Nicotine psychopharmacology research: advancing science, public health, and global policy.
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Animals↗
Biomedical subjects
Klaus A Miczek
Publications and source records attributed to Klaus A Miczek.
Multidisciplinary perspectives on impaired control over substance use.
This article presents the proceedings of a symposium held at the June 2005 meeting of the Research Society on Alcoholism in Santa Barbara, California. Impaired control over substance use has long been considered a central feature of alcohol and drug dependence. However, much remains to be learned about the nature of impaired control, the mechanisms by which acute and chronic substance use can lead to impaired control, and how this construct is best assessed in the laboratory and the clinic. The goal of this symposium was to describe current perspectives on impaired control over alcohol and drug use from diverse research areas, to promote future multidisciplinary work in this area. Four speakers described their work on impaired control using human clinical samples (Dr. Chung), animal models (Dr. Miczek), experimental laboratory paradigms in humans (Dr. Fillmore), and neuroimaging studies (Dr. Easdon). Taken together, the talks highlighted the heterogeneous nature of constructs such as impaired inhibitory control, and patterns of impulsive and compulsive substance use. Future clinical and experimental research should attempt to carefully define and measure particular aspects of impaired control and to seek insights from other disciplines.
Alcoholism↗
Escalated aggressive behavior: dopamine, serotonin and GABA.
The ethical dilemma in aggression research is how to reconcile two divergent objectives, namely to avoid harm and injury as much as possible and, at the same time, how to study behavioral phenomena that validly represent the essence of the neurobiology of aggression. Clinical and preclinical aggression research focuses on different types of aggression. Preclinical studies are usually stimulated by an ethological approach and focus on the phylogeny, ontogeny, survival value and neural mechanisms of ritualized displays and signals. On the other hand, clinical studies focus on violent individuals and pathologically excessive forms of aggressive behavior. This review emphasizes research on escalated forms of aggression in animals and humans and their pharmacotherapy. The current experimental models to generate escalated levels of aggressive behavior in laboratory rely on social instigation, frustrative non-reward and alcohol drinking. These types of aggression are modulated by canonical neurotransmitters like dopamine, serotonin (5-HT) and GABA. It continues to be a main goal of much neurobiological research to find potential targets of pharmacological agents that interact with dopaminergic, GABAergic and serotonergic systems and have high efficacy and selectivity to reduce excessive levels of aggressive and violent behaviors without side-effects. While the mesocorticolimbic dopamine system is implicated in the initiation, execution, termination and consequences of aggressive behavior, drugs with a high affinity for dopamine D2 receptors lack specificity for reducing aggressive behavior. Current investigations point to 5-HT(1B) receptor subtypes as particularly relevant. First, they are differentially expressed in aggression-prone individuals relative to those who are not excessively aggressive. Second, these and also other 5-HT receptor subtypes emerge to be significant targets for anti-aggressive interventions. Positive modulators of GABA(A) receptors with specific subunit configuration may be relevant for heightening aggression, and these sites may be targets for intervention. A prerequisite for rational pharmacotherapies will be adequate characterization of serotonergic and GABAergic receptor regulation in individuals exhibiting escalated aggression.
Aggression↗
Serotonin and aggressive behavior in rodents and nonhuman primates: predispositions and plasticity.
This review analyzes psychosocial and genetic determinants of aggressive behavior in rodents and nonhuman primates and the role of the serotonin (5-HT) system on aggressive behaviors in order to trace possible evolutionary common origins between psychopathological and adaptive forms of aggression. Studies in primates suggest that deficit in serotonin activity, as indicated by the levels of the cerebrospinal fluid (CSF) serotonin major metabolite 5-hydroxyindoleacetic acid (5-HIAA) correlates with impulsive and aggressive behavior. It is possible that CSF 5-HIAA reflects the prevailing serotonergic tone and may be related to an aggressive trait. Superimposed on this tone are phasic serotonin changes that may be related to the inhibition of aggressive acts. Genetic factors determine aggressive behaviors as demonstrated by classic selection and strain comparison studies. Manipulations of genes targeting 5-HT receptors, transporters and enzymes can influence aggression. Some of these genes related to the serotonin transporter (5-HTT) and the monoamine oxidase A (MAO-A) show a polymorphism that may predispose, under specific environmental conditions, certain individuals to display pathological forms of aggression.
Aggression↗
Intense cocaine self-administration after episodic social defeat stress, but not after aggressive behavior: dissociation from corticosterone activation.
