Mano Aliczki

Effects of Endocannabinoid System Modulation on Cognitive and Emotional Behavior

Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain’s endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotines effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

Classical and novel approaches to the preclinical testing of anxiolytics: A critical evaluation

Over 80% of current anxiety studies employ one of the tests that were developed earlier than, or concurrently with the elevated plus-maze, i.e. before 1985. Considering 1985 as a historical reference point, we briefly review here 115 new tests and models of anxiety, the development of which was likely prompted by the poor predictive validity of classical tests as shown here by the comparison of preclinical and clinical findings with putative novel anxiolytics. The new approaches comprise major innovations to classical tests, the pre-test application of manipulations that mimic etiological factors of anxiety disorders, and entirely new approaches including anxiety disorder-specific tests. Thus, intensive test development over the last 27 years created a large pool of novel approaches. However, these are infrequently used and as such, their impact on anxiolytic drug development remains low. We suggest here that test/model development should step over the intensive phase when several new methods are proposed each year and should start selecting and establishing the methodologies that would successfully replace or complement classical tests. We propose here a novel strategy for improving the validity of anxiety testing that includes the retrospective analysis of the predictive validity of new procedures (as opposed to classical pharmacological validation), and a call for concerted international efforts at both the conceptual and practical levels. Similar endeavors proved recently successful with other psychiatric disorders.

The temporal dynamics of the effects of monoacylglycerol lipase blockade on locomotion, anxiety, and body temperature.

Studies with the monoacylglycerol lipase blocker JZL184 have suggested that enhanced 2-arachidonoylglycerol signaling suppresses locomotion, lowers body temperature, and decreases anxiety. Although the neurochemical effects of JZL184 develop within 30 min, its behavioral and autonomic effects have been studied much later. To clarify temporal dynamics, we studied the effects of intraperitoneal injections of JZL184 in mice on home-cage locomotion and body temperature for 120 min using in-vivo biotelemetry. We also studied the effects of 4, 8, and 16 mg/kg JZL184 in the open field and elevated plus maze at various time points. In the home cage, JZL184 blunted injection-induced body temperature increases but exerted no long-term effects. Vehicle injections increased the duration of rapid movements whereas the duration of motionless periods was decreased, a pattern also abolished by JZL184. Although the highest dose exerted a mild long-term effect on the relative duration of motionless periods, JZL184 seemed to have phasic rather than tonic effects in the home cage. By contrast, open field and plus maze behavior was affected 80 and 120 min but not 40 min after treatments, which may indicate tonic rather than phasic effects in these tests. Our findings confirm earlier reports of a mild anxiolytic effect of JZL184, but surprisingly, the compound markedly and dose dependently increased locomotion in the open field in both CD1 and C57BL/6J mice. These findings are difficult to reconcile at present, but suggest that the effects of monoacylglycerol lipase inhibition are more complex than previously believed and may depend strongly on as yet unidentified factors such as environmental conditions, the time of testing, species/strains, etc.

Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission

Neuroanatomical findings revealed that CB1 cannabinoid and 5-HT3 receptors are coexpressed by a subtype of &ggr;-aminobutyric acid (GABA)ergic interneurons in the prefrontal cortex, hippocampus, and basolateral amygdala, three brain regions that are crucial for the control of anxiety. In these regions, serotonergic inputs increase GABA release through 5-HT3 receptors, the phenomenon being retrogradely controlled by cannabinoid neurotransmission. This suggests a functional interaction between 5-HT3 neurotransmission and CB1 signaling. In a first attempt to investigate the behavioral relevance of these interactions, we studied the effects of the selective 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (mCPBG), on plus-maze behavior in NMRI, CD1 wild type, and CB1-KO mice. The genetic disruption of CB1 receptors consistently increased anxiety. This effect was significantly decreased by the 5-HT3 agonist, mCPBG. The dose–response curve was bell-shaped. Surprisingly, mCPBG did not affect the behavior of CD1 wild type and NMRI mice. We hypothesize that in the aforementioned regions, 5-HT3 activation decreases anxiety by promoting GABA release, but this effect is dampened by CB1 signaling. The disruption of CB1 receptors in CB1-KOs released GABA neurons from retrograde inhibition and made the effects of 5-HT3 stimulation conspicuous. Altogether, our findings reveal a functional interaction between 5-HT3 neurotransmission and CB1 signaling. Besides this interaction being an interesting aspect of anxiety control, it may also explain the notoriously inconsistent effects of 5-HT3 ligands on anxiety. If 5-HT3 neurotransmission and CB1 signaling interact, the anxiety-related effects of 5-HT3 ligands may depend on species, strain, and situation-related differences in both 5-HT3 and CB1 receptor expression and function.

The effects of anandamide signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats

RationaleCoping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids.ObjectivesHere, we tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles.MethodsRats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions.ResultsUnder the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both “wariness” induced by aversive conditions and “carelessness” resulting from favorable conditions.ConclusionsURB597 treatment-induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Albeit further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable.

