Biomedical subjects

K Jhamandas

Publications and source records attributed to K Jhamandas.

At least 37 records · Page 2Linked to original sources

PubMed1997

Malonate-induced degeneration of basal forebrain cholinergic neurons: attenuation by lamotrigine, MK-801, and 7-nitroindazole.

Previously, we have reported that intranigral infusions of malonate, an inhibitor of mitochondrial function, lead to the degeneration of the dopaminergic neurons of the nigrostriatal pathway that is mediated, at least in part, through NMDA receptor activation and nitric oxide formation. In the present study, unilateral focal infusions of malonate into the nucleus basalis magnocellularis (nbM) of male Sprague-Dawley rats (weighing 250-300 g) resulted in a dose-related depletion in ipsilateral cortical and amygdaloid choline acetyltransferase (ChAT) activity. Infusion of a 3 mumol dose of malonate into the nbM of vehicle-treated animals resulted in a 41 and 54% decrease in cortical and amygdaloid ChAT activity, respectively. Systemic pretreatment with lamotrigine (16 mg/kg, i.p.) and MK-801 (5 mg/kg, i.p.) attenuated the depletions in cortical and amygdaloid ChAT activity that resulted from an infusion of this dose of malonate into the nbM. Acetylcholinesterase (AChE) histochemistry of the nbM following focal infusion of malonate (3 mumol) showed a marked decrease in the number of AChE-positive neurons that was partially prevented by MK-801 pretreatment. Before examining the role of nitric oxide formation in malonate-induced toxicity, the ability of systemic administration of N omega-nitro-L-arginine (L-NA) to inhibit nitric oxide synthase (NOS) activity in the nbM and cerebellum was investigated. L-NA (2, 10, and 20 mg/kg, i.p.) produced a dose-related inhibition of nbM and cerebellar NOS activity that was maximal following a dose of 10 mg/kg L-NA. This level of NOS inhibition persisted for at least 13 h following L-NA (10 mg/kg) administration. Subsequently, the effect of L-NA pretreatment on malonate toxicity was evaluated. Following pretreatment with L-NA (2 and 10 mg/kg, i.p.), the toxic action of malonate on cortical and amygdaloid ChAT activity was not altered. In addition, infusion of a lower dose of malonate (2 mumol) into the nbM resulted in decreases in cortical and amygdaloid ChAT activity that were not altered by pretreatment with L-NA (2 and 10 mg/kg, i.p.). In 7-nitroindazole (7-NI; 25 and 50 mg/kg, i.p.)-pretreated animals, malonate (3 mumol) produced decreases in cortical and amygdaloid ChAT activity that were attenuated by both doses of 7-NI. Thus, malonate-induced destruction of the basal forebrain cholinergic neurons was attenuated by systemic pretreatment with lamotrigine, MK-801, and 7-NI but not by L-NA.

Animals↗

PubMed1996

Differential action of 7-nitro indazole on rat brain nitric oxide synthase.

We examined the dose-response characteristics of brain nitric oxide synthase (NOS) inhibition following intraperitoneal administration of 7-nitro indazole (7-NI). 7-NI inhibited striatal, hippocampal, cortical, cerebellar and nigral NOS activity in a dose-dependent manner. NOS activity in the striatum and hippocampus could not be inhibited more than 60% while cerebellar and nigral activity was depleted by at least 85%, indicating that 7-NI has differential effects in different brain regions. ED50 values obtained from the 7-NI dose-response curves of the striatum and hippocampus were significantly higher than the ED50 values obtained from the cortex, cerebellum and substantia nigra, further confirming the differential actions of 7-NI. In addition, inhibition of NOS activity 4.5 h following a maximal dose of 7-NI demonstrated differential recovery. At this time point, the cerebellum and hippocampus were more inhibited than the striatum, cortex and substantia nigra. Therefore, the extent of recovery from this inhibition was independent of the level of maximal NOS inhibition in the different brain regions. We suggest determining the extent and duration of NOS inhibition resulting from 7-NI administration prior to using it to study the role of neuronal nitric oxide (NO) in various systems.

Animals↗

PubMed1996

Nitric oxide synthase inhibitors attenuate acute and chronic morphine withdrawal response in the rat locus coeruleus: an in vivo voltammetric study.

