Biomedical subjects

N Dafny

Publications and source records attributed to N Dafny.

At least 19 recordsLinked to original sources

PubMed2001

Effects of lithium chloride on induction and expression of methylphenidate sensitization.

Repeated administration of psychomotor stimulants produces an enduring and progressively enhanced behavioral response known as behavioral sensitization, which has been implicated as a model for psychiatric disorders such as mania, schizophrenia, and drug addiction. The objective of the study was to determine whether lithium chloride (LiCl), an anti-manic agent, is effective in blocking the development and/or the expression of behavioral sensitization to methylphenidate. Male Sprague-Dawley rats (n=64) weighing 170-190 g were randomly divided into seven treatment groups. A computerized animal activity monitor system continuously recorded locomotor activity for 16 days. Effects of LiCl on induction of methylphenidate sensitization were studied by giving LiCl before or during six daily methylphenidate administrations. Effects of LiCl on the expression of methylphenidate sensitization were studied by injecting LiCl after sensitization to methylphenidate was induced. It was shown that LiCl treatment modulated the acute methylphenidate effects by transiently attenuating the locomotor response to methylphenidate during the six daily methylphenidate administrations but neither single nor multiple treatments with LiCl blocked the development or the expression of behavioral sensitization.

Animals↗

PubMed2001

Opiate-like substances mediate norepinephrine-induced but not serotonin-induced antinociception at spinal level: reevaluation by an electrophysiological model of formalin test in rats.

After subcutaneous injection of formalin (5%, 50 microl) into a hindpaw of rats, biphasic excitatory nociceptive discharges were recorded extracellularly in thalamic parafascicular neurons. Intrathecal (i.t.) administration of either norepinephrine (NE. 6 nmol, 10 microl) or serotonin (5-HT, 120 nmol, 10 microl) prior to the second phase significantly inhibited the second phase of the formalin-induced parafascicular nociceptive discharges. Intrathecal naloxone (Nal, 50 nmol, 10 microl) did not show any effect on the parafascicular nociceptive discharges. However, when i.t. Nal was given 5 min before NE, Nal prevented the NE antinociceptive effect. Pre-administration of Nal before 5-HT did not affect the antinociceptive effects of 5-HT on the second phase of nociceptive discharges. These results indicate that opiate-like substances are involved in the mediation of NE-induced antinociception. It is suggested that endogenous NE and 5-HT released from brainstem descending terminals at the spinal level carry out their antinociceptive actions differently.

Animals↗

PubMed2001

Methylphenidate sensitization is modulated by valproate.

Repeated administration of the stimulant methylphenidate (MPD) produces sensitization to its own effects. Glutamate, dopamine, and GABA have been implicated in the underlying mechanism of sensitization to stimulants such as amphetamine and cocaine. We have investigated effects of the GABAergic agent sodium valproate (VAL) on the locomotor response to MPD. Activities of male Sprague-Dawley rats were continuously recorded by a computerized activity monitoring system for 15 days. We studied the dose effect of valproate 1) at 50, 100, and 200 mg/kg (i.p.) on motor activities, 2) on the acute response of motor activities to 2.5 mg/kg MPD, and 3) on behavioral sensitization to subsequent repeated injections of MPD. Valproate alone did not significantly affect motor activities. All three doses of valproate attenuated the acute locomotor effects of MPD, while only the 50 mg/kg dose blocked the development of sensitization to subsequent administration. Possible mechanisms involving substrates for the effect of GABA agonists on sensitization are discussed.

Animals↗

PubMed2001

Blockade of sensitization to methylphenidate by MK-801: partial dissociation from motor effects.