The effects of vasopressin deficiency on aggression and impulsiveness in male and female rats

The role of vasopressin in aggression received much attention in recent years. However, vasopressin has complex roles on social behavior, which are affected by social experience, motivation and hormonal background, suggesting that its effects depend on the condition of subjects. This hypothesis was tested here by studying the impact of vasopressin deficiency on aggressiveness in reproductively naive and reproductively experienced males, as well as in lactating females, with special reference to the patterns and contexts of attack behavior. We also studied effects on impulsiveness, a behavioral feature strongly related to aggression. Vasopressin deficiency did not affect aggressiveness in reproductively experienced males, decreased the share of violent attacks in reproductively inexperienced males without affecting total attack counts, and suppressed maternal aggression in both early and late phases of lactation; violent forms of attack were decreased in the latter but not the former phase. Changes in aggression appeared unrelated to general changes in maternal behaviors. Impulsivity in the delay discounting task was markedly decreased by vasopressin deficiency in lactating females but not males. Taken together, our findings confirm that vasopressin has an impact on aggressiveness, but show that this impact depends on the condition of subjects, and suggest that the effects of vasopressin on maternal aggression develop in conjunction with impulsivity. Interestingly, overall effects on aggression and specific effects on violent attacks dissociated in both males and females, which hints to the possibility that vasopressin has distinct roles in the development of escalated forms of aggression.

Temporal changes in c-Fos activation patterns induced by conditioned fear

Mechanisms underlying shock-induced conditioned fear - a paradigm frequently used to model posttraumatic stress disorder, PTSD - are usually studied shortly after shocks. Some of the brain regions relevant to conditioned fear were activated in all the c-Fos studies published so far, but the overlap between the activated regions was small across studies. We hypothesized that discrepant findings were due to dynamic neural changes that followed shocks, and a more consistent picture would emerge if consequences were studied after a longer interval. Therefore, we exposed rats to a single session of footshocks and studied their behavioral and neural responses one and 28 days later. The neuronal activation marker c-Fos was studied in 24 brain regions relevant for conditioned fear, e.g. in subdivisions of the prefrontal cortex, hippocampus, amygdala, hypothalamic defensive system, brainstem monoaminergic nuclei and periaqueductal gray. The intensity of conditioned fear (as shown by the duration of contextual freezing) was similar at the two time-points, but the associated neuronal changes were qualitatively different. Surprisingly, however, Multiple Regression Analyses suggested that conditioned fear-induced changes in neuronal activation patterns predicted the duration of freezing with high accuracy at both time points. We suggest that exposure to electric shocks is followed by a period of plasticity where the mechanisms that sustain conditioned fear undergo qualitative changes. Neuronal changes observed 28 days but not 1 day after shocks were consistent with those observed in human studies performed in PTSD patients.

Interactions Between Cannabinoid Signaling and Anxiety: A Comparative Analysis of Intervention Tools and Behavioral Effects

Cannabinoid signaling is believed to decrease anxiety, albeit the conflicting nature of evidence is generally acknowledged. Here we provide a comprehensive overview of available findings by grouping them according to the tools that have been used to modulate cannabinoid signaling. The systemic administration of cannabinoid receptor agonists and antagonists led to the most conflicting findings; such treatments may increase, decrease, or leave anxiety unaffected. In addition, antagonists and agonists had similar effects in many instances including their biphasic effects. The effects of genetic manipulations, cannabinoid synthesis or reuptake inhibition as well as the effects of local brain treatments with cannabinoid ligands appear more consistent. We suggest that systemically administered receptor ligands affect cannabinoid signaling globally and as such lack the spatial and temporal specificity of endocannabinoid signaling. By contrast, gene disruption and the indirect modulation of endocannabinoid availability affect ongoing (natural) processes and lead to more specific and consistent effects. Local brain treatments whit receptor ligands are spatially restricted which increases the consistency of findings, but also reveals that cannabinoids affect anxiety in a brain area-specific manner, which further explains the inconsistency of findings with systemically injected ligands. Environmental conditions have a large impact on effects with all techniques, suggesting that endocannabinoid signaling affects coping with environmental challenges rather than unconditionally decreasing anxiety. The relationship between cannabinoid signaling, anxiety and coping styles is largely understudied, but holds great promise for understanding the roles of cannabinoids in behavioral control and may broaden their therapeutic implications.

The effects of lactation on impulsive behavior in vasopressin-deficient Brattleboro rats

Vasopressin (AVP)-deficient Brattleboro rats develop a specific behavioral profile, which-among other things-include altered cognitive performance. This profile is markedly affected by alterations in neuroendocrine state of the animal such as during lactation. Given the links between AVP and cognition we hypothesized that AVP deficiency may lead to changes in impulsivity that is under cognitive control and the changes might be altered by lactation. Comparing virgin and lactating AVP-deficient female Brattleboro rats to their respective controls, we assessed the putative lactation-dependent effects of AVP deficiency on impulsivity in the delay discounting paradigm. Furthermore, to investigate the basis of such effects, we assessed possible interactions of AVP deficiency with GABAergic and serotonergic signaling and stress axis activity, systems playing important roles in impulse control. Our results showed that impulsivity was unaltered by AVP deficiency in virgin rats. In contrast a lactation-induced increase in impulsivity was abolished by AVP deficiency in lactating females. We also found that chlordiazepoxide-induced facilitation of GABAergic and imipramine-induced enhancement of serotonergic activity in virgins led to increased and decreased impulsivity, respectively. In contrast, during lactation these effects were visible only in AVP-deficient rats. These rats also exhibited increased stress axis activity compared to virgin animals, an effect that was abolished by AVP deficiency. Taken together, AVP appears to play a role in the regulation of impulsivity exclusively during lactation: it has an impulsivity increasing effect which is potentially mediated via stress axis-dependent mechanisms and fine-tuning of GABAergic and serotonergic function.