Search PubMed⌕ Search

Biomedical subjects

L A Pohorecky

Publications and source records attributed to L A Pohorecky.

At least 19 recordsLinked to original sources
PubMed2001

Bidirectional changes in ethanol consumption in rats with site-specific antisense down-regulation of 5-hydroxytryptamine2A receptors in brain.

The 5-hydroxytryptamine (5-HT)2A receptor is an important component of the neural substrates underlying ethanol (EtOH) intake and behaviors related to anxiety and stress. Paradoxically, both 5-HT2A agonists and antagonists have been shown to reduce EtOH intake, however the mechanisms underlying these effects are not understood. This inconsistency could possibly be explained by their chronic down-regulation of the 5-HT2A receptor. To further address these findings, the present study sought to functionally characterize the role of localized 5-HT2A receptors in regulating EtOH ingestion by producing central nervous system site-specific receptor down-regulation through infusion of antisense oligonucleotide (ASO). Rats were infused with 5-HT2A receptor ASO into the lateral ventricle (i.c.v.), prefrontal cortex (PFC), central amygdaloid nucleus, medial and lateral division (CeA/L), dorsal raphe nucleus (DRN), or hippocampus (HIP) for a period of 26 days. Subjects were tested for EtOH intake and behaviors related to anxiety and stress. ASO administration i.c.v. and into the CeA/L significantly reduced EtOH intake. PFC 5-HT2A ASO administration increased EtOH intake. Administration of 5-HT2A ASO into the DRN and HIP had no effect on EtOH intake. Intracerebroventricular ASO administration increased activity in a novel open field and increased anxiety-like behavior in the elevated plus maze. PFC ASO administration produced an anxiogenic effect in the elevated plus maze. Intracerbroventricular, PFC, and CeA/L ASO infusions altered adrenocortical function. These differential behavioral effects specific to the anatomical locations targeted for 5-HT2A receptor down-regulation may help resolve a long-standing, apparent inconsistency in the role of 5-HT2A receptors in EtOH consumption.

Alcohol Drinking↗
PubMed2000

Individual differences in pavlovian autoshaping of lever pressing in rats predict stress-induced corticosterone release and mesolimbic levels of monoamines.

Pavlovian autoshaping CRs are directed and reflexive consummatory responses targeted at objects repeatedly paired with rewarding substances. To evaluate the hypothesis that autoshaping may provide an animal learning model of vulnerability to drug abuse, this study relates individual differences in lever-press autoshaping CR performance in rats to stress-induced corticosterone release and tissue monoamine levels in the mesolimbic dopamine tract. Long-Evans rats (n = 14) were given 20 sessions of Pavlovian autoshaping training wherein the insertion of a retractable lever CS was followed by the response-independent presentation of food US. Large between-subjects differences in lever-press autoshaping CR performance were observed, with group high CR frequency (n = 5) performing many more lever press CRs than group low CR frequency (n = 9). Tail-blood samples were obtained before and after the 20th autoshaping session, then 24 h later the rats were sacrificed and dissection yielded tissue samples of nucleus accumbens (NAC), prefrontal cortex (PFC), caudate putamen (CP), and ventral tegmental area (VTA). Serum levels of postsession corticosterone were elevated in group high CR frequency. HPLC revealed that group high CR frequency had higher tissue levels of dopamine and DOPAC in NAC, lower levels of DOPAC/DA turnover in CP, and lower levels of 5-HIAA and lower 5-HIAA/5-HT turnover in VTA. The neurochemical profile of rats that perform more autoshaping CRs share some features of vulnerability to drug abuse.

Animals↗
PubMed1999

Effect of chronic social stress on delta-opioid receptor function in the rat.