The role of MK-801's locomotor effect in blocking the development of sensitization to methylphenidate was investigated utilizing a computerized locomotor activity monitoring system. After 7 days of acclimation to a 12:12 light-dark cycle (lights on at 07:00), male Sprague-Dawley rats (n=62) were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days of recording served as a baseline for each rat, and on day 3 each rat received a saline injection. On days 4 to 9 rats were randomly divided into seven groups: Rats received either six daily s.c. injections of methylphenidate (2.5 mg/kg; Group 1), or six daily i.p. injections of 0.30 mg/kg, 0.05 mg/kg MK-801 (Groups 2 and 3, respectively); two MK-801 pre-treatment groups received a single i.p. injection of 0.05, or 0.30 mg/kg MK-801 one hour prior to 2.5 mg/kg methylphenidate (n=8 each) on day 4 followed by five daily injections of 2.5 mg/kg methylphenidate; and finally, two cotreatment groups received a challenge dose of 2.5 mg/kg methylphenidate on day 4 followed by either 0.05 or 0.30 mg/kg MK-801 i.p. one hour prior to 2.5 mg/kg methylphenidate from days 5 to 9. All groups were allowed five days of no treatment before being re-challenged on day 15 with the same treatment they received on day 4. Methylphenidate and 0.30 mg/kg MK-801 sensitized to their own locomotor effects, but 0.05 mg/kg MK-801, which had no acute motor effects, did not. The administration of MK-801 (0.30 mg/kg) prior to methylphenidate either singly on day 4, or coadministered throughout the repeated methylphenidate treatment phase, blocked the development of sensitization to methylphenidate. However, MK-801 at 0.05 mg/kg delayed the development of sensitization when co-administered on days 5 to 9, but a single injection 1 h prior to methylphenidate on day 4 did not prevent sensitization to subsequent methylphenidate administration. In conclusion, MK-801 prevents sensitization to methylphenidate; motor stimulation by MK-801 is not necessary for short-term prevention or delay of sensitization to methylphenidate but may be necessary for a persistent blockade of sensitization.

Animals↗

PubMed2001

The role of MK-801 in sensitization to stimulants.

Behavioral responses to stimulants can be progressively and persistently enhanced by their repeated administration. This phenomenon, called behavioral sensitization, may underlie substance abuse, psychosis, recurrence in bipolar disorder, or other psychiatric problems. A growing body of work has implicated excitatory amino acid systems in behavioral sensitization. Most of the evidence for a role of excitatory amino acids has come from experiments demonstrating prevention of sensitization by excitatory amino acid antagonists, especially the noncompetitive NMDA receptor antagonist MK-801. Results of studies with MK-801 have varied, however, leading to conflicting interpretations of its relationship to behavioral sensitization. This paper critically discusses the design of experiments that have used MK-801, and interprets data from these experiments in terms of the two leading explanations for the role of MK-801: 1) that sensitization is an example of the family of plastic events that require excitatory amino acid transmission or 2) that interoceptive cues associated with MK-801 lead to state-dependent learning that modifies sensitization because, in essence, the animal does not recognize the stimulant as the same drug if it is given in close association with MK-801. Based on conflicting reports on effects of MK-801, we propose 1) strategies for distinguishing components of MK-801's effects on responses to stimulants, 2) a model that is a hybrid of the two interpretations of its effects on sensitization, and 3) experimental strategies for testing this model.

Amphetamine-Related Disorders↗

PubMed2000

Valproate prevents the induction of sensitization to methylphenidate (ritalin) in rats.

Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system may modify adaptations to drug exposure. Therefore, we have examined the effect of sodium valproate, which enhances GABA function, on the development of sensitization to MPD using an automated, computerized animal activity monitoring system to record each rat's motor activities for 15 consecutive days. Rats were recorded before and after saline injection (Days 1-2) to provide baseline activity. Animals were then randomly assigned to the following three groups that received: (1) 2.5 mg/kg MPD (s.c.) for six consecutive days (Days 3-8), (2) a single dose of valproate (50 mg/kg; i.p.) 1 h prior to the first (Day 3) of six daily doses of MPD (2.5 mg/kg; s.c. ), or (3) five daily doses of valproate (50 mg/kg, i.p.) 1 h prior to MPD (2.5 mg/kg, s.c.) on Days 4-8. There was no drug treatment during the next 5 days (Days 9-13). All rats were then re-challenged with MPD (2.5 mg/kg, s.c.) on Day 14. Group 2 rats were also re-challenged with 50 mg/kg valproate followed by 2.5 mg/kg MPD 1 h later on Day 15. Administration of MPD alone produced a sensitized response. Multiple valproate injections prevented the induction of MPD-elicited sensitization in all four motor indices, while a single valproate injection prevented the induction of MPD-elicited sensitization in two of four motor indices studied. In conclusion, a single injection 50 mg/kg valproate given prior to any MPD treatment partially blocked the induction of MPD sensitization while repeated injections of valproate co-administered with MPD treatment completely prevented this effect.

