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F Weiss

Publications and source records attributed to F Weiss.

At least 37 records · Page 2Linked to original sources
PubMed1996

Neurochemical evidence that postsynaptic nucleus accumbens D3 receptor stimulation enhances cocaine reinforcement.

The mechanism by which two D3 receptor-preferring agonists, 7-hydroxydipropylaminotetralin (7-OH-DPAT) and quinelorane, modulate cocaine reinforcement was examined by monitoring nucleus accumbens dopamine levels with in vivo microdialysis while rats intravenously self-administered the following four different drug solutions consecutively: (1) cocaine; (2) a combination of cocaine plus a low dose of either agonist; (3) either agonist alone; and finally, (4) a physiological saline solution. Both 7-OH-DPAT (4 micrograms/infusion) and quinelorane (0.25 microgram/infusion) decreased cocaine (0.25 mg/infusion) intake in a manner indicating an enhancement of cocaine reinforcement and simultaneously decreased the cocaine-induced elevations in nucleus accumbens dopamine levels by > 50%. Subsequent self-administration of either 7-OH-DPAT (4 micrograms/infusion) or quinelorane (0.25 microgram/infusion) alone resulted in significant, but stable, increases in drug intake, with a concurrent decrease in nucleus accumbens dopamine levels to approximately 50% below nondrug baseline levels. These findings indicate that postsynaptic D3 receptor stimulation in the nucleus accumbens enhances the reinforcing properties of cocaine. In a second experiment, local application of 7-OH-DPAT via reverse dialysis (30 and 100 nM perfusate concentrations) dose-dependently decreased nucleus accumbens dopamine efflux to 76 +/- 3.9 and 61 +/- 6.3% of baseline, respectively, whereas there was no effect of this agonist on dopamine efflux in the ipsilateral striatum of these same animals. Coperfusion with the D3 receptor-preferring antagonist nafadotride dose-dependently blocked the effect of 7-OH-DPAT on nucleus accumbens dopamine efflux. These results suggest that, at low concentrations, 7-OH-DPAT selectively activates D3 receptors in vivo.

Animals↗
PubMed1995

Sensitization of cocaine-stimulated increase in extracellular levels of corticotropin-releasing factor from the rat amygdala after repeated administration as determined by intracranial microdialysis.

Using intracranial microdialysis, the effect of repeated cocaine (30 mg/kg i.p.) versus saline administration for 10 consecutive days upon basal and stimulated release of corticotropin-releasing factor (CRF) was examined in the central amygdaloid nucleus (CeA) of anesthetized rats. No significant differences in basal CRF levels between daily cocaine and saline treated groups were found. However, after cocaine challenge (10 mg/kg i.p.) the increase in CRF overflow was significantly greater in cocaine- as opposed to saline-pretreated rats (266 +/- 55.4% versus 149 +/- 8.5% of basal levels). Local administration of 4-aminopyridine produced a significant increase in CRF efflux (195 +/- 58.5%) in daily cocaine-treated rats with only a weak response in the control group (127 +/- 30.9%). These data demonstrate that repeated administration of cocaine enhances cocaine-induced release of CRF in the rat CeA. The sensitization of CRF release may play a significant role in psychostimulant-induced sensitization phenomena.

Aminopyridines↗
PubMed1995

Rapid induction of tumor necrosis factor alpha in the cerebrospinal fluid after intracerebroventricular injection of lipopolysaccharide revealed by a sensitive capture immuno-PCR assay.

Tumor necrosis factor alpha (TNF-alpha) is an important mediator in many pathophysiologic processes, both in the central nervous system (CNS) and in the periphery. For this study, we have designed a very sensitive immuno-PCR detection system to investigate the time course of TNF-alpha induction in the rat cerebrospinal fluid after intracerebroventricular administration of bacterial lipopolysaccharide (LPS). Immuno-PCR combines antibody specificity with PCR signal amplification and provides a sensitivity in the picomolar range. The enhanced sensitivity of this assay allowed the detection of TNF-alpha in the cerebrospinal fluid as early as 15 min after intracerebroventricular administration of LPS. The present results suggest that the ventricular compartment of the CNS, although confined within the blood-brain barrier, is highly responsive to proinflammatory stimuli such as LPS administration. Insight into the molecular mechanisms underlying this compartmentalization could be key to the pathology and treatment of many CNS diseases, especially the meningitides.