RATIONALE: An intense stress response characterizes both the dominant and submissive individuals during an aggressive confrontation, and these stress responses have enduring neural and behavioral consequences. OBJECTIVES: In spite of similar glucocorticoid and corticolimbic dopamine activation, dominant and defeated individuals appear to diverge in terms of their drug taking. Do rats that are intermittently subjected to defeat stress become more sensitized to cocaine taking relative to rats that engage in aggressive bouts? METHODS: Separate groups of male Long-Evans rats were investigated after an initial 10-day period with four brief episodes of social defeat (intruders) or aggressive behavior (residents): (1) the corticosterone responses to the very first and the last confrontations were measured; (2) the locomotor response to an amphetamine (1 mg/kg) challenge 10 days after the last stress exposure served as an index of behavioral sensitization; (3) intravenous self-administration sessions assessed the reinforcing effects of 0.75 mg/kg/infusion cocaine when available after every fifth response (fixed ratio), when delivered after completing progressively more demanding response requirements (progressive ratio; 0.3 mg/kg/infusion), and when available during a 24-h binge of continuous access (0.3 mg/kg/infusion). RESULTS: Both social defeat of the intruder rat and attack behavior by the resident rat rapidly increased plasma levels of corticosterone after the first and last aggressive confrontation, indicating no habituation to these types of stress. Intermittent social defeat engenders a sensitized locomotor response to a 1 mg/kg amphetamine challenge and increases cocaine self-administration as indicated by more behavioral effort to obtain cocaine infusions and by accumulating more cocaine during 24 h of continuous access (binge). By contrast, experiences with aggressive behavior do not impact on the motorically activating and reinforcing effects of stimulant administrations. CONCLUSIONS: The closely similar corticosterone activation in dominant and subordinate rats, followed by divergent patterns of cocaine self-administration indicates that different forms of social stress have dissociable effects on cocaine taking.
Aggression↗
Escalated aggression as a reward: corticosterone and GABA(A) receptor positive modulators in mice.
RATIONALE: Individuals seek out the opportunity to fight, but the mechanisms behind this positively reinforcing effect of aggression have yet to be understood. OBJECTIVES: The aims of this study were to (1) describe behavioral and corticosterone elevations that occur in aggressive mice conditioned to respond for the opportunity to fight another mouse, (2) determine if corticosterone elevations are necessary for operant responding and escalated aggression, and (3) determine if corticosterone elevations alter the aggression-heightening effects of gamma-aminobutyric acid (GABA)(A) receptor positive modulators. METHODS AND RESULTS: Aggressive male CFW mice were conditioned to respond under the control of a fixed-interval 10-min (FI10) schedule that reinforced their operant behavior by the presentation of an intruder mouse into their home cage. After the FI10, aggressive behavior was ca. 75% higher than the species-typical levels of fighting and plasma corticosterone was more than twice as high after briefly fighting and/or responding on the FI10 schedule. Inhibition of corticosterone synthesis by metyrapone (30-100 mg/kg) reduced both conditioned responding as well as the aggressive behavior after the FI. Although the benzodiazepine midazolam (0.3-3 mg/kg) heightened species-typical aggressive behavior, it did not increase the high level of aggression engendered by the FI schedule. However, midazolam (0.3 mg/kg) and the neurosteroid allopregnanolone (17 mg/kg) both heightened aggression when given after corticosterone synthesis inhibition by metyrapone (56 mg/kg). CONCLUSIONS: These data suggest that corticosterone elevations are required for responding that is motivated by aggressive behavior and for escalated aggression that follows this responding. Corticosterone elevations also appear to inhibit the aggression heightening effect of GABA(A) receptor positive modulators.
Aggression↗
Glutamate receptor subtypes: promising new pharmacotherapeutic targets.
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Animals↗
Brief social defeat stress: long lasting effects on cocaine taking during a binge and zif268 mRNA expression in the amygdala and prefrontal cortex.
Social stress can engender behavioral and neural sensitization and this process appears to enhance the transition to compulsive drug abuse. Exposures to brief social defeat stress in rats have significant consequences on cocaine-reinforced behavior and on the level of functional activation within regions of the mesocorticolimbic dopamine system. The objectives of the current study were to examine the enduring consequences of brief episodes of social defeat stress on cocaine bingeing (during 24 h of continuous access) and on the emergence of neural adaptations as revealed by zif268 immediate early gene expression. Adult, male Long-Evans rats were subjected to four 25 min episodes of social defeat (once every 72 h). After 2 months, cocaine binges or zif268 mRNA gene expression were studied after confirming behavioral cross-sensitization to stimulant challenge. Sensitization to social defeat increased cocaine intake during a 24 h binge, effectively abolishing the typical circadian pattern of intake. Furthermore, 60 days after exposure to the sensitizing regimen of social defeat, levels of functional activation, measured by zif268 mRNA expression, in the central and medial amygdala were increased, while levels of activation in the medial prefrontal cortex were decreased. Persistent stress-induced levels of zif268 in the central and medial amygdala were attenuated by an injection of amphetamine (1.0 mg/kg). Divergent changes in zif268 within the amygdala and cortex 2 months after social defeat stress indicate the vulnerability of distinct cellular populations in networks that modulate the behavioral actions of psychomotor stimulants.