Animals↗

PubMed2000

Valproate modulates the expression of methylphenidate (ritalin) sensitization.

Repeated administration of amphetamine, cocaine, and methylphenidate (MPD) has been reported to elicit behavioral sensitization to their locomotor and stereotypic effects in rodents. GABAergic drugs have been shown to inhibit behavioral effects of stimulants. The objective of the present study was to determine whether single or multiple administration of sodium valproate, a GABA agonist, would prevent the expression of sensitization to the locomotor effect of MPD once it has developed. Twenty-eight male Sprague-Dawley rats were randomized into three treatment groups: a control group received only 2.5 mg/kg MPD during the 14-day cycle, a group received a single 50 mg/kg valproate injection on Day 9, and a group received multiple 50 mg/kg valproate injection on Days 9-13. Rats were housed in test cages and behavioral activities were recorded for 14 consecutive days. All injections were given between 12:00 h and 14:00 h. Multiple injection of MPD elicited sensitization to its locomotor and stereotypic effects. Single administration of valproate did not block the expression of sensitization in the four locomotor indices measured. However, multiple administration of valproate prevented MPD sensitization to horizontal activity, total distance and number of stereotypic movements.

Animals↗

PubMed2000

Norepinephrine modulates single hypothalamic arcuate neurons via alpha(1)and beta adrenergic receptors.

The effects of norepinephrine (NE) on the electrophysiological activities of single hypothalamic arcuate neurons were studied using extracellular recording of 385 neurons from 169 brain slices in rats. The results showed that: (1) of 236 neurons selected randomly and tested with NE application, 137 (58.0%) were excited, 67 (28.4%) were inhibited, and 32 (13.6%) failed to respond; (2) substitution of low Ca(2+)-high Mg(2+) artificial cerebrospinal fluid (ACSF) for normal ACSF abolished the NE-induced inhibitory effect but failed to abolish the excitatory effect; (3) both the NE-induced excitatory and inhibitory effects were antagonized partly by phentolamine, prazosin, and propranolol but not by yohimbine; (4) naloxone and glibenclamide, a blocker of adenosine triphosphate-sensitive (K(ATP)) channels, blocked the NE-induced inhibitory effect; and (5) neurons that were inhibited by NE were also inhibited by morphine and cromakalim, an agonist of K(ATP) channels, and moreover, the morphine-induced inhibitory effect could be blocked by glibenclamide, while the cromakalim-induced inhibitory effect was not blocked by naloxone. These results imply that: (a) NE excites arcuate neurons through a mechanism that is insensitive to lowering the extracellular Ca(2+) suggesting a direct postsynaptic response through alpha(1)- and beta-adrenergic receptors, while NE inhibits cells through at least an inhibitory interneuron in arcuate and so is dependent on a Ca(2+)-sensitive presynaptic release mechanism; and (b) the inhibitory interneuron may be opioidergic, being excited first through alpha(1)- and beta-adrenergic receptors, after which the released opioids inhibit the neurons being recorded with an involvement of activation of K(ATP) channels. This possibility needs to be substantiated in much more detail.

Action Potentials↗

PubMed2000

Diurnal differences in sensitization to methylphenidate.

Using a computerized monitoring system, we investigated the development of motor sensitization to methylphenidate (MPD) in the rat, and determined whether sensitization was dependent on the time of drug administration. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by 5 days of single injections of 2.5 mg/kg MPD (days 5-9). After 5 days without injection (days 10-14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate challenge doses and four different times of administration: 08:00, 14:00, 20:00, or 02:00 h. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded. Sensitization to MPD was dependent on the time of administration, the motor index studied, and the challenge dose used. It was more pronounced for forward ambulation than for rearing, with no augmented response to stereotypic effects. The expression of the sensitized response was dose-dependent and mainly observed with the 0.6 and 2.5 mg/kg challenge dose groups. The development of sensitization to MPD was also time-dependent with the most robust sensitization occurring during the light phase, while no sensitization was observed during the middle of the dark phase. In addition, repeated MPD administration caused a significant increase in the amount of nocturnal forward ambulation that persisted long after cessation of drug treatment.

