Biomedical subjects

Nachum Dafny

Publications and source records attributed to Nachum Dafny.

15 recordsLinked to original sources

PubMed2006

Sensory-evoked potentials recordings from the ventral tegmental area, nucleus accumbens, prefrontal cortex, and caudate nucleus and locomotor activity are modulated in dose-response characteristics by methylphenidate.

Most of the studies investigating the effects of methylphenidate (MPD) are using behavioral and biochemical approaches. There are some electrophysiological studies about the effects of MPD on spontaneous electrical activity; however, there is none about the effects of MPD on sensory inputs. The objectives of the present study were to investigate the MPD dose-response characteristics on locomotor activity and sensory inputs using acoustic stimuli. Freely behaving rats previously implanted with semi-microelectrodes were used to record from four brain areas known to be sites of psychostimulant action. For locomotor behavior assessment, rats received saline on experimental day 1 and an acute administration of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Using an automated, computerized activity-monitoring system, locomotor behavior was recorded for 2-h postinjection on both days. For the electrophysiological experiments, animals were implanted with permanent electrodes in the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and caudate nucleus (CN) under general anesthesia. Five to seven days after electrode implantation, they were used to study the effects of three different MPD doses on the response to sensory inputs. The lowest dose of MPD (0.6 mg/kg, i.p.) failed to alter locomotor activity, while the two higher MPD doses (2.5 and 10.0 mg/kg) elicited increase in locomotion, with the 10.0 mg/kg dose increased at least twice as much as the 2.5 mg/kg dose. However, the same three MPD doses elicited significant attenuation of sensory inputs in dose-response characteristics, i.e., as MPD dose increased, evoked sensory inputs decreased. These opposite effects (motor activation and sensory input suppression) were further discussed.

Acoustic Stimulation↗

PubMed2006

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

BACKGROUND: Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). METHODS: The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. RESULTS: Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. CONCLUSION: These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Journal Article↗

PubMed2006

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants.

BACKGROUND: The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. METHODS: The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system. RESULTS: Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals. CONCLUSION: MDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Journal Article↗

PubMed2005

The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects.

Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.

Age Factors↗

PubMed2005

Interferon and the central nervous system.

Interferons (IFNs) were discovered as natural antiviral substances produced during viral infection and were initially characterized for their ability to "interfere" with viral replication, slow cell proliferation, and profound alteration of immunity. The IFNs are synthesized and secreted by monocytes, macrophages, T-lymphocytes, neurons, and glia cells. The different IFNs are classified into three classes: alpha, beta, and gamma. alpha-IFN produced in the brain exerts direct effects on the brain and endocrine system by activating the neurosecretory hypothalamic neurons and regulates the hypothalamic-pituitary-adrenocortical axis. IFNs modulate neurophysiological activities of many brain region involving in pain, temperature, and food intake regulation. alpha-IFN administration activates the sympathetic nerves innervating components of the immune system. IFNs may serve as regulatory mediators between the central nervous system, the immune system, and endocrine system. IFN is used as immunologic therapy to treat various hematologic malignancies and infectious ailments and autoimmune diseases.

Animals↗

PubMed2005

c-Fos antisense oligodeoxynucleotide offsets behavioral nociceptive responses and both up-regulations of c-Fos protein and dynorphin a (1-8) in dorsal horn: a study using the formalin test in rats.

The formalin test was used to elicit acute and chronic pain in rats, and antisense oligodeoxynucleotide (AS-ODN) was used as a tool to modulate the expression of nociceptive behavioral and neurochemical responses. AS-ODN complementary to c-Fos mRNA was administered intrathecally (i.t.) 4 h before formalin injection in the experimental group. Normal saline or reverse AS-ODN was pre-administered i.t. at the same time in two control groups (saline and reverse AS-ODN). The results showed that the acute phase of nociceptive behavior showed no change by AS-ODN administration, whereas the tonic phase of nociceptive licking and biting behavior was significantly suppressed by AS-ODN as compared with the saline or the reverse AS-ODN group, respectively (p < .05 and p < .01). At the same time, both Fos-like immunoreactive (FLI) neurons and density of dynorphin-like immunoreactivities (DLI) were decreased significantly (p < .05 and p < .01) in the AS-ODN group as compared with that in two control groups. The results indicate that the long-lasting nociceptive responses elicited by sustained noxious inputs are based on the up-regulation of c-Fos gene expression, which in turn induces the upregulation of Dyn A production. It is proposed that intensified Dyn A production in the dorsal horn may be pivotal for the appearance of chronic pain.

Animals↗

PubMed2005

Sex differences in tail-flick latency of non-stressed and stressed rats.