Previous studies have shown that stressors modify endogenous opioid systems. However, the consequences of social stress on the function of endogenous opioid systems is not well documented. The present studies investigated the effect of rank and housing condition on response to SNC-80, a delta receptor agonist. Triad-housed rats were assessed for dominance status by their behavior and alteration in body weights. At 3 and 50 days, triad- and individually housed rats were injected with SNC-80 (35 mg/kg i.p.) or saline, and evaluated using a test battery consisting of open field behaviors, rectal temperature, analgesia, and air-puff-induced ultrasonic vocalizations. After 50 days of housing, plasma corticosterone, adrenal catecholamines, and the density of cyclic[D-penicillamine2-D-penicillamine2]enkephalin-stimu lat ed guanylyl 5'-[gamma[35S]thio]-triphosphate binding in the prefrontal cortex, the amygdala, nucleus accumbens, thalamus, arcuate, and median eminence were also determined. The first 24 h of triad housing resulted in loss of body weight in subdominant (betas and gammas) but not dominant alpha rats. SCN-80-induced hypothermia was smaller, and there was no depression of headpoke and locomotor behavior in the periphery and the center of the field of alpha rats, in contrast to subdominant and singly housed rats. Rank status did not influence SNC-80's analgesic effect or its inhibition of air-puff-induced ultrasonic vocalizations. Plasma corticosterone levels of alphas and gammas were lower compared with betas and singly housed rats. Agonist stimulation of delta receptor guanylyl 5'-[gamma[35S]thio]-triphosphate binding was lateralized in prefrontal cortex and amygdala, but not nucleus accumbens. Binding was highest in all brain areas of singly housed rats and lowest in the thalamus of beta and of gamma rats. Lateralized binding in amygdala, high locomotor activity, and sensory sensitivity correlated positively with greater sensitivity to SNC-80-induced depression in these measures. Higher binding in the right amygdala correlated with higher plasma corticosterone levels. These findings indicate that dominant rats displayed stimulant rather than depressant responses to delta-opioid activation. Therefore in rodents rank-related stress can alter responsiveness of the endogenous opioid system, and dominance can increase the excitatory effects of delta agonists.

Adrenal Glands↗
PubMed1998

Effects of ethanol on Pavlovian autoshaping in rats.

Approach responses, consummatory behaviors, and directed motor responses maintained by food reward resemble autoshaping CRs and are increased by lower doses of ethanol. This study evaluated the effects of presession i.p. injections of ethanol doses (0.00, 0.25, 0.50, 0.70. or 1.00 g/kg) on the acquisition of lever-press autoshaping CR performance in groups of male Long-Evans hooded rats. Paired groups received 15 daily sessions of Pavlovian autoshaping procedures, wherein the insertion of a retractable lever for 5 s (CS) was followed by the response-independent presentation of food (US). Ethanol facilitated lever-press autoshaping CR acquisition, as revealed by dose-related increases in the number of trials on which CRs were performed. The form of the dose-effect curve was inverted U-shaped with maximal responding induced during sessions 1-5 by the 0.70 g/kg ethanol dose. A similar dose-effect curve was observed during sessions 11-15, revealing that the effects of ethanol on autoshaping CR performance were relatively stable. A pseudoconditioning control group injected presession with 0.50 g/kg ethanol received training wherein the food US was presented randomly with respect to the lever CS. Few lever-presses were performed by the Random 0.50 group, indicating that ethanol's effects on autoshaping CR acquisition and maintenance observed in the Paired 0.50 group were not due to its psychomotor activating effects. A non-injection control group performed more autoshaping CRs than did the control group injected presession with saline, indicating that daily presession i.p. injections per se suppress autoshaping CR performance. Results reveal that low doses of ethanol enhance Pavlovian conditioning of directed motor and consummatory-like responding maintained by food reward. Implications for autoshaping accounts of impulsivity and drug abuse are considered.

Animals↗
PubMed1998

Ethanol induces impulsive-like responding in a delay-of-reward operant choice procedure: impulsivity predicts autoshaping.

