Magnesium-deficient diet alters depression- and anxiety-related behavior in mice--influence of desipramine and Hypericum perforatum extract

A relation between magnesium (Mg) status and mood disorders has been suggested, but evidence remains inconsistent. Therefore, we examined in mice whether Mg-depletion would alter behavior evaluated in established animal models of depression and anxiety and whether these effects would be sensitive to antidepressants. Compared to control mice fed with normal diet, mice receiving a low Mg diet (10% of daily requirement) for several weeks displayed increased immobility time in the forced swim test, indicating enhanced depression-like behavior. In addition, the partial Mg-depletion increased anxiety-related behavior in the light/dark and open field test, while locomotor activity or motor coordination was not influenced. Chronic oral administration of desipramine (30 mg/kg/day), or Hypericum extract LI160 (Hyp, 380 mg/kg/day) prevented the “pro-depression-like” forced swim behavior in Mg-depleted mice. Furthermore, the increase in anxiety-related behavior of Mg-depleted mice was abolished in both the open field and light dark test by Hyp. Taken together, we report that Mg-depletion leads to enhanced depression- and anxiety-related behavior in mice, which was further validated by the reversibility of the behavioral changes by known antidepressant and anxiolytic substances. Further, the utility of Mg-depletion as a new screening model for clinically active antidepressant and anxiolytic drugs is suggested.     

Hippocampal volume and internalizing behavior problems in adolescence

Adolescence is characterized by dynamic changes in structural brain maturation. At the same time, adolescence is a critical time for the development of affective and anxiety-related disorders. Individual differences in typically developing children and adolescents may prove more valuable for identifying which brain regions correspond with internalizing behavior problems (i.e., anxious/depressive, withdrawal and somatic symptoms) on a continuous scale compared to clinical studies. Participants were 179 (92 males, 87 females) typically developing children and adolescents between ages 8 and 17. Hippocampal and amygdala volumes were measured automatically with FreeSurfer. Internalizing behavior was assessed with the Child Behavior Checklist (CBCL) completed by the parent, and associated with hippocampal and amygdala volumes. Hippocampal volume was inversely related with the total internalizing problems scale of the CBCL, irrespective of gender, age, or informant (mother or father). The effects were most prominent for the withdrawal and anxiety/depression subscales and the left hippocampus: more withdrawal and anxiety/depression was related to smaller left hippocampal volume. No associations were found between internalizing behavior and amygdala volume. This study shows that typically developing children and adolescents with high internalizing behavior share some of the neuroanatomical features of adult depression and anxiety-related disorders.     

Effects of altered amygdalar neuropeptide Y expression on anxiety-related behaviors.

Neuropeptide Y (NPY) decreases anxiety-related behaviors in various animal models of anxiety. The purpose of the present study was to examine the role of the amygdalar NPY system in anxiety-related responses in the elevated plus maze. The first experiment determined if herpes virus-mediated alterations in amygdalar NPY levels would alter anxiety-related behaviors in the elevated plus maze. Viral vectors encoding NPY, NPY antisense, or LacZ (control virus) were bilaterally injected into the amygdala, and 4 days postinjection, rats were tested in the elevated plus maze test. NPY-like immunoreactivity (NPY-ir) was measured in the amygdala of these rats. In rats injected with the viral vector encoding NPY, reduced anxiety-related behaviors in the elevated plus maze accompanied by moderate increases in NPY-ir were detected compared to NPY-antisense viral vector-treated subjects. Elevated plus maze behavior did not differ compared to LacZ-treated controls. NPY overexpression at this time point was also suggested by enhanced NPY mRNA expression seen in the amygdala 4 days postinjection using real-time polymerase chain reaction analysis. Experiment 2 was conducted to provide further evidence for a role of amygdalar NPY in regulating anxiety-related behaviors in the elevated plus maze test. The nonpeptide NPY Y1 receptor antagonist, BIBP 3226 (1.5 microg/microl), was bilaterally injected into the amygdala and rats were tested in the elevated plus maze test. Rats receiving BIBP 3226 exhibited increased anxiety-related behaviors in this test. The results of these experiments provide further support for the role of amygdalar NPY in anxiety-related behaviors.     

