach. All rats were subsequently administered an elevated plus maze test as a measure of innate approach-avoidance conflict (anxiety). DMS D1R antagonism decreased anxiety, while DMS D2R and both DLS D1R and D2R antagonism increased anxiety. Our findings suggest that under motivational conflict, activation of DMS D1-like receptors facilitates approach, while activation of D2-like receptors suppress approach behavior. Furthermore, anxiety is regulated by dorsal striatal-mediated dopaminergic mechanisms.

A study of the effects of maternal high fat diet on behavioural responses to acute and repeated administrations of cocaine in rat offspring.

Building on previous work in the field, we examined the effect of maternal high fat diet (HFD) during gestation and lactation on the sensitivity of male and female adult offspring to acute and repeated cocaine exposures, and to the expression of cocaine-induced anxiety in the elevated plus maze (EPM). In both male and female offspring, acute injections of cocaine induced a strong locomotor-activating effect; repeated injections produced a robust conditioned locomotor response to the context in which they were given cocaine, and heightened activity in response to a subsequent acute challenge of cocaine. Although female offspring of HFD relative to control house chow diet (CHD) dams exhibited a generally elevated level of locomotor activity, this effect was not further enhanced by cocaine administration/s and there were no significant interactions between maternal diet and cocaine in either male or female offspring. Finally, female offspring of HFD relative to CHD dams exhibited enhanced behavioral anxiety in the EPM, an effect that was reversed when the offspring were exposed to cocaine 48 h prior. Although, in contradiction to our hypotheses, the present study failed to demonstrate an effect of maternal diet on the locomotor-activating effects of cocaine, it did replicate all of the established findings upon which its rationale and predictions were based. Thus, we believe that our results provide important context for future studies.

Repeated Cocaine Exposure Attenuates the Desire to Actively Avoid: A Novel Active Avoidance Runway Task.

Drug addiction is a disorder in which drug seeking persists despite aversive consequences. While it is well documented in animal models of drug sensitization that repeated drug exposure enhances positive incentive motivation for drug and natural reinforcers, its effect on negative incentive motivation, defined here as the motivation to avoid a cued aversive outcome, remains an open question. In the present study, we designed a novel active avoidance (AA) runway paradigm to assess the effects of repeated cocaine exposure on the motivation to avoid an aversive outcome. Cocaine and saline pre-exposed rats were first trained to perform a conditioned AA lever press response to prevent the occurrence of foot shock administrations. The rats were subsequently tested in a runway apparatus, wherein they were required to traverse the length of a straight alley maze to reach the lever and emit a conditioned AA response. Run times were measured as an indication of negative incentive motivation. Cocaine pre-exposed rats demonstrated longer latencies to emit the conditioned AA response but showed no differences in latency to initiate runway behavior, nor in their acquisition of the AA response compared to the saline pre-exposed controls. Subsequent testing in an elevated plus maze revealed no differences in the expression of anxiety in cocaine pre-exposed rats compared to saline pre-exposed controls. Our results indicate that prior repeated cocaine exposure attenuated cued negative incentive motivation, which suggests that drug addiction may be attributable to a decrease in motivation to avoid aversive consequences associated with drug use.

Dissociable roles of the nucleus accumbens D1 and D2 receptors in regulating cue-elicited approach-avoidance conflict decision-making.