Amphetamine↗
Prolonged effects of repeated social defeat stress on mRNA expression and function of mu-opioid receptors in the ventral tegmental area of rats.
Social defeat stress alters the activity of mesocorticolimbic dopamine projections from the ventral tegmental area (VTA), a process that has been implicated in the development of sensitization and drug-seeking behavior. We showed previously that acute brief social defeat stress increased short-term expression of mu-opioid receptor mRNA in the VTA. The present study assessed the presence and functional significance of mu-opioid receptor mRNA expression 1 week after the last episode of social defeat stress. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat, and subsequent exposures behind a protective screen once a day for 5 days. Regional mu-receptor mRNA levels were assessed by in situ hybridization histochemistry, and the amount of mRNA labeling was measured in the VTA and the substantia nigra (SN). Expression of mu-opioid receptor mRNA was significantly higher in defeated rats relative to handled control animals in the VTA, but not in the SN. In an additional group of rats, bilateral local intra-VTA injection of the selective mu-opioid receptor agonist DAMGO (1.0 microg per side) was performed 7-10 days after the last defeat stress or handling control procedure. Baseline motor activity did not differ between control and stressed rats. Intra-VTA DAMGO significantly increased locomotor activity in stressed rats compared to handled control rats. These results suggest that repeated social stress upregulates VTA mu-opioid receptors and can produce locomotor activation via stimulation of these receptors. This locomotor effect is probably the consequence of enhanced disinhibition of mesolimbic dopamine neurons.
Analgesics, Opioid↗
Overview of workshop on drug abuse and suicidal behavior.
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Adolescent↗
Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors.
RATIONALE: Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear. OBJECTIVE: We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801). METHODS: In adult, male CFW mice, sensitization was induced by either ten daily injections of D-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined. RESULTS: The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization. CONCLUSIONS: These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.
Amphetamine↗
Repeated maternal separation: differences in cocaine-induced behavioral sensitization in adult male and female mice.
RATIONALE: Repeated maternal separations profoundly alter the adult stress response, the development of the hypothalamic-pituitary-adrenal axis, and prominently, the GABAergic and monoaminergic systems. These neural changes are postulated to influence the vulnerability to drugs of abuse implicating glucocortocoids in the behavioral responses to psychomotor stimulants. OBJECTIVE: To investigate whether repeated brief maternal separation stress increases behavioral sensitization to cocaine in adult male and female mice, and to assess any concurrent changes in hippocampal glucocorticoid receptors and accumbal dopamine transporters. METHODS: Half of the litters were separated from the nest for 1 h/day from post-natal days 1 to 13. Starting on post-natal day 50, all mice were injected with either cocaine (10.0 mg/kg) or saline for 10 consecutive days. Locomotor activity was assessed in an open field on days 50, 54 and 59 via a tracking system. Approximately 10 and 40 days later, all mice were challenged with 7.5 mg/kg cocaine. RESULTS: Repeated maternal separation increased the hyperlocomotor response to 10.0 mg/kg cocaine regardless of gender. During expression tests (days 69/71, 99), male, but not female, mice with a history of maternal separation exhibited significant sensitized hyperactivity in response to cocaine. Male mice that were maternally separated and had no history of cocaine sensitization, demonstrated cross-sensitization to 7.5 mg/kg cocaine. Immunohistochemical analysis revealed that the hippocampal CA1 glucocorticoid receptor and nucleus accumbens dopamine transporter proteins were expressed more in females than in males, regardless of maternal separation experience. CONCLUSIONS: Repeated maternal separation is a stressor that can induce heightened sensitivity to low doses of cocaine, as expressed by hyperactivity. Furthermore, sex differences in glucocorticoid receptor and dopamine transporter expression may be responsible for the sexual dimorphic expression of behavioral sensitization to cocaine.
Animals↗
Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists.