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticityand depression-like behavior in mice

Whether benzodiazepines(BZD) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain.The present study designed four preclinical experiments to determine the effects of BZD using chronic unpredictable stress model.In Experiment 1,several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests(FST and TST) as well as hippocampal structural plasticity markers.Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 week.In Experiment 2,mice received p.o.administration of three diazepam dosages prior to each variate stress session for 4 week.This treatment significantly antagonized the elevation of stress-induced corticosterone levels.Diazepam 0.5 and 1 mg·kg-1 blocked the detrimental effects of chronic stress.In Experiment 3,after 7 week of stress sessions,daily po diazepam administration during 1 week recovery phase dose-dependently accelerated the recovery of stressed mice.In Experiment 4,1 week diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect,whereas 4 week diazepam administration produced opposite effects.Hence,diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones.Considering the adverse effect of long-term diazepam administration on hippocampal plasticity,the preventive effects of diazepam may depend on the proper dose.Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.     

Airjet and FG-7142-induced Fos expression differs in rats selectively bred for high and low anxiety-related behavior

We reported recently that two rat lines bred for either high (HAB) or low (LAB) anxiety-related behavior display differential Fos expression in restricted parts of the fear/anxiety circuitry when exposed to mild anxiety evoked in exploratory anxiety tests. Since different forms of anxiety are thought to activate different parts of the anxiety circuitry, we investigated now whether (1) an aversive stimulus which elicits escape behavior (airjet) and (2) the anxiogenic/panicogenic drug FG-7142 would reveal further differences in Fos expression as a marker of neuronal activation between HAB and LAB rats. Both airjet exposure and FG-7142 induced Fos expression in both lines in various anxiety-related brain areas. HAB rats, which displayed exaggerated escape responses during airjet exposure, exhibited increased Fos expression in brain areas including the hypothalamus, periaqueductal gray and locus coeruleus, as well as blunted Fos activation in the cingulate cortex in response to airjet and/or FG-7142. The results corroborate previous findings showing that trait anxiety affects neuronal excitability in hypothalamic and medial prefrontal areas. Furthermore, by using airjet as well as FG-7142, we now reveal that enhanced trait anxiety is also associated with neuronal hyperexcitability in the locus coeruleus and the periaqueductal gray, suggesting that investigation of an array of different anxiogenic stimuli is important for the detection of altered neuronal processing in trait anxiety.     

GABAA receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat

Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA_A receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA_A receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA_A receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv.     

Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin.

To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)- or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH(2))(5) Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.     

Behavioral effects of Bcl-2 deficiency: implications for affective disorders

New hypotheses regarding affective disorders suggest a critical role for cellular resilience and plasticity. Bcl-2 is a central protein in these processes and is elevated by mood stabilizers and antidepressants. In previous studies, mice with targeted mutations of Bcl-2 showed anxiety-related behavioral changes. The present study further explored the relationship between Bcl-2 and behavior using mice with a targeted mutation but with a different background strain than previously tested. Bcl-2 heterozygous mice (B6;129S2-Bcl-2/J) were tested in models of depression, mania and anxiety. Compared to Wild Type (WT) controls, mutant mice showed behaviors modeling two facets of mania: increased reward seeking and amphetamine sensitization. Moreover, the sensitization was attenuated by chronic pretreatment with lithium. In contrast to previous data, the mutation did not affect measures of anxiety. Although data are still minimal, it supports additional studies of the role of Bcl-2 in affective and anxiety disorders. The importance of background strain in behavioral phenotypes of mutant mice is known and the current lack of effect on anxiety measures may be related to high baseline anxiety of WTanimals. More precise studies of Bcl-2 in affective and anxiety disorders will be possible when specific pharmacological modulators of Bcl-2 become available.     