Autoshaping conditioned responses (CRs) are reflexive and targeted motor responses expressed as a result of experience with reward. To evaluate the hypothesis that autoshaping may be a form of impulsive responding, within-subjects correlations between performance on autoshaping and impulsivity tasks were assessed in 15 Long-Evans hooded rats. Autoshaping procedures [insertion of retractable lever conditioned stimulus (CS) followed by the response-independent delivery of food (US)] were followed by testing for impulsive-like responding in a two-choice lever-press operant delay-of-reward procedure (immediate small food reward versus delayed large food reward). Delay-of-reward functions revealed two distinct subject populations. Subjects in the Sensitive group (n=7) were more impulsive-like, increasing immediate reward choices at longer delays for large reward, while those in the Insensitive group (n=8) responded predominantly on only one lever. During the prior autoshaping phase, the Sensitive group had performed more autoshaping CRs, and correlations revealed that impulsive subjects acquired the autoshaping CR in fewer trials. In the Sensitive group, acute injections of ethanol (0, 0.25, 0.50, 1.00, 1.50 g/kg) given immediately before delay-of-reward sessions yielded an inverted U-shaped dose-response curve with increased impulsivity induced by the 0.25, 0.50, and 1.00 g/kg doses of ethanol, while choice strategy of the Insensitive group was not influenced by ethanol dose. Ethanol induced impulsive-like responding only in rats that were flexible in their response strategy (Sensitive group), and this group also performed more autoshaping CRs. Data support the hypothesis that autoshaping and impulsivity are linked.

Animals↗
PubMed1995

An air-puff stimulus method for elicitation of ultrasonic vocalizations in rats.

Rat 22 kHz ultrasonic vocalizations (USVs) are thought to reflect an aversive behavioral state, perhaps a type of anxiety or fear, and have proven useful in the study of the neural mechanisms of these states. This paper describes a simple procedure for presentation of an aversive but non-painful air-puff stimulus for the elicitation of USVs from rats. When directed at the rat's dorsal or dorsolateral head and neck region, this stimulus reliably elicits ultrasonic vocalizations from nearly all rats tested and as such represents a valuable alternative to other stimuli such as aggressive encounters, electric shock, or acoustic startle. The USV response may attenuate with repeated testing, yet remains readily inducible and is therefore suitable for studies involving habituation. The materials for generating this stimulus and the accompanying testing procedure comprise an efficient method with which this aversively motivated rodent behavior can be examined. The potential utility of this technique in studies of aversively motivated behaviors and its relevance to studies of startle responding is discussed.

Animals↗
PubMed1993

Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats.

The effect of the opioid receptor antagonist, naltrexone, on ethanol-induced changes in extracellular dopamine and serotonin in the nucleus accumbens was investigated using in vivo microdialysis in awake, freely moving rats. Locally applied ethanol (5% infused transprobe) resulted in substantial increases in dopamine in dialysate. Administration of naltrexone (cumulative dosing with 0.25-1.0 mg/kg i.p.) during ethanol administration dose-dependently reversed ethanol-induced increases in extracellular dopamine and its metabolite homovanillic acid but not serotonin. These data demonstrate an essential role for the endogenous opioid system in stimulation of dopamine release by ethanol in a brain area associated with reward and support the opioid system as a prime target for pharmacological modulation of the rewarding effects and consumption of ethanol.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Ethanol prevents desensitization of 5-HT2 receptor-mediated responses consequent to defeat in territorial aggression.

The effect of intruder status in territorial aggression on behavior in the elevated plus-maze, the open field and on 5-HT2 receptor-mediated behaviors was evaluated in male Long-Evans hooded rats. Intruders (350 g) were placed in the home cages of aggressive resident rats (475-600 g) and removed after 20 roll-tumble fights. On the following day, the rats were tested on the elevated plus-maze, and behavior in the open field was evaluated after injection with the 5-HT2/1C receptor agonist, DOI (1.0 mg/kg). The number of headshakes following DOI injection are thought to be an indicator of 5-HT2 receptor function. Although several other stressors were evaluated, only defeat in territorial aggression caused a significant decrement in the number of headshakes following DOI injection. To determine if ethanol (ET) could decrease the behavioral consequences of defeat, the effect of ET (1.25 g/kg) given before and immediately after aggression on behavior 24 hours later was evaluated. Although ET treatment had no effect on the control group that did not experience aggression, the ET treatment attenuated the desensitization of 5-HT2 receptor-mediated responses induced by aggression and severely exacerbated the anxiety-like effects as measured in the elevated plus-maze. These data suggest that (1) 5-HT2 receptor sensitivity decreases as a consequence of defeat, but not after several other stressors; (2) defeat in territorial aggression results in significant anxiety-like effects in the elevated plus-maze 24 hours later; and (3) these anxiety-like effects are exacerbated when ET is given before, and immediately after, the aggression.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1993

Observations of novel behaviors as indices of ethanol withdrawal-induced anxiety.