Animals↗
PubMed1995

Measures of cocaine-seeking behavior using a multiple schedule of food and drug self-administration in rats.

Animal models of human drug abuse measuring (i) cocaine-seeking behavior maintained by primary or secondary reinforcers, (ii) the time to extinction of cocaine-seeking behavior, and (iii) following extinction, reinstatement of operant responding resulting in presentation of a cocaine-associated stimulus were developed in rats. Animals were trained to respond on a multiple schedule of food and intravenous cocaine reinforcement during which either food or cocaine paired with auditory or visual stimuli were available during four alternating 30-min schedule components. At the beginning of each experimental session, a 10-min component (stimulus component) was introduced during which the stimuli associated with the primary reinforcers were made available response-contingently. Subsequent non-contingent presentation of food or cocaine at the beginning of the stimulus component produced a significant increase in lever-pressing resulting in presentation of the respective reinforcer-associated stimulus. Removal of cocaine and the associated stimulus during all schedule components led to extinction of drug-seeking behavior within six days. Lever-pressing resulting in presentation of the drug-associated stimulus was subsequently by non-contingent delivery of cocaine, but not by non-contingent presentation of the stimulus alone. These results suggest that different aspects of cocaine-seeking behavior, such as operant responding resulting in presentation of a cocaine-associated external stimulus, time to extinction in the absence of primary reinforcement, and reinstatement of responding following extinction can be measured in the rat. These tests may provide useful tools for the assessment of potential treatment drugs for human cocaine abuse.

Animals↗
PubMed1995

Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine.

To test the hypothesis that cocaine withdrawal is associated with abnormalities in serotonin (5-HT) neurotransmission, 5-HT concentrations in the nucleus accumbens (NAC) of rats were analyzed with microdialysis both during and after 12 h of unlimited-access intravenous cocaine self-administration. For comparison with previous work, dopamine (DA) levels were also monitored. Self-administration produced sustained increases of both 5-HT and DA to approximately 340% of base line. During the first 6 h of withdrawal, dialysate 5-HT concentrations decreased to 41% of base-line levels obtained before self-administration and to 25% of levels in drug-naive control animals. During the same period, dialysate DA decreased to 72% of presession base-line concentrations but did not decline below control levels. Extracellular 5-HT concentrations were subsequently estimated by use of a quantitative microdialysis technique. After 12 h of self-administration extracellular 5-HT levels were significantly lower (0.6 +/- 0.3 nM) than levels in drug-naive animals (2.0 +/- 0.5 nM) or in rats given only limited-access to cocaine (3 h/day; 1.4 +/- 0.2 nM). Additionally, after 12 h of self-administration low concentrations of intra-accumbens 5-HT applied by reverse dialysis significantly elevated DA efflux. This effect was not observed in either control animals or in rats given only limited access to cocaine. These results suggest that deficient 5-HT neurotransmission may be a significant factor in the cocaine withdrawal symptomatology and provide key information regarding nondopaminergic mechanisms involved in cocaine dependence.

Animals↗
PubMed1995

Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis.

Previous research has suggested a role for corticotropin-releasing factor (CRF) in the anxiogenic effects of stressful stimuli and ethanol withdrawal. This hypothesis was explored in a series of experiments using intracranial microdialysis to monitor CRF-like immunoreactivity (CRF-IR) in the extracellular compartment of the rat amygdala. The synaptic origin of CRF-IR release in the amygdala was determined in vitro by assessing the Ca2+ dependency of 4-aminopyridine stimulated CRF-IR release from tissue preparations of rat amygdala. In vivo experiments were performed in awake rats after the placement of microdialysis probes in the amygdala. In the first experiment, transient restraint stress (20 min) produced an increase of CRF-IR release (basal levels, 1.19 +/- 0.15 fmol/50 microliters; stress levels, 4.54 +/- 1.33 fmol/50 microliters; p < 0.05) that returned to basal values within 1 hr. When 4-aminopyridine (5 mM) was added to the perfusion medium, it consistently increased CRF-IR release (4.83 +/- 0.92 fmol/50 microliters, p < 0.05). In the second experiment, CRF-IR release was measured during ethanol withdrawal in rats previously maintained for 2-3 weeks on a liquid diet containing ethanol (8.5%). Basal CRF-IR levels were 2.10 +/- 0.43 fmol/50 microliters in ethanol exposed rats and 1.30 +/- 0.19 fmol/50 microliters in control rats. During withdrawal, a progressive increase of CRF-IR levels over time was observed, reaching peak values at 10-12 hr after the onset of withdrawal (10.65 +/- 0.49 fmol/50 microliters vs 1.15 +/- 0.30 fmol/50 microliters of control rats, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1994

The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal.