Positive correlation between peripheral blood granulocyte oxidative status and level of anxiety in mice

Oxidative stress is involved in many acute and chronic diseases including cancer, cardiovascular disorders and neurodegenerative diseases. We studied the relationship between the level of intracellular reactive oxygen species in peripheral granulocytes and the estimated anxiety level of mice using the behavioral light/dark choice test. Our results indicate a linear and significant relationship between the intracellular redox status of peripheral blood granulocytes and different parameters of anxiety-related behavior including latency time (R(2)=0.737, P<0.001), cumulative time spent in the lit box (R(2)=0.612, P<0.01) and number of entries into the lit box (R(2)=0.661, P<0.01). These results suggest a positive relationship between peripheral oxidative status and level of anxiety in mice.     

Fluoxetine disrupts the integration of anxiety and aversive memories.

Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.     

A mixed polyunsaturated fatty acid diet normalizes hippocampal neurogenesis and reduces anxiety in serotonin transporter knockout rats

The aim of this study was to investigate the effects of a mixed dietary intervention on behavioral symptoms in serotonin transporter knockout (5-HTT?/?) rats modeling the human 5-HTT length polymorphic region short-allele. Twenty female 5-HTT?/? and 19 wild-type (5-HTT?/?) rats were fed for 3 months on a mixed polyunsaturated fatty acid (PUFA) diet comprising n-3 PUFAs, B vitamins and phospholipids, or an isocaloric control diet, and a subgroup was subsequently tested in an array of anxiety-related behavioral tests. All brains were harvested and immunostained for doublecortin, a neurogenesis marker. In addition, hippocampal volume was measured. 5-HTT?/? rats on the control diet displayed increased anxiety-related behavioral responses, and impaired fear extinction. These effects were completely offset by the mixed PUFA diet, whereas this diet had no behavioral effect in 5-HTT?/? rats. In parallel, dentate gyrus doublecortin immunoreactivity was increased in 5-HTT?/? rats fed on the control diet, which was reversed by the mixed PUFA diet. Hippocampal volume was unaffected by the mixed PUFA diet in 5-HTT?/? subjects, whereas it increased in 5-HTT?/? rats. We conclude that a mixed n-3 PUFA diet ameliorates anxiety-related symptoms in a genotype-dependent manner, potentially by normalizing neurogenesis. We suggest that such a mixed diet may serve as an attractive adjuvant to treat anxiety in 5-HTT length polymorphic region short-allele carriers.     

Symptom Reduction and Sobriety in the Male Alcoholic

The relationship between subjective symptom reduction and sobriety was studied for 82 male alcoholics who had completed an inpatient Alcoholic Rehabilitation Unit that included six or more biofeedback/relaxation sessions. Specific symptom relief for anxiety was significantly correlated with sobriety. In addition, the reduction of symptoms showed a positive trend with sobriety. The discussion focuses on the relationship of anxiety-related symptoms and alcohol abuse.     

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites.

Clinically, it is well known that chronic pain induces depression, anxiety, and a reduced quality of life. There have been many reports on the relationship between pain and emotion. We previously reported that chronic pain induced anxiety with changes in opioidergic function in the central nervous system. In this study, we evaluated the anxiolytic-like effects of several types of antidepressants under a chronic neuropathic pain-like state and searched for the brain site of action where antidepressants show anxiolytic or antinociceptive effects. Sciatic nerve-ligated mice exhibited thermal hyperalgesia and tactile allodynia from days 7 to 28 after nerve ligation. At 4 weeks after ligation, these mice showed a significant anxiety-related behavior in the light-dark test and the elevated plus-maze test. Under these conditions, repeated administration of antidepressants, including the tricyclic antidepressant (TCA) imipramine, the serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran, and the selective serotonin reuptake inhibitor (SSRI) paroxetine, significantly prevented the anxiety-related behaviors induced by chronic neuropathic pain. These antidepressants also produced a significant reduction in thermal hyperalgesia and tactile allodynia. Moreover, the microinjection of paroxetine into the basolateral amygdala or cingulate cortex reduced anxiety-related behavior, and microinjection into the primary somatosensory cortex significantly attenuated thermal hyperalgesia. These findings suggest that serotonergic antidepressants are effective for treating anxiety associated with chronic neuropathic pain and may be useful for treating neuropathic pain with emotional dysfunction such as anxiety. Furthermore, SSRIs show anxiolytic and antinociceptive effects by acting on different brain regions.     