One of the prominent symptoms in alcoholics during withdrawal is an intense feeling of anxiety. Recently new tests have become available which may index anxiety in rodents. We have evaluated two such tests in our model of withdrawal from ethanol (ET) in rats. Rats were given either ET in milk (7-13 g/kg/4 days) or equicaloric dextrin maltose in milk via implanted gastric cannuli. Rats were scored for classical withdrawal symptoms (tremors, convulsions, stereotyped behavior), for stimulus-elicited ultrasonic vocalizations (USVs), and in one study for exploration of novel objects placed in their home cage at various points after the last dose of ET. In Sprague-Dawley rats, classical withdrawal symptoms were highest between 8-12 hours, and disappeared by 36 hours. Latency to explore a novel object was unchanged, but duration was depressed between 10-30 hours, and was recovered by 70 hours. Following a less intense Day 1 treatment regimen in Long-Evans rats, the vocalizations were greatly increased in number, and peak response occurred sooner (6 hours post-infusion) and was of shorter overall duration (50 hours). Pretreatment with diazepam (1.25-5.0 mg/kg) depressed the number of vocalizations during ET withdrawal (ETW), which suggests that this measure could index anxiety in animal models of withdrawal from ET.

Animals↗
PubMed1992

Daily dose of ethanol and the development and decay of acute and chronic tolerance and physical dependence in rats.

Using behavioral and physiological measures, we compared the rates of development and decay of acute and chronic tolerance to ethanol (ET) and the severity of the withdrawal syndrome. Male rats were treated with 6, 9, or 12 g/kg/day ET or equicaloric dextrin maltose, delivered intragastrically. Although treatment duration varied, the total dose of ET was kept constant at 162 g/kg/rat for the three groups. The effects of a cumulative test dose of ET or equicaloric dextrin maltose, after exposure to a total of 0, 42, 83, 126, and 162 g/kg ET, and at 3, 5, and 7 days after termination of the chronic treatments, were evaluated on rectal temperature, dowel performance, and tail-flick and startle responses. After the initial five tolerance tests, chronic treatments were discontinued and rats were tested in a modified open-field apparatus and for their startle response to an auditory stimulus at 8, 12, 16, 20, 32, and 40 h later. With all measures, little tolerance developed in the 6-g/kg/day group. On the other hand, development of chronic tolerance was fastest in rats treated with the 12-g/kg/dose of ET. Chronic tolerance did not develop to ET's depressant effect on the startle response. Acute tolerance declined with chronicity of treatment in animals given the largest daily dose of ET. During withdrawal, and in contrast to the dextrin maltose-treated animals, there was impairment in all measures taken during the modified open-field test and hypersensitivity of the startle response for all three chronic ET-treated animals. Greatest behavioral impairment occurred in animals treated with 12 g/kg/day, and some impairment was still evident 40 h after the last dose of ET. Thus, the severity of the withdrawal syndrome was greatest in the group displaying the most acute and chronic tolerance.

Alcoholic Intoxication↗
PubMed1992

Zacopride, a 5-HT3 receptor antagonist, reduces voluntary ethanol consumption in rats.

The effect of the selective 5-HT3 receptor antagonist, zacopride, was assessed in male Sprague-Dawley rats in free choice (6% ethanol and water) experiments. In Experiment 1, single zacopride (0.01-10 mg/kg, IP) injections failed to alter ethanol (ET) consumption during 1-h restricted ET access. In Experiment 2, zacopride (5.0 and 10 mg/kg, IP) injected twice daily for 5 days significantly reduced ET intake and ET preference during 24-h free access to 6% ET and water without altering the total volume of fluid consumed. Thus, the schedule of ET access (i.e., free vs. restricted) and/or the duration of drug treatment may determine the efficacy of pharmacological agents in altering ET preference. 5-HT3 receptor blockade may reduce serotonin/dopamine-mediated maintenance of ET preference; a process that may proceed via extinction mechanisms.

Animals↗
PubMed1991

Stress and alcohol interaction: an update of human research.