RATIONALE: Approach and avoidance decisions are made when an animal experiences a state of motivational conflict inflicted by stimuli imbued with both positive and negative valences. The nucleus accumbens (NAc), a site where valenced information and action selection converge, has recently been found to be critically involved in the resolution of approach-avoidance conflict. However, the individual roles of the region's dopamine receptor D1 (D1R)- and D2 (D2R)-expressing medium spiny neurons (MSNs) in regulating conflict resolution have not been well established. OBJECTIVES: Here, we examined the roles of NAc D1R and D2R in cue-elicited approach-avoidance decision-making. METHODS: Using a conditioned mixed-valence conflict paradigm, rats were initially trained in a radial maze to associate separate visuotactile cues with sucrose reward, foot shock punishment, and no outcome. Following acquisition of the cue-outcome associations, rats were subjected to a conditioned approach-avoidance conflict scenario, in which they were presented with a maze arm containing a superimposition of the reward and punishment cues, and another arm containing neutral cues. RESULTS: Post-training intra-NAc D1R antagonism (SCH23390) led to an avoidance of the arm containing the mixed-valence cue over the neutral arm, whereas intra-NAc D2R antagonism (sulpiride) resulted in rats exhibiting a preference for the mixed-valence arm. CONCLUSION: Our results suggest that NAc D1R and D2R exert differential control over decision-making involving cue-elicited approach-avoidance conflict resolution.

Footshock stress reinstates cocaine seeking in rats after extended post-stress delays.

RATIONALE: Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement. OBJECTIVE: The objectives of the study were to determine for how long footshock remains effective in inducing the reinstatement of cocaine seeking if testing is delayed after termination of the stressor and to determine whether the context in which a post-stress delay is carried out influences the magnitude of reinstatement. MATERIALS AND METHODS: Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. After extinction, tests for reinstatement by intermittent footshock (20 min; 0.8 mA) were conducted after post-stress delays of up to 60 min. Although footshock was always administered in the self-administration (SA) chamber, delays were given either in the SA chamber or home cage (HC). RESULTS: Footshock induced reinstatement after post-stress delays of up to 40 min. No differences in responding during tests for reinstatement were observed between animals in the SA chamber and under HC conditions. CONCLUSION: Within a limited time window, footshock is effective in reinstating cocaine seeking, when testing is delayed after termination of the stressor. Together with previous work from this laboratory, the findings are consistent with the idea that stress can induce the reinstatement of drug seeking by conditioning excitation to the context in which it is administered and that this conditioned excitation can overcome the inhibitory processes maintaining extinction responding, even after a post-stress delay.

Central injections of CRF reinstate cocaine seeking in rats after postinjection delays of up to 3 h: an influence of time and environmental context.

RATIONALE: In drug addicts, the induction of drug craving is not always associated with an immediate opportunity to take drugs again. It is, therefore, important to study how delays in opportunity for drug seeking affect the time-course of relapse. Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) is a stressor that reinstates heroin and alcohol seeking in rats, when administered just before tests for reinstatement. It is not known whether CRF reinstates cocaine seeking; moreover, the effect of delaying testing for reinstatement, after CRF injection, has not been studied. OBJECTIVES: To determine whether i.c.v. CRF induces reinstatement of cocaine seeking after postinjection delays of up to 3 h and to determine whether the context in which a delay is experienced influences the time-course of CRF-induced reinstatement. METHODS: Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished and testing for reinstatement by i.c.v. CRF (0.5 microg) was conducted. Animals were tested after postinjection delays of up to 3 h; the delays were experienced either in the self-administration (SA) chamber or home cage (HC). RESULTS: When delays were spent in the SA chambers, CRF induced reinstatement in all delay groups. When delays were spent in the HC, CRF did not induce reinstatement after a 2-h delay. CONCLUSIONS: We argue that the effects we observed are consistent with a contextual conditioning account of reinstatement, whereby CRF that was experienced in the context of the SA chamber served to elicit a conditioned excitatory response developed to that context during training.

A role for corticotropin-releasing factor in the long-term expression of behavioral sensitization to cocaine.

Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.

A study of the lasting effects of cocaine pre-exposure on anxiety-like behaviors under baseline conditions and in response to central injections of corticotropin-releasing factor.