Serotonin transporter gene variants and behavior: a comprehensive review

The serotonin system modulates affective, cognitive and behavioral processes. A key molecular structure of this system, the serotonin transporter (SERT) gene, has been associated with many human behaviors, both normal and pathological. This article aim is a comprehensive overview of the human behavioral features influenced by SERT gene variants and to suggest some comprehensive hypotheses. In particular, the SERTPR insertion/deletion polymorphism has been related to hippocampal volume and amygdala response and it has been found to influence anxiety-related personality traits and anxiety disorders; in mood disorders it showed some influences on age at onset, periodicity, illness recurrence, rapid cycling, antidepressants response and depressive reaction to stressful life events. Psychosomatic disorders, suicide, alcoholism, smoking, eating disorders, attention deficit hyperactivity disorders and autism have been also found to be related to SERTPR variants. SERT gene variants seem therefore to modulate a wide range of aspects in both normal and affected individuals, many of which are possibly due to indirect correlations between such human features.     

Implication of neuropeptide-Y Y2 receptors in the effects of immune stress on emotional, locomotor and social behavior of mice

Neuropeptide Y (NPY) is involved in the regulation of emotional behavior, and there is indirect evidence for a role of NPY in the cerebral responses to peripheral immune challenge. Since the NPY receptors involved in these reactions are not known, we investigated the effect of Escherichia coli lipopolysaccharide (LPS) on emotional, locomotor and social behavior, body temperature and circulating corticosterone in female Y2 (Y2-/-) and Y4 (Y4-/-) receptor knockout mice. LPS (0.1mg/kg injected IP 2.5h before testing) increased rectal temperature in control and Y4-/- mice to a larger degree than in Y2-/- animals. Both Y2-/- and Y4-/- mice exhibited reduced anxiety-related and depression-like behavior in the open field, elevated plus-maze and tail suspension test, respectively. While depression-like behavior was not changed by LPS, anxiety-related behavior was enhanced by LPS in Y2-/-, but not control and Y4-/- animals. Y2-/- mice were also particularly susceptible to the effect of LPS to attenuate locomotor behavior and social interaction with another mouse. The corticosterone response to LPS was blunted in Y2-/- mice which presented elevated levels of circulating corticosterone following vehicle treatment. These data show that Y2-/- mice are particularly sensitive to the effects of LPS-evoked immune stress to attenuate locomotion and social interaction and to increase anxiety-like behavior, while the LPS-induced rise of temperature and circulating corticosterone is suppressed by Y2 receptor knockout. Our observations attest to an important role of endogenous NPY acting via Y2 receptors in the cerebral response to peripheral immune challenge.     

Synaptic gating and ADHD: a biological theory of comorbidity of ADHD and anxiety.

To derive a biologically based theory of comorbidity in Attention Deficit Hyperactivity Disorder (ADHD). Theoretical concepts and empirical studies were reviewed to determine whether the behavioral inhibition concept provided an understanding of biological processes involved in comorbidity in ADHD. Empirical studies of ADHD have shown comorbidity of ADHD and anxiety, while studies of behavioral inhibition tend to suggest independent disruptive and anxiety traits. This paradox can be resolved by an understanding of the dynamics of mesolimbic dopamine (DA) systems, where reward and delay of reinforcement are determined by tonic/phasic DA relationships, resulting in impulsive 'fearless' responses when impaired. On the other hand, comorbid anxiety is related to impaired synaptic processes, which selectively gate fear (or aggressive) responses from the amygdala at the accumbens. Monosynaptic convergence between prefrontal, hippocampal, and amygdala projection neurons at the accumbens allows the operation of a synaptic gating mechanism between prefrontal cortex (PFC), hippocampus, and amygdala. Impairment of this mechanism by lowered PFC inhibition allows greater amygdala input, and anxiety-related processes more impact, over the accumbens. In conclusion, a dual theory incorporating long-term tonic/phasic mesolimbic DA relationships and secondly impairment of PFC and hippocampal inputs to synaptic gating of anxiety at the accumbens has implications for comorbidity in ADHD, as well as for possible pharmacological interventions, utilizing either stimulant or axiolytic interventions. The use of DA partial agonists may also be of interest.     