Animals↗

PubMed2000

MK-801 blocks the development of sensitization to the locomotor effects of methylphenidate.

Male Sprague-Dawley rats were divided to three groups (each n = 8) and were housed in test cages where motor activity was recorded continuously for 16 days using a computerized motor activity monitoring system to determine whether repeated administration of MK-801 could block the development and/or the expression of sensitization to the locomotor effects of methylphenidate (MPD). One group of rats received six daily injections (days 4-9) of 0.30 mg/kg MK-801, followed by 5 days without injection (days 10-14) and re-challenged (day 15) with 0.30 mg/kg MK-801. The second group received a challenge dose of 2.5 mg/kg MPD (day 4) followed by 5 days of co-treatment with MK-801 (0.30 mg/kg) given 1 h prior to MPD (days 5-9). This group was then re-challenged with MPD (2.5 mg/kg) on day 15. The last group received six daily injections of 2.5 mg/kg MPD (days 4-9). They were then split into two subgroups of rats which received either no treatment (control) or five daily injections of 0.30 mg/kg MK-801 (days 10-14) before being re-challenged on day 15 with 2.5 mg/kg MPD. MK-801 sensitized to its own locomotor effects. MK-801 given after sensitization had developed (i.e., days 10-14) was able to mask the expression of a sensitized response on day 15, but the effect was only transient since the sensitized response was present 3 weeks later. Moreover, MK-801, when coadministered during the repeated treatment phase was able to block the development of a sensitized response, which suggest that NMDA receptors involved in the process of MPD sensitization.

Animals↗

PubMed1999

Diurnal differences in amphetamine sensitization.

A computerized motor activity monitoring system was used to investigate the development and time dependence of sensitization to repeated exposure of amphetamine. Male Sprague-Dawley rats were acclimated for 7 days to light/dark cycle (0700 h:1900 h) in the testing room, and were then housed in the test cages for 16 days of continuous recording. The locomotor responses to s.c. administration of amphetamine (0.3, 0.6, or 1.2 mg/kg) were compared before and after five daily injections of 0.6 mg/kg of amphetamine. Different groups of rats were administered drug at either 0800 h, 1400 h, 2000 h, or 0200 h. The locomotor indices studied were total distance and vertical activity. Sensitization was more pronounced for total distance (i.e., forward ambulation) than for vertical activity (i.e., rearing), and its expression was dependent on the challenge dose. Sensitization was also time-dependent, with the strongest sensitized response occurring during the middle of the dark cycle (0200 h). Repeated administration of amphetamine (0.6 mg/kg) did not cause post-stimulant depression as has been seen at higher doses.

Amphetamine↗

PubMed1999

Interrelations of opioids with monoamines in descending inhibition of nociceptive transmission at the spinal level: an immunocytochemical study.

