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Biomedical subjects

Klaus A Miczek

Publications and source records attributed to Klaus A Miczek.

9 recordsLinked to original sources
PubMed2003

Vocalizations during withdrawal from opiates and cocaine: possible expressions of affective distress.

Intense anxiety has been postulated to trigger relapse to abuse of opiates and psychomotor stimulants. Preclinical research methodologies need to be developed to adequately characterize the affective or emotional component of withdrawal. Classically, withdrawal from psychomotor stimulants and opiates focuses on somatic and autonomic indices, foremost based on observational assessments and, additionally, on measures of disrupted conditioned behavior. These measures depict the intensity and time course of withdrawal from specific doses of opiates and psychomotor stimulants, but require large numbers of subjects due to single use of each individual. Behavioral disruptions have been attributed to anhedonia, a core symptom of drug withdrawal, as well as major depressive and psychotic disorders. In spite of some pharmacological validation, inferences about anxiety-like disturbances, based on observed somatic and autonomic signs or on changes in conditioned responses, have to remain tentative. High-pitched vocalizations may communicate affective expressions and, in rodents, different kinds of ultrasonic vocalizations communicate maternal separation distress in infants, accompany the intensely arousing phases of agonistic confrontations, signal submission and distress in defensive responses to threats and painful events, and are part of the excitatory and inhibitory phases of sexual behavior. While acute treatment with opiates, psychomotor stimulants, alcohol and benzodiazepines suppresses ultrasonic vocalizations in the 22-25-kHz range, rats emit high rates of ultrasonic vocalizations upon withdrawal from prolonged exposure to these drugs, particularly if they have been startled. Peak rates of ultrasonic distress calls occur ca. 1-3 days after cessation of cocaine or opiate treatment and decline within 5-7 days. Ultrasonic vocalizations during withdrawal from cocaine, alcohol or benzodiazepines can be attenuated by renewed access to the drug. It will be informative to learn how the neural circuit mediating vocalizations interacts with the ones subserving self-administration of alcohol, opiates and psychomotor stimulants.

Animals↗
PubMed2003

5-HT1A agonists: alcohol drinking in rats and squirrel monkeys.

RATIONALE: Increased alcohol intake after administration of low doses of 5-HT(1A )agonists is thought to be due to a reduction in 5-HT impulse flow due to activation of 5-HT(1A) somatodendritic receptors, whereas decreased alcohol drinking found after administration of higher doses of 5-HT(1A) agonists may be mediated by action at postsynaptic 5-HT(1A) receptors. OBJECTIVE: This study compares Long-Evans rats and squirrel monkeys to examine the hypothesis that low doses of the 5-HT(1A) selective agonists, 8-OH-DPAT and alnespirone, will preferentially increase, and at higher doses decrease alcohol drinking, and whether these effects can be antagonized by WAY 100635. METHODS: Male Long-Evans rats were induced to drink from two bottles, one containing a solution of 10% ethanol and 1% sucrose (w/v), the other containing an equally preferred concentration of sucrose. Squirrel monkeys also drank from two bottles, one containing a solution of 2% ethanol and 15% sucrose (w/v), the other, water. RESULTS: In rats, low doses of both 8-OH-DPAT (0.018-0.03 mg/kg) and alnespirone (0.3-3.0 mg/kg) increased alcohol drinking by ca. 100% without altering sucrose intake. The highest dose of 8-OH-DPAT (0.1 mg/kg) suppressed intake of both solutions without significant motor impairment. Pretreatment with WAY 100635 (0.1 mg/kg), shifted the entire dose-effect curve of 8-OH-DPAT to the right, and antagonized the effects of the 0.56 mg/kg dose of alnespirone. In the monkeys, administration of both agonists dose-dependently decreased alcohol intake and were behaviorally sedative. CONCLUSIONS: These results support the hypothesis that in rats, 5-HT(1A) receptor stimulation activates somatodendritic receptors at lower doses and postsynaptic receptors at higher doses, each with opposite effects on alcohol intake. The absence of such biphasic dose-effect curves in monkeys suggests a different function of 5-HT(1A) somatodendritic receptors in rats and monkeys, at least with regard to alcohol drinking.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Aggressive behavior as a reinforcer in mice: activation by allopregnanolone.