The present study was conducted to assess whether there are sex differences between male and female subjects in their response to noxious stimuli under non-stressed and stressed conditions. Tail-flick latency assay was used as an experimental tool on 12 adult male and 12 adult female Sprague-Dawley rats before immobilization (i.e., non-stressed condition) and after 30, 120, 240, and 360 min of continuous immobilization (i.e., stressed conditions). It was found that the non-stressed female rats exhibited significantly longer response latency to noxious thermal stimuli than the non-stressed male rats. Stressed conditions caused by immobilization of the animal inside a ventilated restrainer significantly prolonged the tail-flick latency thresholds of both sexes. Female and male rats did not develop any adaptation after 120, 240, and 360 min of immobilization compared to their 30 min of immobilization, as demonstrated by the tail-flick assay. Moreover, the difference in the tail-flick latency between male and female rats was reduced as the duration of immobilization in the restrainer lengthened. At 30 min of immobilization, the significant difference between the sexes reduced to p < .05 compared to p < .01 before immobilization, and to statistically non-significant differences after 120, 240, and 360 min of immobilization. Results from this study suggested that female rats had longer tail-flick latency than male rats in non-stressed environment, and the difference in tail-flick latency after immobilization between the sexes became less significant with time. In addition, 360 min of immobilization was not enough to adapt to the restrainer, as shown by the tail-flick assay.

Animals↗

PubMed2004

Serotonin modulates hypothalamic neuronal activity.

Effects of serotonin (5-HT) on electrophysiological activities of single hypothalamic arcuate neurons in rat brain slices were observed by extracellular recording. The results showed that (1) of 385 arcuate neurons observed, the patterns of spontaneous firing were divided into 3 categories: "slow irregular" (46.0%), "fast continuous" (22.6%), and "bursting" firing (31.4%); (2) of 149 neurons tested for 5-HT, most (55.0%) responded to the drug by decreasing firing rate, 22.2% by increasing firing rate, 11.4% exhibit biphasic pattern, and 11.4% did not respond to 5-HT application; (3) substitution of low Ca2-high Mg2+ artificial cerebrospinal fluid (ACSF) for normal ACSF did not abolish the 5-HT-induced excitatory effect while it did abolish the 5-HT-induced inhibitory effect, suggesting the effect in latter cases was elicited by a Ca2+-dependent release of neuroactive substances; (4) cyproheptadine, a non-selective 5-HT receptor antagonist, antagonized the 5-HT-induced excitatory effect in all neurons tested, while pindolol, a 5-HT1A/1B receptor antagonist, antagonized the 5-HT-induced excitatory effect in 50% of neurons tested; (5) both cyproheptadine and pindolol antagonized the 5-HT-induced inhibitory effect; and (6) bicuculline, a GABAA receptor antagonist, antagonized the 5-HT-induced inhibitory effect. These results suggest that 5-HT may exert its excitatory effects directly through 5-HT1A/1B and other subtypes of 5-HT-receptors located on the surface of the neurons recorded, while its inhibitory effects are mediated indirectly through the activation of a local inhibitory GABAergic interneuron.

Action Potentials↗

PubMed2004

ATP-sensitive potassium channels and endogenous adenosine are involved in spinal antinociception produced by locus coeruleus stimulation.

The effects of locus coeruleus stimulation on nociceptive evoked discharges of thalamic parafascicular (PF) neurons were investigated in lightly urethane-anesthetized rats, aiming to study the mechanisms underlying these effects. Intrathecal (i.t.) administration of aminophylline (an adenosine antagonist), glibenclamide (an ATP-sensitive potassium [K+(ATP)] channels blocker), nicrorandil (Nico; an agonist of K+(ATP) channel and a K+(ATP) channel opener), and 5'-N-ethylcarboxamido-adenosine (NECA; an adenosine agonist) were used. The results showed that (1) locus coeruleus stimulation significantly inhibited the nociceptive evoked discharges of parafascicular neurons, (2) locus coeruleus stimulation-produced antinociception in PF neurons was blocked by both it. glibenclamide and i.t. aminophylline, (3) nociceptive discharges of PF neurons were also suppressed by both i.t. NECA and i.t. nicorandil, and (4) i.t. glibenclamide showed no effect on the suppression of nociceptive discharges induced by NECA, whereas aminophylline blocked the suppression of nociceptive discharges induced by nicorandil. These results suggest that (a) K+(ATP) channels and endogenous adenosine may be involved in the mediation of antinociception induced by norepinephrine, which is released in the dorsal horn by descending fibers originating from the locus coeruleus and (b) the opening of K+(ATP) channels may precede the release of endogenous adenosine in the process of suppressing nociceptive transmission at the spinal level.