In summary, endogenous CRF has been demonstrated to play an important role in the endocrine but also autonomic and behavioral responses to a stressor and to mediate some of the signs and symptoms observed in human affective and anxiety disorders. These findings led to the hypothesis that the anxiety that characterizes drug withdrawal, such as ethanol withdrawal in humans, may be related in part to the action of CRF-producing neurons in the CNS. Indeed, rats made dependent on an ethanol liquid diet showed significant signs of enhanced stress responsiveness that was blocked by intracerebral administration of a CRF antagonist. At this time little is known about the specific site of action for endogenous CRF. However, recent studies using local administration of CRF antagonist and in vivo CRF microdialysis suggest that the central nucleus of the amygdala may be an important site for the increases in CRF activity associated with the anxiogenic effects of ethanol withdrawal. Although preliminary, these results propound that ethanol dependence may involve a prolonged dysregulation of the CRF system in the basal forebrain that may contribute to the increased motivational effect of ethanol withdrawal.

Alcoholism↗
PubMed1994

A ketamine mixture anesthetic inhibits neuroendocrine and behavioral consequences of cocaine administration.

Cocaine is known to affect different brain systems, particularly those associated with arousal, motor and motivational functions. In order to identify a possible neurochemical link among these systems, we investigated the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and dissociative anesthetic, ketamine (as a mixture with the sedatives acepromazine and xylazine) on the secretion of pituitary adrenocorticotropin hormone (ACTH) and on the development of behavioral sensitization induced by cocaine. Pretreatment with the ketamine anesthetic mixture (1.6 ml/kg; s.c.) completely blocked the stimulation of ACTH by cocaine (5 mg/kg, i.v.; administered 30 min after the ketamine mixture) without interfering with ACTH secretion induced by exogenous corticotropin-releasing factor (CRF; 5 micrograms/kg; i.v.) or interleukin-1 beta (IL-1 beta; 100 ng/kg; i.v.). Administration of the ketamine mixture prior to each of five repeated cocaine injections (15 mg/kg; i.p.) also completely reversed the behavioral sensitization observed in saline-treated control animals. Administration of the anesthetic mixture did not appear to impair the dopamine (DA) re-uptake blocking properties of cocaine in the nucleus accumbens since substantial increases in extracellular DA were observed in the presence of the ketamine mixture. In addition to the present results, no behavioral sensitization was also observed in rats anesthetized with a different general anesthetic (pentobarbital, 50 mg/kg) under similar conditions to that of the ketamine mixture. Taken together, these results are in accordance with the hypothesis that stimulation of excitatory amino acid receptor function may be just one of the mechanisms whereby cocaine exerts its effects on neuroendocrine and behavioral activating systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Alcohol, the reward system and dependence.

Evidence is presented to show that multiple neurotransmitter systems of the brain reward systems including GABA, glutamate, dopamine, serotonin and opioid peptides are involved in alcohol reinforcement. Dependence is associated with changes in many of these same systems, but also with changes in other neurotransmitters, such as brain corticotropin releasing factor. A midbrain forebrain circuitry that involves parts of the nucleus accumbens and amygdala is hypothesized to be the focus for the neuropharmacology of alcohol reinforcement.

Alcoholism↗
PubMed1994

Circulation and sensation at the fingertips of claw hands.