RATIONALE: The neurobiological mechanisms that underlie the motivation to engage in an aggressive confrontation remain to be investigated. OBJECTIVE: The objective was to develop a method to differentiate pharmacologically the performance elements of aggressive behavior from behaviors that precede an aggressive encounter. METHODS AND RESULTS: Male CFW mice were housed as "residents" and trained to poke their nose in a hole in a panel placed into the home cage. After fulfilling a specific response requirement, an "intruder" male mouse was introduced for a brief aggressive encounter. In experiment I, the mice were maintained on a fixed ratio schedule of ten responses (FR10) and after stable responding, extinction and stimulus control were assessed by switching the active hole in an ABA design. In experiment II and III, the mice were maintained on a fixed interval schedule of 10 min (FI10 min) and responded with accelerating rates towards the end of the interval (mean index of curvature was 0.37). In experiment III, the mice were given the GABA(A) receptor positive modulator allopregnanolone (5.6-17 mg/kg or vehicle, IP), before responding on an FI10 min schedule reinforced by a 5-min aggressive encounter. Allopregnanolone had bitonic effects on FI responding and aggressive behavior. The low dose of allopregnanolone nearly doubled overall response rate without affecting the index of curvature, attack bites or sideways threats. The moderate dose increased attack behaviors by about 45% and had little effect on response rate and the index of curvature. In contrast, the higher dose decreased the index of curvature but had no effect on aggressive behavior or overall response rate. CONCLUSIONS: These data support previous demonstrations that certain GABA(A) positive modulators heighten aggressive behavior. Moreover, examining operant responding that is reinforced by the opportunity for aggression, it may be possible to dissociate pharmacological effects on the behaviors leading up to an aggressive encounter from their effects on specific aggressive acts.

Aggression↗
PubMed2002

Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems.

BACKGROUND AND RATIONALE: Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. OBJECTIVE: To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options. RESULTS AND CONCLUSIONS: (1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D(2) receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABA(A) receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.

Adaptation, Psychological↗
PubMed2002

Effects of corticotropin-releasing hormone on distress vocalizations and locomotion in maternally separated mouse pups.

The behavioral effects of corticotropin-releasing hormone (CRH) appear to depend on the baseline state of arousal of the animal. In this study, this hypothesis was tested using a 4-min maternal separation procedure in 7-day-old male and female mouse pups (outbred CFW strain). Two intensities of stress were used to assess the effects of intracerebroventricularly administered r/hCRH: a mild stress condition where the ambient temperature was close to nest temperature (30 degrees C) and rates of maternal separation-induced ultrasonic vocalizations (USVs) were relatively low (ca. 25/4 min), and a more stressful condition where the temperature was 19 degrees C and the rates of USVs were high (ca. 250/4 min). Differential effects of CRH on vocalization rate and locomotor behavior were observed to be dependent on the level of stress. In the more stressful 19 degrees C condition, r/hCRH dose-dependently reduced the number of USVs without affecting motor behavior, as indexed by grid crossings. In contrast, in the 30 degrees C condition, only the highest dose of r/hCRH reduced calling while r/hCRH activated motor behavior over a wider range of doses. These effects were independent of hypothalamus-pituitary-adrenal (HPA) axis activity, as measured by plasma corticosterone levels. The present study indicates that in mouse pups, the effects of CRH administration depend on baseline levels of arousal and that the behavioral effects of CRH administration can be dissociated under mild and more stressful conditions.

Animals↗
PubMed2002

Aggression escalated by social instigation or by discontinuation of reinforcement ("frustration") in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist.

Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT(1B) receptor is critically involved in the modulation of escalated aggression.

Aggression↗
PubMed2001

Repeated alcohol: behavioral sensitization and alcohol-heightened aggression in mice.

RATIONALE: Repeated administration of psychomotor stimulants or opiates can induce behavioral sensitization, typically detected as progressive and long-lasting increases in the motor-activating effects of these drugs. This phenomenon may be relevant to seizure susceptibility, drug self-administration, and sexual behavior. Repeated administration of alcohol can also induce behavioral sensitization and may have consequences on how alcohol affects aggressive behavior. OBJECTIVES: To (1) determine the enduring nature of locomotor sensitization to alcohol; (2) examine subsequent changes to morphine and amphetamine effects on locomotor behavior; and (3) test whether behavioral sensitization to alcohol or morphine is relevant to alcohol-heightened aggression. METHODS AND RESULTS: In the first experiment, male CFW mice were given ten injections of alcohol (2.4 g/kg/day), morphine (30.0 mg/kg/day), or saline. Video tracking confirmed locomotor sensitization--an approximate 200% increase in the motor-stimulating effects of these drugs. Challenges with 2.0 g/kg alcohol revealed that locomotor sensitization to alcohol persisted for at least 2 months. Alcohol-sensitized mice showed evidence of cross-tolerance to the sedative effects of morphine (5 mg/kg) but showed no evidence of cross-sensitization to the stimulant effects of 30.0 mg/kg morphine or 1.0 mg/kg amphetamine. In the second experiment, under conditions resulting in species-typical aggressive behavior against a male intruder, there were no differences in the aggressive behavior relative to saline control mice following alcohol or morphine sensitization. However, in the mice sensitized to alcohol, but not to morphine, there was a vertical shift in the dose-effect curve for moderate doses of alcohol (0.6-1.7 g/kg, p.o.). In addition, twice as many alcohol-sensitized mice consistently showed alcohol-heightened aggression when compared with the saline control mice (74% vs 37%, respectively). CONCLUSIONS: Repeated administration of alcohol can sensitize locomotor stimulation and may also render mice more vulnerable to increased aggression after alcohol. Moreover, the results suggest that at least some of the neuroadaptations caused by repeated administration of alcohol are relevant to alcohol-heightened aggression.

Aggression↗