Neuropeptides in anxiety modulation

This review is focused on the involvement of neuropeptides in the modulation of physiological and pathological anxiety. Neuropeptides play a major role as endogenous modulators of complex behaviours, including anxiety-related behaviour and psychopathology, particularly due to their high number and diversity, the dynamics of release patterns in distinct brain areas and the multiple and variable modes of interneuronal communication they are involved in. Manipulations of central neuropeptidergic systems to reveal their role in anxiety (and often comorbid depression-like behaviour) include a broad spectrum of loss-of-function and gain-of-function approaches. This article concentrates on those neuropeptides for which an involvement as endogenous anxiolytic or anxiogenic modulators is well established by such complementary approaches. Particular attention is paid to corticotropin-releasing hormone (CRH) and vasopressin (AVP) which, closely linked to stress, neuroendocrine regulation, social behaviour and learning/memory, play critical roles in the regulation of anxiety-related behaviour of rodents. Provided that their neurobiology, neuroendocrinology and molecular-genetic background are well characterized, these and other neuropeptidergic systems may be promising targets for future anxiolytic strategies.     

Transdiagnostic processes linking anxiety symptoms and substance use problems among adolescents

Numerous anxiety syndromes co-occur with substance use problems in adolescents, though the mechanisms underlying these comorbidities are not well understood. There are 3 transdiagnostic processes—anxiety sensitivity (fear of anxiety-related sensations), distress tolerance (capacity to withstand emotional distress), and negative urgency (propensity to respond impulsively to negative emotion)—that have been implicated in various anxiety and substance use problems. To examine whether anxiety sensitivity, distress tolerance, and negative urgency statistically mediated relations between symptoms of 3 different anxiety disorders (social anxiety, generalized anxiety, and panic disorders) and alcohol and cannabis use problems, cross-sectional analysis of high school students in Los Angeles (N = 3002) was assessed via paper and pencil questionnaires. When mediators were entered simultaneously, negative urgency accounted for a significant 33 to 85% of the covariance between anxiety symptomatology and substance use problems over and above the other trandiagnostic processes. This pattern was consistent across all 3 anxiety syndromes and both alcohol and cannabis problems. Anxiety sensitivity and distress tolerance did not account for positive associations between anxiety symptoms and substance use problems. Negative urgency may be an important mechanism underlying the relationship between various types of anxiety and substance use problems in adolescence, and thus represents a possible target for preventive interventions targeting adolescent anxiety and substance use.     

Alcohol self-administration in two rat lines selectively bred for extremes in anxiety-related behavior.

According to the tension reduction hypothesis, individuals with an elevated anxiety level may be more sensitive to the anxiolytic effects of alcohol and may, therefore, have a higher predisposition to consume alcohol. To examine this hypothesis, we studied the drinking behavior as well as the sensitivity to the anxiolytic effect of alcohol in two rat lines that were bred and selected for differences in anxiety-related behavior on the elevated plus-maze: the extremely anxious HAB (high anxiety-related behavior) and the non-anxious LAB (low anxiety-related behavior) lines. Alcohol self-administration and the occurrence of an alcohol deprivation effect were studied in female and male HAB and LAB rats in a free-choice, 4-bottle home cage paradigm. The sensitivity of HAB and LAB rats to the anxiolytic effect of alcohol was assessed by testing their behavior on the elevated plus-maze after an acute application of ethanol. During the first days of voluntary ethanol drinking, the ethanol intake and preference of female LABs was significantly higher than that of female HABs. Although not statistically significant, the same trend could be seen in male LABs. Moreover, male as well as female LAB but not HAB rats showed a significant alcohol deprivation effect after abstinence. There were no differences when saccharin was presented to naive animals, indicating that the different ethanol drinking behavior of HAB and LAB rats does not represent a general difference in the consumption of new liquids. Application of ethanol resulted in an anxiolytic effect in HAB but not in LAB rats on the elevated plus-maze. In summary, increased inborn anxiety and voluntary ethanol consumption of HAB and LAB rats were correlated to some extent; however, this relationship was a negative one. It is concluded that, although such a relationship might exist in some individuals, increased levels of inborn anxiety and alcohol consumption are not necessarily related.