Measurements of skin blood flow (by laser Doppler flowmetry) and temperature were made under environmental conditions promoting peripheral vasodilatation at the fingertips of a disfigured 'clawed' hand in 12 leprosy patients long-resident at Baba Baghi Leprosy Hospital, Tabriz, Iran. Sensory function was assessed by measuring the responses to light touch, pain and temperature of each finger, and peripheral autonomic function was gauged by estimating palmer sweating and by measuring skin vasomotor reflexes in response to inspiratory gasp. In 2 patients all measured fingers had laser Dopper flux (LDFlux) values and skin temperatures lower than the 95% confidence limits for the mean of 20 healthy controls, i.e. were impaired; in 2 patients all fingers had normal values for LDFlux and temperature; and in 8 patients there was a combination of impairment with most fingers normal for these parameters but with the small finger most commonly impaired. There were 10 (67%) fingers with impaired LDFlux and temperature values who had significant sensory impairment, whereas only 5 (18%) of the fingers with normal LDFlux values and temperatures had a similar sensory deficit. Overall, the fingers with the most impaired sensation had significantly (P < 0.05) lower LDFlux and temperature values than those with no sensory deficit. Microcirculatory impairment was not related to disordered skin vasometer reflexes or dysfunction of sweating. We concluded that the relationship between motor (skeletal muscle) nerve paralysis and any subsequent sensory neuropathy and/or microcirculatory impairment is more complex than might be expected from previous understanding of the disease.

Adult↗
PubMed1994

Role for the mesocortical dopamine system in the motivating effects of cocaine.

The search for a neurobiological substrate for the stimulant and reinforcing properties of cocaine has focused for some time on a particular part of the forebrain, the mesocorticolimbic dopamine (DA) system. This mesocorticolimbic DA system innervates the region of the nucleus accumbens (NACC) (ventral striatum) in the anterior part of the basal forebrain and appears to play a critical role in mediating the acute reinforcing effects of cocaine and amphetamine. This chapter reviews the role of mesocorticolimbic DA in the reinforcing properties of psychomotor stimulants as measured by intravenous (IV) drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for studying nondopaminergic modulation of the reinforcing actions of cocaine.

Animals↗
PubMed1993

The role of limbic and hypothalamic corticotropin-releasing factor in behavioral responses to stress.

CRF in the central nervous system appears to have activating properties on behavior and to coordinate behavioral responses to stress. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by a CRF antagonist, alpha-helical CRF9-41. The CRF antagonist reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stress that can be modified by suppression of endogenous CRF activity therein. Hence, consistent with the dual role of other hypothalamic-releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters, CRF may coordinate coping responses to stress at several bodily levels (Fig. 6). Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.

Animals↗
PubMed1993

Animal models of drug craving.

Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Animals↗
PubMed1993

Corticotropin-releasing factor release from the mediobasal hypothalamus of the rat as measured by microdialysis.

Procedures were developed to permit the measurement of corticotropin-releasing factor in perfusate collected from microdialysis probes implanted in various brain areas of anesthetized and awake rats. Initially in vitro experiments were carried out to optimize the recovery of corticotropin-releasing factor and the radioimmunoassay conditions. Addition of a specific antiserum against corticotropin-releasing factor to the perfusion medium (artificial cerebrospinal fluid) increased the relative in vitro recovery over a range of different flow rates (1-10 microliters/min) using commercially available microdialysis probes with a membrane cutoff of 20,000 mol. wt. This procedure increased recovery from 3% to 6% at flow rate of 2.5 microliters/min, and from 4% to 8% at a flow rate of 5 microliters/min. In vivo experiments were performed with a flow rate of 3.3 microliters/min and 50-microliters fractions were used for radioimmunoassay. In each experiment, the standard curve of the radioimmunoassay was constructed from aliquots of the same medium used to perfuse the probe. Basal levels of corticotropin-releasing factor in dialysate collected from the mediobasal hypothalamus of anesthetized rats were estimated to be 0.75 +/- 0.07 fmol/50 microliters. Raising the concentration of potassium (60 mM) in the perfusate increased corticotropin-releasing factor levels to 2.04 +/- 0.37 fmol/50 microliters. Hypertonic stress induced by intraperitoneal injection of 1.5M NaCl (20 ml/kg) elevated the levels to 1.32 +/- 0.07 fmol/50 microliters. A marked increase of corticotropin-releasing factor levels was also produced by a 10-min pulse of the potassium-channel blocker 4-aminopyridine (10 mM) included in the perfusate. A second stimulation pulse with 4-aminopyridine, administered 2 h after the first pulse again increased the levels, with a mean ratio between the first and second pulse of 0.97. Corticotropin-releasing factor efflux produced by the second stimulation pulse was completely inhibited by perfusion with calcium-free medium containing calcium-chelating agent ethyleneglycol tetraacetic acid (10 mM). In separate experiments, microdialysis probes were implanted in several brain areas of anesthetized rats. Basal and potassium-evoked levels of corticotropin-releasing factor were measured in dialysate collected from the amygdala (1.20 +/- 0.22 and 2.05 +/- 0.48 fmol/50 microliters, respectively) and frontal cortex (0.51 +/- 0.10 and 1.64 +/- 0.15 fmol/50 microliters, respectively). Corticotropin-releasing factor levels in the dorsal part of the third ventricle and in the striatum were below the detection limits. In awake rats, corticotropin-releasing factor levels in the mediobasal hypothalamus were 0.98 +/- 0.03 fmol/50 microliters.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants.