Previous studies have demonstrated that activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) associated with opioid and non-opioid drug withdrawal syndromes. Using an in vivo voltammetric approach, we have examined the role of nitric oxide (NO), which mediates NMDA receptor function, in this withdrawal-induced LC hyperactivity. In the anaesthetized rat, acute morphine treatment (10 micrograms, i.c.v.) suppressed (55.7 +/- 4.4% of baseline) the catechol oxidation current (CA-OC) recorded from the LC using differential normal pulse voltammetry (DNPV). A subsequent intravenous injection of naloxone (2 mg/kg, i.v.) reversed the drug-induced inhibition of LC response and produced an increase (118.9 +/- 2.3% of baseline) in CA-OC above baseline, indicative of an acute withdrawal response. Systemic (100 mg/kg) and intracerebroventricular (i.c.v.) (100 micrograms) pretreatment of animals with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) blocked the naloxone-induced LC withdrawal response without influencing the inhibitory effect of morphine on LC activity. In animals chronically infused with morphine (15 micrograms/h, i.c.v., 5 days) a naloxone challenge (2 mg/kg, i.v.) produced significant increase (253.7 +/- 19.3% of baseline) in CA-OC signal. This LC withdrawal response was significantly reduced by pretreatment with L-NAME (100 micrograms, i.c.v.) or N omega-nitro-L-arginine (L-NOARG 10 micrograms, i.c.v.). In unanaesthetized animals pretreated with chronic morphine, systemic (100 mg/kg) and central L-NAME (100 micrograms) pretreatment suppressed some of the behavioural signs of withdrawal precipitated by naloxone (10 mg/kg) injection. As doses of the NOS inhibitors used in this study have previously been reported to produce significant inhibition of brain NOS activity, their effect on opioid withdrawal response most likely is due to NOS inhibition. The results of this study indicate that NO plays an intermediary role in the LC neuronal hyperactivity associated with both acute and chronic morphine withdrawal.

Analysis of Variance↗

PubMed1996

Innocuous hair deflection evokes a nociceptive-like activation of catechol oxidation in the rat locus coeruleus following intrathecal strychnine: a biochemical index of allodynia using in vivo voltammetry.

Blockade of spinal glycinergic inhibition with intrathecal (i.t.) strychnine induces a reversible allodynia-like state in both conscious and lightly-anaesthetized rats. Since the locus coeruleus (LC) is activated by noxious stimuli, we determined the effect of non-noxious hair deflection (HD) on noradrenergic neuronal activity in the LC of rats treated with i.t. strychnine. Differential normal pulse voltammetry was used to measure the catechol oxidation current (CA.OC), an index of LC activity. Rats were maintained in a light plane of anaesthesia with i.v. urethane and i.t. strychnine (40 micrograms) was injected near the L1-L2 segment. HD, applied to the caudal dermatomes affected by i.t. strychnine, evoked a significant increase (max. 141 +/- 7%, n = 5, P < 0.05) in CA.OC and mean arterial pressure as compared to baseline (no strychnine). In contrast, HD had no significant effect on CA.OC or mean arterial pressure in the saline-treated rats (n = 5). Pre-treatment with i.t. MK801 (30 micrograms) significantly blocked the increase in CA.OC and mean arterial pressure evoked by HD in strychnine-treated rats. The results of this study indicated that HD, in the presence of i.t. strychnine but not saline, can evoke noradrenergic activity in the LC of lightly anaesthetized rats. This effect on the LC is: (1) comparable to that observed with noxious stimulation without i.t. strychnine; (2) segmentally localized, corresponding to the spinal site of strychnine injection; and (3) mediated by spinal NMDA receptors, consistent with the role of excitatory amino acids in sensory transmission. These data provide the first neurochemical evidence that HD, in the presence of i.t. strychnine, is a nociceptive event, supporting the use of this preparation as an experimental model of allodynia.

Animals↗

PubMed1996

A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia.

Tolerance to morphine analgesia is believed to result from a neuronal adaptation produced by continuous drug administration, although the precise mechanisms involved have yet to be established. Recently, we reported selective alterations in rat spinal calcitonin gene-related peptide (CGRP) markers in morphine-tolerant animals. In fact, increases in CGRP-like immunostaining and decrements in specific [125]hCGRP binding in the superficial laminae of the dorsal horn were correlated with the development of tolerance to the spinal antinociceptive action of morphine. Other spinally located peptides such as substance P, galanin, and neuropeptide Y were unaffected. Thus, the major goal of the present study was to investigate whether the development of tolerance to spinally infused morphine could be modulated by the blockade of dorsal horn CGRP receptors using the potent CGRP antagonist hCGRP(8-37). Indeed, cotreatments with hCGRP(8-37) prevented, in a dose-dependent manner, the development of tolerance to morphine-induced analgesia in both the rat tail-flick/tail-immersion and paw-pressure tests. Moreover, alterations in spinal CGRP markers seen in morphine-tolerant animals were not observed after a coadministration of morphine and hCGRP(8-37). These results demonstrate the existence of specific interaction between CGRP and the development of tolerance to the spinal antinociceptive effects of morphine. They also suggest that CGRP receptor antagonists could become useful adjuncts in the treatment of pain and tolerance to the antinociceptive effects of morphine.