The literature on alcohol and stress in human subjects carried out since 1981 is reviewed. The review covers selected aspects of the interaction of alcohol and stress. (1) Most of the review focuses on the role of stress on alcohol ingestion. Retrospective research based on data from the Health and Nutrition Examination Survey indicated an increase in alcohol consumption with anxiety in certain groups of, as yet not well characterized, individuals. For example, although still insufficiently documented, stress does not appear to play a significant role in alcohol ingestion by women and the elderly. By contrast, stress does appear to play a role in the control of alcohol ingestion by adolescents. Prospective studies employing questionnaire-interview formats generally support an effect of stress on alcohol ingestion. However, studies employing male college aged social drinkers did not find a correlation between levels of stress and ingestion of alcohol. Alcoholics also differ in the reasons for drinking alcohol, but generally ingest alcohol to lessen anxiety/stress. It is clear that the Tension Reduction Hypothesis as originally postulated is no longer adequate. Many new models based on an interaction of alcohol and stress have been proposed to explain the control of alcohol consumption. Considering the multidimensionality of factors that appear to contribute to the control of alcohol ingestion, it is unlikely that a single model could possibly be relevant to alcohol ingestion under all conditions. More likely different models may be relevant to alcohol consumption under specific conditions, or for specific populations. (2) Alcohol has been reported to decrease anxiety in agoraphobics. The self-medication by agoraphobics may contribute significantly to their alcohol abuse. (3) Alcohol has also been reported to decrease tremor of the hands in stressed subjects as well as in patients with essential tremor. (4) Although a number of studies have employed electrodermal activity in studies aimed at the interaction of alcohol and stress, the results have been rather inconsistent. (5) The controversy on the purported beneficial effect of alcohol on the cardiovascular system persists. A number of studies have shown a J- or U-shaped relationship between alcohol ingestion and incidence of coronary heart disease. Alcohol may also influence stress-induced changes in blood pressure. Although a number of studies have demonstrated lower blood pressure in individuals ingesting less than two drinks per day compared with abstainers or heavy alcohol imbibers, the evidence is not conclusive. (6) It is not clear whether the interaction of alcohol and stress involves alterations in plasma catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Development of tolerance to and physical dependence on ethanol: daily versus repeated cycles treatment with ethanol.

We examined the effect of various treatment schedules with ethanol on the development of tolerance and the severity of withdrawal in rats. Tolerance to ethanol was examined after a challenge dose of ethanol using rectal temperature, dowel performance, and tail flick response; open field activity and the startle response were determined during withdrawal. Animals treated daily with ethanol developed greater tolerance, and also lost it faster, compared with animals subjected to repeated cycles of 3 days of ethanol treatment followed by 3 drug-free days. Also, the severity of withdrawal was greater in animals treated daily with ethanol. In the second study, we examined the development of tolerance and withdrawal severity of animals subjected to three different schedules of daily ethanol administration. Overall, the animals receiving continuous infusion of ethanol showed the most severe withdrawal and had, except for dowel performance, the fastest loss of tolerance to ethanol.

Alcohol Drinking↗
PubMed1990

Interaction of ethanol and stress: research with experimental animals--an update.

Research on the interaction of ethanol (ET) and stress published since 1981 is reviewed. Chronic physical stressors were found to increase the ingestion of ET compared to nonstressed animals. With foodshock, ingestion of ET decreased during the stress session but rose afterwards. The elevation of ET ingestion produced by daily immobilization was long-lasting and was related to individual initial preference for ET. Psychological stressors also increased ingestion of ET. In rat colonies, dominant rats ingested less ET, whereas submissive rats had the highest intake. Factors that modify the ingestion of ET include neonatal experience and REM sleep deprivation. Early weaning increased, while postnatal handling decreased preference for ET. The effect of postnatal handling may be influenced by genetics. Stress, applied during adult life or prenatally, modifies some, but not all, the acute effects of ET. There were marked individual differences in the interaction of ET and stress with respect to ingestion of ET. Conversely, ET may modify stress-induced behavioural and neurochemical changes. This interaction may be stressor specific. Some stressors increase the ET's effects, whereas others may decrease or not affect them. In brain, ET has been shown to lessen the stress-induced decrease in noradrenaline and 5-hydroxytryptamine (serotonin) levels and those in noradrenaline turnover and alpha 1-receptor binding. Stress-induced changes in plasma catecholamines, corticosterone, non-esterified fatty acids and amino acids, and in the decline in adrenal catecholamines are also lessened by pretreatment with ET. Possible mechanisms for the ET-stress interaction are discussed. These include mediation via the GABA-benzodiazepine-ionophore complex, endogenous opioids, the hypothalamo-pituitary-adrenocortical axis and the noradrenergic system.