Dopaminergic neurotransmission in the nucleus accumbens may be an important factor in ethanol reinforcement and genetically determined ethanol preference. This hypothesis was tested by measuring dopamine (DA) release by intracranial microdialysis during voluntary oral ethanol self-administration in alcohol-preferring (P) and genetically heterogeneous Wistar rats. The animals were trained to respond for ethanol (10% w/v) or water in a free-choice operant task. Extracellular DA levels in the nucleus accumbens were subsequently monitored during 30-min self-administration sessions and a 15-min "waiting period" before session onset. Ethanol self-administration in all animals was followed by a significant, dose-dependent rise in DA release with maximal effects at approximately 15 min after peak intake. Dose-effect functions revealed significantly steeper slopes for the DA-releasing effects of ethanol in P than in genetically heterogeneous Wistar rats. Over an identical range of ethanol doses and blood alcohol levels, increases in DA efflux ranged from 143% to 459% of basal levels in P rats but only from 142% to 212% in Wistar rats. To differentiate the pharmacological effects of ethanol from the effects of operant responding, additional groups of P and Wistar rats were tested during self-administration of saccharin (0.05% w/v). By contrast with ethanol, saccharin did not substantially elevate extracellular DA levels. A significant, transient increase in DA efflux was, however, observed in both strains of rats during the presession waiting period in the absence of ethanol or saccharin availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration.

The effects of withdrawal from cocaine on extracellular dopamine (DA) levels in the nucleus accumbens (NAC) were examined by intracranial microdialysis in awake rats after periods (9.5-21.75 h) of unlimited-access, intravenous cocaine self-administration. Cocaine withdrawal was associated with significant reductions in basal DA overflow that persisted up to 12 h. Maximal inhibition of DA release (mean +/- S.E.M. 66.15 +/- 3.30 percent of basal levels) was observed between 4-6 h after cessation of cocaine intake and was positively correlated (r = 0.88) with the duration of the preceding self-administration episode. The results suggest that suppression of basal DA release in the NAC is an adaptive consequence of sustained cocaine exposure and may in part underlie the post-cocaine anhedonia observed in behavioral models of cocaine withdrawal.

Animals↗
PubMed1992

Neuropharmacology of cocaine and ethanol dependence.

Drug addiction includes two important characteristics, chronic compulsive or uncontrollable drug use and a withdrawal syndrome when use of the drug is stopped. Animal models for the motivational components of drug dependence have been developed allowing a systematic exploration of the neurobiological mechanisms of drug dependence. The reinforcing actions of acute cocaine as measured by intravenous cocaine self-administration appear to be mediated by the presynaptic release of dopamine in the region of the nucleus accumbens and may preferentially involve the dopamine D-1 receptor subtype. The nucleus accumbens circuitry involved in the reinforcing actions of cocaine may include the ventral pallidum and may be modulated by serotonin. Chronic cocaine produces increases in brain reward thresholds that may reflect the "dysphoria" and anhedonia associated with cocaine dependence and suggests a dysregulation of brain reward systems possibly involving dopamine. Reliable measures for the acute reinforcing effects of ethanol in nondependent animals have been established in the rat using a lever press operant and a taste habituation procedure. Important roles have been established for serotonin, GABA, dopamine, and opioids in the acute reinforcing properties of ethanol, perhaps acting on some of the same neural circuitry subsuming the reinforcing actions of other drugs of abuse. Studies of the motivational aspects of ethanol dependence have suggested a functional role for brain corticotropin-releasing factor. These results suggest that the neurobiology of drug dependence involves not only neurotransmitters that mediate the acute reinforcing properties of drugs, but also the aversive motivational and emotional aspects of drug withdrawal. Advances in our understanding of brain changes associated with the switch from acute effects to chronic actions may provide a key to our understanding of not only drug dependence, but also psychopathology such as, anxiety, and affective disorders.

Alcoholism↗