Anxiety-like behaviors emerge with repeated exposure to and short-term withdrawal from cocaine. The stress-related neuropeptide, corticotropin-releasing factor (CRF), has been implicated in the anxiogenic effects of cocaine withdrawal, as well as in some of the long-lasting effects of cocaine. One objective of the present experiments was to determine whether repeated exposures to cocaine, under conditions that induce anxiety in the initial withdrawal period, would induce longer-lasting anxiogenic responses. A second objective was to determine whether any such effects would be potentiated by CRF. In Experiment 1, animals were injected once daily for 7 days with cocaine (30 mg/kg, i.p.) or saline in the home cages and, after a 10-day drug-free period, were given an i.c.v. injection of CRF (0.5 or 5.0 micro g) or vehicle, followed by a 5-min test for anxiety in the elevated plus maze or light-dark transition apparatus. In Experiment 2, animals were given the cocaine or saline injections in a distinct environment. At test, they were placed in the distinct environment after the CRF (0.5 micro g) or vehicle injection and were subsequently tested for anxiety. Cocaine produced enhanced levels of anxiety when pre-exposures were given in a distinct environment, but not when they were given in the home cage. In neither case did cocaine differentially alter anxiety-like responses to CRF. The results suggest that a "reminder" of the drug experience, such as re-exposure to cocaine-paired contextual cues, may be necessary to induce elevated levels of anxiety after the initial withdrawal period. In addition, although the results do not rule out a role for endogenous CRF in lasting cocaine-induced anxiogenic responses, they suggest that an increased sensitivity of CRF receptors to the peptide is not responsible for the effect.

Effects of central neurokinin-1 receptor antagonism on cocaine- and opiate-induced locomotor activity and self-administration behaviour in rats.

The neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 (NK-1) receptor, have been implicated in some of the reward-related behavioural effects of abused drugs, including psychostimulants and opiates. The first objective of the present series of experiments was to assess the role of the NK-1 receptor in two reward-related behavioural effects of cocaine: locomotor activity and self-administration. In tests for locomotor activity, rats were given intracerebroventricular (ICV) infusions of the selective NK-1 receptor antagonist, GR82334 (0, 10, 50 pmol), prior to systemic injections of cocaine. In self-administration experiments, rats were trained to self-administer cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Following acquisition of stable responding, animals were pretreated with GR82334 (0, 2, 10, 50 pmol; ICV) prior to subsequent self-administration sessions. Based on evidence suggesting a potentially selective role for NK-1 receptors in opiate reward, we also examined the effects of GR82334 on morphine-induced locomotor activity and heroin self-administration. Results showed that GR82334 had no effect on cocaine-induced locomotor activity or cocaine self-administration, but attenuated morphine-induced locomotor activity and increased heroin self-administration. These findings suggest that endogenous activity at NK-1 receptors may play a specific role in opiate-induced, but not cocaine-induced, locomotor activation and reinforcement.

Activation of central neurotensin receptors reinstates cocaine seeking in the rat: modulation by a D1/D5, but not D2/D3, receptor antagonist.

RATIONALE: Neurotensin (NT) has been implicated in some of the behavioral effects of psychostimulants. Thus, there is reason to think that NT may play a role in the reinstatement of cocaine seeking, and that it may do so via an interaction with dopamine (DA). OBJECTIVES: To assess (1) whether NT and an NT analog, D-TYR[11]NT, induce reinstatement of cocaine seeking; (2) whether the effects of NT receptor activation on reinstatement can be modulated by D1/D5 or D2/D3 antagonists; (3) the specificity of the effects of NT receptor activation on the reinstatement of cocaine seeking. METHODS: In Experiment 1, rats were initially trained to self-administer cocaine. Following a subsequent period of extinction training, they were tested for the reinstatement of cocaine seeking by NT or D-TYR[11]NT (15, 30 microg i.c.v.). In Experiment 2, rats were pretreated with the D1/D5 antagonist, SCH 23390 (0.05, 0.10 mg/kg i.p.) or the D2/D3 antagonist, raclopride (0.25, 0.50 mg/kg i.p.), prior to testing for reinstatement by D-TYR[11]NT (15 microg i.c.v.). In Experiment 3, rats that had been trained to self-administer sucrose pellets were tested for the reinstatement of sucrose seeking by D-TYR[11]NT (15, 30 microg i.c.v.). RESULTS: (1) Both NT and D-TYR[11]NT produced robust reinstatement of cocaine seeking; (2) the effect of the analog was attenuated by pretreatment with the D1/D5, but not D2/D3, receptor antagonist; (3) the analog did not induce the reinstatement of sucrose seeking. CONCLUSIONS: The findings suggest that an interaction between NT and DA may contribute to the neurobiology of reinstatement in animals with a history of cocaine self-administration.