This study was designed to reexamine a previous proposal of whether the opioid-like substances (OLS) being acting mainly as an intrinsic spinal mediator in the descending inhibition of nociception of the bulbospinally projecting NE-ergic, and/or 5-HT-ergic terminals in the dorsal horn by using an immunocytochemical method. The effects of intrathecal (i.t.) phentolamine (Ph), cyproheptadine (Cyp), and naloxone (Nal), administered separately or coadministered by two of them, on the expression of Fos-like-immunoreactive (FLI) neurons were observed on both sides of the lumbar dorsal horn of rats, in which equal volumes of formalin were injected into two hindpaws and the ipsilateral dorsolateral funiculus (DLF) was transected at the thoracic level antecedently. The results showed: (1) when rats were pretreated with i.t. saline, the number of nociceptive FLI neurons was significantly lowered 44% (p<0.01) on the side of the lumbar dorsal horn with intact DLF compared to the opposite side with sectioned DLF; (2) when rats were separately pretreated with i.t. Ph, Cyp and Nal, the reduction of FLI neurons on the DLF-intact side were decreased by 27% (p<0.01), 21% (p<0.01), and 25% (p<0.01), respectively; (3) when rats were pretreated with combined i.t. Ph+Cyp, the reduction on the intact side was eliminated almost completely (4%); (4) when rats were pretreated with combined i.t. Ph+Nal, the reduction on the intact side was 21% (p<0.01); and (5) when rats were pretreated with i.t. Cyp+Nal, the reduction on the intact side was 9.1%. These results suggest that: (1) nearly all the suppressive action exerted by the DLF-descending fibers are produced by the release of either NE or 5-HT as neurotransmitters at the spinal level; (2) most of the opioid-like substances act as an intrinsic spinal mediator mainly for the descending NE-ergic, but in a lesser extent for the 5-HT-ergic terminals in the dorsal horn circuitry; and (3) some OLS-ergic interneurons may only be activated by local nociceptive input.

Adrenergic alpha-Antagonists↗

PubMed1999

Endogenous adenosine involved in the mediation of spinal antinociception produced by stimulating locus coeruleus.

The focus of this study was to investigate whether spinal adenosine is involved in mediating descending nociceptive modulation by the locus coeruleus (LC). Nociceptive evoked responses in parafascicular (PF) neurons were studied before and after electrical stimulation of the LC as well as before and after intrathecal (i.t.) administration of phentolamine (Ph) or aminophylline (Aph), an adenosine receptor antagonist, and 5'ethylcarboxamidoadenosine (NECA), an adenosine agonist. The main results were as follows: (1) the nociceptive evoked responses recorded in PF neurons were suppressed by LC stimulation; (2) pretreatment with i.t., Ph (40 nmol) reversed the LC effects, i.e., the suppressive effect of LC stimulation on the PF nociceptive evoked responses was reversed in the presence of Ph; (3) smaller doses of i.t. Aph (120 nmol) blocked only the suppressive effect produced by LC stimulation, while larger doses (240 nmol) reversed the LC stimulation, i.e., the LC stimulation exerted a facilatatory effect; and (4) i.t. application of NECA, an adenosine agonist, suppressed the nociceptive discharges in PF neurons. The results suggest that spinal adenosine may be involved in the mediation of the spinal antinociceptive effect produced by LC stimulation.

Adenosine↗

PubMed1998

Dose-related effects of MK-801 on acute and chronic methylphenidate administration.

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has been shown to modulate both the effects of stimulants, such as amphetamine and cocaine, in producing locomotion and the chronic effects of stimulants in producing sensitization. In this study, we examine the interactions between MK-801 and the stimulant methylphenidate. Three different doses of MK-801 were administered 60 min prior to methylphenidate injection (2.5 mg/kg) and the acute response to MK-801 alone and the coadministration with methylphenidate were characterized. MK-801 alone was found to produce dose-dependent locomotor activation. The 0.15 mg/kg dose of MK-801 had no effect on the response to methylphenidate, while the 0. 3 and 0.6 mg/kg doses augmented the methylphenidate response. The effect of pretreatment with MK-801 on subsequent repeated methylphenidate administration was assessed. For all three doses tested, MK-801 pretreatment blocked the progressive locomotor sensitization expected during repeated methylphenidate administration. These findings suggest that MK-801 may exert a long-lasting effect on learning and memory process that result in a blocking of the development of sensitization.

Animals↗

PubMed1998

Adenosine mediates spinal norepinephrine-produced antinociception as revealed by nociceptive discharges in parafascicular neurons in rats.

The effects of intrathecal pretreatment with aminophylline on intrathecal norepinephrine-produced or serotonin-produced suppression of noxiously evoked discharges in thalamic parafascicular neurons were investigated in 35 urethane-anesthetized rats. The results showed that: (1) both intrathecal norepinephrine (15 nmol) or serotonin (20 nmol) produced significant suppression of noxiously evoked discharges in parafascicular neurons; (2) intrathecal aminophylline (120 nmol) blocked the norepinephrine-produced suppression of noxiously evoked discharges, while the same dose of aminophylline exhibited no significant effect on the serotonin-produced suppression of these discharges in parafascicular neurons. The results suggest that spinal norepinephrine-produced, but not serotonin-produced, antinociceptive effects may be mediated by adenosine as one of successive chemical links in the spinal dorsal horn circuitry.