Alcohol Drinking↗
PubMed1989

Norepinephrine-induced diuresis in chronically ethanol-treated rats.

Previous research from this laboratory indicated that noradrenergic mechanisms might mediate ethanol diuresis. Experiments described here examined changes in sensitivity of noradrenergic mechanisms in animals chronically treated with ethanol. Norepinephrine hydrochloride (0-12 micrograms intracerebroventricularly) produced dose-dependent diuresis in control (dextrin maltose) and ethanol (8-11 g/kg/day) treated rats on the first day of treatment. Tolerance to ethanol diuresis was present after 10 days of ethanol treatment. Lack of responsiveness to norepinephrine-induced diuresis was evident only on the 20th day of treatment in both the ethanol and dextrin-maltose groups of rats. These results indicate a temporal dissociation between the tolerance to ethanol-induced and norepinephrine-induced diuresis and suggest that norepinephrine may not play a primary role in the development of tolerance to the diuretic action of ethanol.

Animals↗
PubMed1989

Effects of ethanol on plasma corticosterone and rectal temperature modification by U50488H and WIN 44441-3.

Endogenous opiates are believed to subserve various behaviors and physiological functions. We have examined the effect of U50488H (0-12 mg/kg), a kappa agonist, and WIN 44441-3 (0-4.0 mg/kg), a kappa antagonist, on ethanol (ET)-induced changes in rectal temperature and in plasma corticosterone (CS) levels in rats. The 12 mg/kg dose of U50488H produced marked hypothermia, the other doses either produced hyperthermia comparable to that seen in control animals, or had no effect. The 0.5 mg/kg of WIN44441-3 had a small hypothermic effect while the 4.0 mg/kg produced hyperthermia. U50488H potentiated and the low dose of WIN 44441-3 reversed the hypothermic effect of ethanol. By contrast, neither WIN 44441-3 nor U50488H pretreatments affected the ethanol-induced elevation in plasma CS. These results indicate that kappa agonists increase plasma CS concentration and affect thermoregulatory mechanisms. Furthermore, our data indicate a possible role of endogenous kappa opioids in the hypothermic effect of ethanol, but not in the elevation of plasma CS.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Effects of ethanol in an open field apparatus: modification by U50488H and WIN 44441-3.

The effects of U50488H, a kappa agonist, and WIN 44441-3, a kappa antagonist, and their modification of the effects of ethanol, on the behavior of rats in a modified open field apparatus, was examined. Crossover activity was increased by U50488H. Headpoke activity was decreased by WIN 44441-3 and increased by U50488H. Rearing activity was increased by WIN 44441-3 but was not affected by U50488H. The effect of both drugs was dose related, with the largest doses having no effect. Ethanol (0.5 g/kg) stimulated crossover activity while it depressed rearing, headpoke and corner activities; except for crossover activity the 2.0 g/kg dose of ethanol depressed these activities. Pretreatment with WIN 44441-3 (0.5 mg/kg) potentiated the stimulant effect of ethanol on crossover activity and partially reversed the depressant effect of ethanol on rearing and headpoke activities. U50488H potentiated the ethanol-induced depression of headpoke and reversed the depression of corner activity. Pretreatment with U50488H had no effect on ethanol's action on crossover and rearing behaviors. Our results indicate that kappa opiate receptors may mediate some behaviors exhibited by rats in a modified open field apparatus. Activation of these receptors increases locomotor and headpoke activity but had no effect on rearing activity. Furthermore, the 0.5 g/kg dose of ethanol has differential effects on different measures of open field behavior, while the 2.0 g/kg dose was largely depressant. Our data suggest that some of these effects of ethanol may be mediated via kappa opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