Cocaine pre-exposure enhances CRF-induced expression of c-fos mRNA in the central nucleus of the amygdala: an effect that parallels the effects of cocaine pre-exposure on CRF-induced locomotor activity.

There is evidence that cocaine pre-exposure produces changes in the responsivity of central corticotropin-releasing factor (CRF) systems and that these systems mediate some of the drug-related behavioural effects of acute stressors. The present experiment was conducted to assess the effects of repeated cocaine exposure on CRF-induced neuronal activation within two regions of the extended amygdala, the central nucleus of the amygdala (CeA) and lateral bed nucleus of the stria terminalis (BNST). In addition, CRF-induced neuronal activation was compared with CRF-induced locomotor activity. Rats were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2-6 in homecages) or saline. After 10 drug-free days, locomotor responsiveness to intracerebroventricular (i.c.v.) injections of CRF and Vehicle was assessed over 2-h test periods. Twenty-four to 48 h following testing for locomotor activity, animals were injected with either CRF or Vehicle, 30 min before being sacrificed. Subsequently, the brains were processed by in situ hybridization for c-fos mRNA, a widely used marker of neuronal activation, in the CeA and BNST. In CeA, i.c.v. CRF enhanced the expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals; in the same animals, i.c.v. CRF resulted in enhanced locomotor activity in cocaine, but not saline, pre-exposed animals. The results demonstrate that repeated exposure to cocaine changes the neuronal response to CRF in the CeA; furthermore, they suggest that these changes in the CeA could potentially be of functional significance in the effects of repeated cocaine exposure on CRF-induced locomotor activity.

Activation of central neurokinin-1 receptors induces reinstatement of cocaine-seeking behavior.

A number of neurochemical systems have been implicated in mediating relapse to drug-seeking behavior. Substance P (SP) is a neuropeptide that interacts with some of these systems, suggesting a possible role for SP and its preferred receptor, the neurokinin-1 (NK-1) receptor, in the mediation of relapse. In this study, we examined whether selective activation of NK-1 receptors induces reinstatement of cocaine-seeking behavior, and whether endogenous activity at these receptors is involved in mediating cocaine-induced reinstatement. For each experiment, rats were trained to self-administer cocaine for 8--10 days, and following a period of extinction, tests for reinstatement were given. To examine the effects of NK-1 receptor activation on reinstatement of cocaine-seeking behavior, animals received an intracerebroventricular (ICV) infusion of the selective NK-1 receptor agonist, [Sar(9)Met(O(2))(11)]-SP (0, 1, 3 microg), immediately prior to the test session. To examine the role of endogenous NK-1 receptor activity on cocaine-induced reinstatement, rats were pretreated with ICV infusions of the selective NK-1 receptor antagonists, RP 67580 (0, 0.1, 0.5, 2.5 nmol) or GR 82334 (0, 2, 10, 50 pmol), prior to systemic priming injections of cocaine (10mg/kg or 20mg/kg; i.p.). The results showed that [Sar(9)Met(O(2))(11)]-SP induced reinstatement of cocaine-seeking behavior, but that RP 67580 and GR 82334 had no effect on cocaine-induced reinstatement. These findings suggest that while activation of NK-1 receptors is capable of inducing reinstatement of cocaine-seeking behavior, endogenous activity at these receptors is not involved in mediating the priming effects of cocaine on reinstatement of drug-seeking behavior.