Adenosine↗

PubMed1998

Diurnal differences in rat's motor response to amphetamine.

The dose-response characteristics and time-course of amphetamine's effect on motor activity after a single injection given to rats at four different times of the light/dark cycle was investigated using a computerized infrared motor activity recording system. After 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or 0.6, 1.25 or 10 mg/kg amphetamine at 08.00, 14.00, 20.00 or 02.00. Recording was then resumed for an additional 36 to 48 h. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity and number of stereotypic movements. All doses (0.6. 1.25 and 10 mg/kg) significantly elevated (P < 0.01) locomotor activity compared to baseline at all times of administration. At all injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (P < 0.001). The effect of the lower doses (0.6 and 1.25 mg/kg) on forward locomotion remained the same throughout the light/dark cycle regardless of the large difference in baseline motor activity between the light and dark phases. However, the effects of 10 mg/kg amphetamine on general stereotypic behavior, as well as the ability to cause subsequent depression of nocturnal forward ambulation, were dependent on the time of drug administration. These results showed that the circadian rhythms of locomotor and stereotypic effects of amphetamine are different.

Amphetamine↗

PubMed1998

Locus coeruleus modulates thalamic nociceptive responses via adrenoceptors.

This study investigated the parafascicular (PF) neuronal nociceptive responses and their modulation following electrical stimulation of the locus coeruleus (LC) and intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration of two alpha-adrenoceptor antagonists, the alpha2-antagonist, yohimbine, and the alpha1-antagonist, prazosin. The main results were as follows: (1) the nociceptive evoked discharges in PF neurons were suppressed by preceding stimulation of LC; (2) the suppressive effect of LC stimulation on PF neurons was replaced by a facilitatory effect following pretreatment of i.t. yohimbine in 14 units tested, while i.t. prazosin failed to alter the LC-induced suppression, even when the prazosin dose was doubled; (3) i.c.v. pretreatment with prazosin strengthened the suppressive effect of LC stimulation on PF neurons; (4) i.c.v. norepinephrine (NE) administration induced, in PF neurons, a biphasic response to noxious stimulation; an early, brief (about 10 min) inhibitory effect followed by a late, long-lasting facilitatory effect; and (5) i.c.v. pretreatment of yohimbine or prazosin prevented the inhibitory or facilitatory responses released by NE, respectively. These results provide evidence that: (1) the LC-descending projections exhibit a suppressive effect on nociceptive transmission at the spinal level through alpha2-receptors; and (2) the LC-ascending projections exhibit dual effects, facilitatory and inhibitory, at the medial thalamus (PF) level through alpha1- and alpha2-receptors, respectively.

Adrenergic alpha-Agonists↗

PubMed1998

Different GABA-receptor types are involved in the 5-HT-induced antinociception at the spinal level: a behavioral study.

The effects of intrathecally (i.t.) administered GABA(A)-receptor antagonist picrotoxin or bicuculline on the antinociception produced by i.t. serotonin (5-HT), gamma-aminobutyric acid (GABA), muscimol--the GABA(A) agonist or baclofen--the GABA(B) agonist were investigated and compared using the tail-flick assay in rats. The results showed that 1) both i.t. picrotoxin (1.5 nmol) and i.t. bicuculline (0.5 nmol) exhibited a partial and later-emerged blockade on the antinociception produced by 5-HT (120 nmol) or GABA (1.5 nmol); 2) both i.t. picrotoxin and i.t. bicuculline, with the same dosages, completely blocked the antinociception produced by muscimol (1.0 nmol), but showed no effects on that produced by baclofen (0.3 nmol). The results suggest that GABA may mediate the 5-HT-induced antinociception at the spinal level, with the GABA(B)-receptors exhibiting the effect at the early-stage and the GABA(A)-receptors at the later stage of the 5-HT-induced antinociception.

Analgesics↗