Action Potentials↗

PubMed2004

Differential locomotor responses in male rats from three strains to acute methylphenidate.

Genetic variability is an important consideration in the study of the effect of drugs on humans and animals. Specifically, the effect of drugs on behavior varies from one rat strain to another. Methylphenidate (MPI), commonly known as Ritalin, is a psychostimulant with a pharmacological profile similar to amphetamine and cocaine, and is widely used in the treatment of attention deficit/hyperactivity disorder (ADHD). The purpose of this study was to examine the acute dose-response characteristics of MPD on three different male rat strains: spontaneously hypertensive/hyperactive rats (SHR), Wistar-Kyoto (WKY) rats, and Sprague-Dawley (SD) rats. Results showed clear differences in the pattern of behavioral response to the various MPD doses among the three rat strains. The 0.6 mg/kg MPD dose had no effect on any of the strains. At the dose of 2.5 mg/kg MPD, WKY rats reached peak locomotor activity within the initial 10 min, whereas SHR and SD rats reached peak activity in approximately 30 min. Furthermore, the effects on locomotor activity of SHR were longer in duration and higher in locomotor activity, whereas the effects on SD rats were shorter in duration and amplitude. Following the 10.0 mg/kg MPD, WKY, and SD mats reached their peak locomotor activity within 80 min post-injection, whereas SHR reached their peak locomotor activity within the initial 10 min post-injection. In addition, the SHR strain exhibited increased behavioral sensitivity to MPD as expressed by the latency, duration, and amplitude of their response. In conclusion, the dose-response experiment on the acute effects of MPD demonstrated that there are genetic differences in the responses to MPD.

Animals↗

PubMed2003

Chronic pretreatment with methylphenidate induces cross-sensitization with amphetamine.

Consequence of the long-term use of psychostimulants as treatment for attention deficit/hyperactivity disorder (ADHD) is unknown, particularly whether treatment with psychostimulants at an early age increases an individual's potential for cross-sensitization to other stimulants exposed at a later age. Cross-sensitization occurs when pretreatment with one stimulant leads to greater sensitivity to another stimulant. The aims of this study were to investigate whether chronic treatment with methylphenidate (MPD; Ritalin) in both juvenile and adult rats induced cross-sensitization to amphetamine at a later time and whether this cross-sensitization to amphetamine was age-dependent. Male Sprague-Dawley rats were randomly divided into four treatment groups: (1) group treated intraperitoneally (i.p.) with saline as juveniles and adults, (2) group treated with 0.6 mg/kg amphetamine, i.p., as juveniles and adults, (3) group treated with 2.5 mg/kg MPD, i.p., as juveniles and adults, and (4) group treated with saline, i.p., as juveniles and 2.5 mg/kg MPD, i.p., as adults. All of the animals received an amphetamine (0.6 mg/kg, i.p.) challenge on the last experimental day. We examined the effects of chronic MPD treatment in juvenile and adult rats on their locomotor response to an acute amphetamine exposure. Three different locomotor indices were studied using an automated activity monitoring system. Changes in the locomotor responses to amphetamine of these animals were compared to those of control rats that were pretreated with saline as juveniles and as adults. It was found that prior chronic treatment with MPD produced cross-sensitization to the locomotor response to amphetamine as observed in the horizontal activity and total distance traveled. It also appears that this cross-sensitization to amphetamine may not be dependent on the age of the subjects, i.e., whether subjects were juvenile or adult rats when they received drugs, but rather it depended on the behavioral index examined.

Aging↗

PubMed2003

Strain differences in the behavioral responses of male rats to chronically administered methylphenidate.

Genetic variability in the behavioral responses of experimental subjects to psychostimulants such as amphetamine and cocaine have been reported. However, genetic differences in the locomotor responses of rat strains to methylphenidate (MPD), a commonly used psychostimulant in the treatment of attention deficit/hyperactivity disorder, have not been extensively investigated. Research using genetically defined rodent strains can enhance our understanding of the role genetic factors play in drug-related behaviors and the development of animal models for drug-sensitive diseases or behaviors. The objective of the present study was to investigate strain differences in the locomotor responses to MPD among three rat strains: Sprague-Dawley (SD), Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR). Eight-week-old adult, male SD, WKY, and SHR were given a regimen of daily MPD administration (0.6, 2.5, or 10 mg/kg, i.p.) for 6 consecutive days followed by 3 days of washout and a day of MPD re-challenge with similar dosages as previously used. An automated activity monitoring system recorded their horizontal activity, total distance traveled, rearing, stereotypic movements, and number of discrete movements. Repeated administration of 0.6 mg/kg MPD produced no significant effect on locomotor activity compared with saline in all three strains. However, there were strain differences in the locomotor activity of SD, SHR, and WKY rats to repeated 2.5- and 10-mg/kg MPD treatment. Repeated administration of 2.5 mg/kg MPD elicited locomotor sensitization in SD and WKY rats but not in SHR. Repeated administration of 10 mg/kg MPD induced locomotor tolerance in SD and WKY rats, while SHR had variable locomotor responses to this MPD dose. In conclusion, rat strains play a significant role in the response to acute and chronic administration of MPD.