RATIONALE: Positive modulators of the benzodiazepine/GABA(A) receptor complex can heighten aggressive behavior; the GABA(A)/alpha(1) subunit may play a critical role in benzodiazepine-modulated aggressive behavior. OBJECTIVE: The carboline derivatives, beta-CCt and 3-PBC, antagonists with preferential action at the GABA(A) receptors with alpha(1) subunits, may antagonize benzodiazepine-heightened aggression, thus implicating the alpha(1) subunit in heightened aggression. METHODS: The GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4c]-pyridin-3-ol (THIP) (0.01-3.0 mg/kg), and the benzodiazepine receptor agonists midazolam (0.3-3.0 mg/kg) and triazolam (0.003-3.0 mg/kg) were administered to adult male resident rats to assess the drugs' effects on their aggressive behavior toward an intruder. Then beta-CCt (0.3-10.0 mg/kg) and 3-PBC (0.3-17.0 mg/kg) were each administered in conjunction with midazolam. The salient elements of aggressive and non-aggressive behavior were measured by analyzing video recordings and encoding each behavioral act and posture in terms of its frequency and duration of occurrence. RESULTS: Midazolam significantly increased the duration of aggressive behaviors at 1.0 and 1.7 mg/kg, and triazolam increased attack bite frequency at 0.03 mg/kg, both implicating GABA(A) receptors with benzodiazepine binding sites in aggressive behavior. In the present dose range, THIP did not affect any behaviors. The broad-spectrum benzodiazepine antagonist, flumazenil (1.0 mg/kg), antagonized the aggression-heightening effects of midazolam. beta-CCt (0.3-10.0 mg/kg) and 3-PBC (0.3-17.0 mg/kg) also antagonized the aggression-heightening effects of midazolam (1.0 mg/kg). CONCLUSIONS: These results implicate both the GABA(A) gamma and alpha(1) subunits in benzodiazepine-heightened aggression.
Aggression↗
Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits.
The question of how ostensibly aversive social stress experiences in an aggressive confrontation can persistently increase intense drug taking such as cocaine 'bingeing' needs to be resolved. The biology of social conflict highlights distinctive behavioral, cardiovascular and endocrine profiles of dominant and subordinate animals, as seen also in rodents and primates under laboratory conditions. In contrast to continuous subordination stress that produces chronic pathophysiological consequences and often is fatal, animals adapt to brief episodes of social defeat stress, but show enduring functional activation in mesocorticolimbic microcircuits. Uncontrollable episodes of social defeat stress produce long-lasting tolerance to opiate analgesia and, concurrently, behavioral sensitization to challenges with either amphetamine or cocaine. One week after a single social defeat stress, cross-sensitization to cocaine is evident in terms of enhanced motor activity as well as in terms of increased Fos labeling in the periaqueductal grey area, the locus coeruleus, and the dorsal raphe nuclei. When challenged with a low amphetamine dose, the behavioral and neural effects of repeated brief episodes of social defeat stress persist for months. Previous exposure to social defeat stress can (1). significantly shorten the latency to acquire cocaine self-administration, (2). maintain this behavior at low cocaine unit doses, (3). significantly increase the levels of cocaine taking during a 24 h binge of continuous drug availability, (4). dysregulate the timing of consecutive infusions, and (5). abolish the circadian pattern of self-administration. Amygdaloid modulation, especially originating from central and basolateral nuclei, of dopaminergic pathways via peptidergic and glutamatergic neurons appears to be a key mechanism by which social defeat stress affects cocaine self-administration. Social stress alters the feedback from prefrontal cortex and thereby may contribute to the dysregulation of dopaminergic activity that is necessary for cocaine self-administration.
Aggression↗
Role of alcohol consumption in escalation to violence.
No other drug has been associated with aggressive and violent behavior more than alcohol has. A major characteristic of the link between alcohol and social interactions is the very large variation in who becomes more aggressive while drinking and who does not. Tracing the origins of these individual differences has led to a focus on predispositions, such as the antisocial behavior of Type 2 alcoholics. Successful development of an experimental procedure to model heightened aggressive behavior after voluntary consumption of alcohol has facilitated the neurobiologic analysis of the link between alcohol and aggression. From a pharmacologic perspective, consumption of low to moderate doses of alcohol engenders heightened aggressive behavior in a significant minority of individuals before the circulation of appreciable amounts of the aldehyde metabolite. Ionophoric receptors such as NMDA, 5-HT(3) and GABA(A) have been identified in the brain as major sites of action for alcohol in the dose range that is relevant for engendering heightened aggression. Actions at the GABA(A) receptor complex that depend on particular GABA(A) subunits appear to be necessary for alcohol-heightened aggression. Genes that encode the synthesis of these alpha and gamma subunits are potentially significant markers for those individuals that are prone to engage in heightened aggressive behavior after the consumption of alcohol. Of particular importance are the reciprocal interactions between GABA and serotonin. Activating specific serotonin receptor subtypes such as 5-HT(1B) receptors reduces alcohol-heightened aggressive behavior. How these GABAergic and serotonergic corticolimbic mechanisms for alcohol-heightened aggression develop during the adolescent period remains an area of urgent study.