Analgesics, Opioid↗

PubMed1996

Attenuation of malonate-induced degeneration of the nigrostriatal pathway by inhibitors of nitric oxide synthase.

Focal infusions of the succinate dehydrogenase inhibitor, malonate, into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a substantial depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity. The percentage decrease in striatal TH activity following intranigral malonate (0.5 mumol/0.5 microliter) infusion was similar at 4 (58%) and 7 days (62%) post-infusion. To assess the role of N-methyl-D-aspartate (NMDA) receptor activation in malonate neurotoxicity, animals were pretreated with the NMDA receptor antagonist MK-801 (2 x 5 mg/kg, i.p.). Four days post-infusion of malonate (0.5 mumol/0.5 microliter) into the SNc, striatal TH activity was depleted by 58% in vehicle pretreated animals and 14% in the presence of MK-801 indicating a significant neuroprotective effect of MK-801 on malonate action. To determine the role of nitric oxide (NO) in malonate-induced nigral toxicity, the actions of malonate were evaluated in the presence of the nitric oxide synthase (NOS) inhibitors, 7-nitro indazole (7-NI) and N omega-nitro-L-arginine methyl ester (L- NAME). Systemic injections of 7-NI (20, 30, 40, 50 and 75 mg/kg, i.p.) produced a dose-related inhibition of nigral NOS activity which was maximal at a dose of 40 mg/kg. Intranigral infusion of malonate with 20 and 50 mg/kg 7-NI pretreatment produced a 46 and 31% decrease in striatal TH activity, respectively. Thus, a significant protective effect at the higher but not lower dose of 7-NI was observed. Pretreatment with a L- NAME regimen (2 x 250 mg/kg; i.p.), previously shown to inhibit brain NOS activity by greater than 86%, also produced a significant neuroprotective effect against malonate-induced neurotoxicity (30% decrease). The results of this study suggest that malonate-induced toxicity to the dopaminergic neurons of the nigrostriatal pathway is mediated, at least in part, by NMDA receptor activation and the formation of NO.

Analysis of Variance↗

PubMed1996

Role of opioid receptors in the spinal antinociceptive effects of neuropeptide FF analogues.

1. Neuropeptide FF (NPFF) has been shown to produce antinociceptive effects and enhance morphine-induced antinociception after intrathecal (i.t.) injection. In this study, the spinal effects of two NPFF analogues, -D-Tyr1,(NMe)Phe3-NPFF (1DMe) and [D-Tyr1,D-Leu2,D-Phe3]NPFF (3D), which are resistant to degradation and exhibit a high affinity for NPFF binding sites, were examined in tests of thermal and mechanical nociception. 2. 1DMe and 3D produced potent dose-dependent spinal antinociception in the tail-flick test. On a molar basis, 1DMe was 20 and 50 times more potent than 3D and morphine, respectively, and high doses of 1DMe and 3D produced a sustained antinociceptive effect without visible signs of motor impairment. 3. Spinal antinociceptive effects produced by 1DMe (0.86 nmol) or 3D (8.6 nmol) were significantly reduced by i.t. co-administration of naloxone (11 nmol) or i.t. pre-administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 9.25 nmol) or beta-funaltrexamine (beta-FNA, 2 nmol) or naltrindole (2.2 nmol). The doses of the mu-antagonists (CTOP and beta-FNA) or the delta-antagonist (naltrindole) used in 1DMe and 3D experiments blocked the antinociceptive effects of mu- or delta-receptor-selective agonists. 4. When administered in combination with antinociceptive doses of the mu-receptor agonist, morphine (13.2 nmol) or the delta-receptor agonist, [D-Ala2]deltorphin I (20 nmol), sub-effective dose of 1DMe or 3D (0.009 nmol) enhanced and prolonged the spinal effects of these opioid agonists. 5. The results of this study show that spinal mu- and delta-opioid receptors play a role in antinociception produced by NPFF analogues. These results also suggest a role for NPFF in modulation of nociceptive signals at the spinal level.