Animals↗

PubMed2002

Valproate prevents the induction and the expression of MK-801 sensitization.

Repeated administration of psychostimulants such as amphetamine, cocaine, and methylphenidate has been shown to induce behavioral sensitization. Sodium valproate, an anticonvulsant agent that enhances GABA activity, and dizocilpine (MK-801), a non-competitive NMDA receptor antagonist, can block the sensitization elicited by psychostimulants. MK-801 also has been demonstrated to sensitize to itself. The objective of the present study was to determine whether valproate disrupts the behavioral sensitization elicited by MK-801. Male Sprague-Dawley rats were given a regimen of repeated MK-801 injections (0.3 mg/kg, i.p.) that produced behavioral sensitization. They were also given valproate, at a dosage (50 mg/kg, i.p.) that prevented behavioral sensitization to stimulants, either during or after multiple MK-801 injections. After the washout period, animals were then re-challenged with MK-801 to determine whether valproate disrupted the behavioral sensitization elicited by MK-801. An activity monitoring system recorded horizontal activity, total distance, and vertical activity of the animals following drug treatment. Results of their locomotor responses demonstrated that valproate disrupted the development/induction and the expression of sensitization to MK-801, as it did to methylphenidate.

Animals↗

PubMed2002

Disruption of sensitization to methylphenidate by a single administration of MK-801.

Blockade of sensitization to methylphenidate by a single injection of MK-801 was investigated using a computerized activity monitoring system. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. After 2 days of baseline recording and a saline injection on day 3, the rats were randomly divided into four experimental groups. All received 2.5 mg/kg of methylphenidate (s.c.) once a day from days 4 to 9, then after five days of no treatment, they were re-challenged with 2.5 mg/kg of methylphenidate on day 15. One group received only methylphenidate, while the other three groups also received a single i.p. injection of MK-801 (0.30 mg/kg) either 24 h (day 3) or 1 h prior to the first of the six methylphenidate injections (day 4), or 1 h prior to the second methylphenidate injection (day 5). A single injection of MK-801 on day 4 (1 h prior to methylphenidate) blocked the development of sensitization to methylphenidate, since a sensitized response could not be elicited six days after cessation of repeated methylphenidate administration (day 15). However, sensitization to methylphenidate still occurred in the groups receiving MK-801 (0.30 mg/kg) on day 5, indicating that the mechanism by which a single injection of MK-801 disrupts sensitization to methylphenidate is sensitive to timing and is not a direct long-term effect. In conclusion, a single injection of MK-801 persistently blocks the development of sensitization to methylphenidate only if it is given with methylphenidate on the first day of the repetitive treatment phase.

Animals↗

PubMed1988

Dorsal raphe stimulation modulates nociceptive responses in thalamic parafascicular neurons via an ascending pathway: further studies on ascending pain modulation pathways.

A study on the nociceptive responses of single cells within the nucleus parafascicularis (PF) thalami of the rat was undertaken to clarify the reported observations of a pain suppression pathway to this nucleus from the dorsal raphe (DR) nucleus. Two types of nociceptive neuron were identified in the PF which were classified as 'nociceptive-on' and 'nociceptive-off' neurons, respectively. DR stimulation exhibits a simple monophasic 'dose-dependent' relationship between the degree of the inhibition elicited and the stimulation intensity used on the 'nociceptive-off' cells. In contrast, biphasic effects following DR stimulation on the 'nociceptive-on' cells was obtained, with low intensities eliciting suppression while high intensities excited the cells. These effects of low intensity DR stimulation upon the responses of the 'nociceptive-on' cells were diminished but not prevented by transection of the well-known bulbospinal inhibitory fibers descending in the dorsal half of the spinal cord, while the effects of DR stimulation upon the 'nociceptive-off' cells remain unchanged following spinal transection. Thus, our results show that DR stimulation modulates the nociceptive responsiveness of the PF by way of supraspinal pathways in addition to the previously described descending paths.

Animals↗