Aggression↗
Escalated aggressive behavior: new pharmacotherapeutic approaches and opportunities.
Psychopharmacologic studies of aggressive behavior in animals under controlled laboratory conditions have been instrumental in developing and evaluating specific and effective novel drug treatments that reduce aggressive behavior. An initial contribution of this research is to create experimental conditions that enable the display of aggressive and defensive acts and postures in species that engage in either dominance or territorial or maternal aggression. Quantitative ethological analyses allow the precise delineation of the sequential organization of aggressive bursts, providing a benchmark for assessing excessive or pathological forms of aggressive behavior. A second contribution of preclinical research is the development of experimental models of escalated forms of aggressive behavior, such as focusing on genetic predispositions or social provocations and frustrative experiences. A critical role of preclinical research is in the pharmacological and neurochemical analysis of aggressive behavior; for example, a host of undesirable side effects prompted a shift from classic dopaminergic neuroleptic compounds to the more recently developed atypical neuroleptics with effective and more specific anti-aggressive effects. The long-established role of brain serotonin in impulsive and escalated forms of aggressive behavior continues to be a focus of preclinical studies. New evidence differentiates dynamic state changes in corticolimbic serotonergic neurons during the termination of aggressive behavior from the deficient-serotonin trait in violence-prone individuals. It can be anticipated that currently developed tools for targeting the genes that code for specific subtypes of serotonin receptors will offer new therapeutic options for reducing aggressive behavior, and the 5-HT(1B) receptor appears to be a promising target. The modulation of GABA and GABA(A) receptors by 5-HT in corticolimbic neurons promises to be particularly relevant for specific forms of escalated aggressive behavior such as alcohol-heightened aggression.
Aggression↗
GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice.
RATIONALE: The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved. OBJECTIVE: Beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) and zolpidem act preferentially at GABAA receptors containing the alpha1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression. METHODS: Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists beta-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period. RESULTS: Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or beta-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg beta-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation. CONCLUSIONS: Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.
Aggression↗
Anxiolytic-like effects of escitalopram, citalopram, and R-citalopram in maternally separated mouse pups.
The S-enantiomer of citalopram, escitalopram, is a selective serotonin reuptake inhibitor (SSRI) that appears to be responsible for citalopram's antidepressant and anxiolytic effects. Clinically, escitalopram is reported to have fewer adverse side effects than do other SSRIs. This study compared escitalopram to other antidepressants in a preclinical procedure predicting anxiolytic-like effects of drugs. Carworth Farms Webster (CFW) mouse pups (7 days old) were separated from the dam and maintained at a temperature of 34 degrees C. Forty-five minutes after administering citalopram (0.56-10 mg/kg), escitalopram (0.0056-3 mg/kg), R-citalopram (1-10 mg/kg), paroxetine (0.3-3 mg/kg), fluoxetine (1-30 mg/kg), or venlafaxine (3-56 mg/kg) subcutaneously, the pups were placed individually on a 19.5 degrees C surface for 4 min. Ultrasonic vocalizations (USVs) (30-80 kHz), grid crossing, rolling (i.e., the pup turned on one side or its back), and colonic temperature were recorded. All the drugs reduced USV emission; escitalopram was the most potent (ED(50) 0.05 mg/kg), followed by paroxetine (0.17 mg/kg), citalopram (1.2 mg/kg), fluoxetine (4.3 mg/kg), R-citalopram (6 mg/kg), and venlafaxine (7 mg/kg). The doses that decreased USVs differed from those that increased motor activity. Increased grid crossing occurred after low doses of paroxetine (0.03 or 0.1 mg/kg) and fluoxetine (1 mg/kg), but only after the highest doses of the citalopram enantiomers and venlafaxine (0.3, 10, and 56 mg/kg, respectively). Except for escitalopram and venlafaxine, high doses of the treatments increased rolling. R-Citalopram caused a 10-fold rightward shift in escitalopram's dose-effect curve, suggesting that R-citalopram inhibits escitalopram's anxiolytic-like effects. These data support clinical findings that escitalopram is a potent, well tolerated SSRI with anxiolytic-like effects.
Animals↗