Amino Acid Sequence↗

PubMed1995

Involvement of excitatory amino acid pathways in the expression of precipitated opioid withdrawal in the rostral ventrolateral medulla: an in vivo voltammetric study.

Previous studies have shown that catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) become hyperactive during opioid withdrawal. In the present study, the role of excitatory amino acid pathways in the expression of opioid withdrawal in the RVLM was examined by using differential pulse voltammetry (DNPV) to measure changes in the catecholamine oxidation current (CA.OC) following naloxone challenge in rats treated with acute or chronic morphine. Acute morphine (10 micrograms i.c.v.) significantly reduced the CA.OC signal in the RVLM and the mean arterial pressure to 37.1 +/- 6.6% and 21.1 +/- 3.5% below baseline, respectively. Naloxone (1 mg kg-1 i.v.) reversed the morphine effect and produced a significant increase in the CA.OC signal to 25.6 +/- 15.2% above baseline. In animals treated with chronic morphine (10 micrograms h-1 i.c.v., 5 days), naloxone (1 mg kg-1 i.v.) produced a significant increase in the CA.OC signal to 54.2 +/- 16.5% above baseline. Both the nonselective excitatory amino acid antagonist, gamma-D-glutamylglycine (DGG, 200 micrograms i.c.v.) and the selective NMDA antagonist, D(-)-amino-7-phosphonoheptanoic acid (D-APH, 25 micrograms i.c.v.) attenuated the naloxone-induced increase in the CA.OC by 50.7% and 46.0% respectively. In morphine naive animals, DGG and D-APH depressed the CA.OC by 42.8 +/- 8.7% and 17.7 +/- 9.8%, respectively. To the extent that the CA.OC is an index of neuronal activity, these results suggest that RVLM hyperactivity during morphine withdrawal is dependent, in part, upon activation of NMDA receptors.

Animals↗

PubMed1995

Enhancement of 7-nitro indazole-induced inhibition of brain nitric oxide synthase by norharmane.

7-Nitro indazole (7-NI) has been used as a selective inhibitor of neuronal nitric oxide synthase (NOS) in vivo. This agent has a short duration of action which may be due to its metabolism. The structure of 7-NI resembles that of tryptophan which can be metabolized by the enzyme indolamine 2,3-dioxygenase (IDO). If 7-NI is also metabolized by this enzyme, then inhibition of IDO should augment the action of 7-NI on brain NOS activity. This possibility was examined by investigating the potential of norharmane, an IDO inhibitor, on the inhibitory effect of 7-NI on NOS catalytic activity (3, 4.5 and 7.5 h post-injection of 7-NI) in five brain regions. Norharmane, which alone did not alter NOS activity, enhanced the action of 7-NI on NOS activity in the cortex (4.5 and 7.5 h), hippocampus (3 h) and substantia nigra (3, 4.5 and 7.5 h) but not in the cerebellum or striatum. This suggests that IDO activity may, at least in part, be responsible for the relatively short duration of 7-NI action.

Amino Acid Oxidoreductases↗

PubMed1995

Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis.

Focal infusions of N-methyl-D-aspartate (NMDA) or an endogenous NMDA agonist, quinolinic acid (QUIN), into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a dose-dependent depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity, a biochemical marker for dopaminergic neurons. To assess the intermediary role of nitric oxide in the neurotoxicity elicited by these toxins, their action was tested in animals treated with N omega-nitro-L-arginine methyl ester (L-NAME). Systemic injections (2 injections; 8 h apart) of L-NAME (100, 150 and 250 mg/kg) produced a dose-related inhibition of cerebellar nitric oxide synthase (NOS) activity. The time-course of cerebellar NOS inhibition following L-NAME (250 mg/kg) was rapid in onset and lasted for at least 24 h following the second injection. An L-NAME treatment regimen of 250 mg/kg, with the second injection given 24 h prior to assessment of NOS activity, produced an 87 and 91% inhibition of cerebellar and nigral NOS activity, respectively. Intranigral infusion of 40 and 60 nmol QUIN reduced ipsilateral striatal TH activity by 62 and 75%, respectively. However, 40 and 60 nmol QUIN infusions into animals pretreated with L-NAME (250 mg/kg) reduced striatal TH activity by 83 and 96%, respectively. Intranigral infusion of 15 and 30 nmol NMDA produced a 48 and 77% decrease in striatal TH activity, respectively, whereas the same doses of NMDA given to animals pretreated with L-NAME (250 mg/kg) resulted in a 59 and 88% decrease in TH activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMed1995

Physostigmine, but not 3,4-diaminopyridine, improves radial maze performance in memory-impaired rats.

The results of some studies suggest that 3,4-diaminopyridine (3,4-DAP), a drug that enhances the release of acetylcholine, may improve memory. The present study examined the ability of 3,4-DAP to reverse the memory impairment produced by scopolamine and the ability of 3,4-DAP and physostigmine to reverse the memory impairment produced by quinolinic acid lesions of the nucleus basalis magnocellularis (nbm) in rats. Mnemonic functioning was assessed with the use of a partially baited eight-arm radial maze. Entries into arms that were never baited were defined as reference memory errors; entries into baited arms from which the food already had been eaten were defined as working memory errors. In Experiment 1, 0.1 mg/kg scopolamine produced a significant increase in working and reference memory errors. Various doses of 3,4-DAP had no significant ameliorative effect on the mnemonic deficit. In Experiment 2, cholinergic function was impaired using a unilateral intra-nbm injection of quinolinic acid (120 nmol in 1.0 microliter). These lesions reduced the levels of the cholinergic marker, choline acetyltransferase, in the cortex by more than 40%. Results showed that the nbm lesion animals were significantly more impaired on the working than reference memory component of the task. Physostigmine (0.01, 0.05, 0.10, 0.20, 0.50 mg/kg) dose-dependently decreased the number of working but not reference memory errors. 3,4-DAP (10(-8), 10(-6), 10(-4), 10(-2), 10(0) mg/kg) had no reliable effect. It was concluded that physostigmine, but not 3,4-DAP, ameliorates memory impairments following decreases in cholinergic function.

4-Aminopyridine↗

PubMed1995

Nucleus basalis lesions: implication of basoamygdaloid cholinergic pathways in memory.

Previous studies have shown a lack of association between cortical choline acetyltransferase (ChAT) activity and severity of memory impairment following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). It recently has been proposed that the differential effects of NBM injections of various excitotoxins on amygdaloid and cortical ChAT may explain this result. The present study evaluated the mnemonic effect of unilateral intra-NBM infusions of the excitotoxins phthalic acid and quisqualic acid, which decrease ChAT activity primarily in the amygdala and cortex, respectively. Rats were trained in a double Y-maze, lesioned, and allowed to recover for 1 week prior to memory assessment. Behavioral results showed impaired working but not reference memory following phthalic acid lesions, and no significant effect following quisqualic acid lesions. Biochemical analysis in a second group of subjects confirmed that phthalic acid lesions produced a large decrease in basolateral amygdaloid ChAT, but had little effect on cortical ChAT activity. Conversely, quisqualic acid lesions produced a large decrease in cortical, but not basolateral amygdaloid, ChAT activity. These results suggest that the NBM amygdalopetal cholinergic pathways play a role in mnemonic functioning.

Amygdala↗

PubMed1995

Tolerance to the antinociceptive properties of morphine in the rat spinal cord: alteration of calcitonin gene-related peptide-like immunostaining and receptor binding sites.

Tolerance to the spinal antinociceptive effects of morphine develops rapidly after its chronic administration. The mechanism involved in this phenomenon is unclear, but it is unlikely due to a direct regulation of spinal opioid peptides and their receptor binding sites. A variety of neuropeptides, especially the neurokinins and calcitonin gene-related peptide (CGRP) are concentrated in primary sensory afferents and have thus been proposed to play significant roles in spinal nociceptive mechanisms. However, their functions in the development of tolerance to the antinociceptive properties of morphine have not been explored fully. We therefore investigated the possible involvement of various sensory neuropeptides including CGRP, substance P, galanin, neurotensin and neuropeptide Y and their receptors in the dorsal horn of the spinal cord during the development of tolerance to the antinociceptive action of intrathecal morphine. Morphine sulfate (7.5 micrograms/microliters/hr) was administered continuously at lumbar level L4 using mini-osmotic pumps for 3, 5, 7 and 14 days. Tolerance to the antinociceptive effect of morphine was verified with the tail-immersion test and became evident on the 5th day of treatment. In tolerant animals, there was a marked increase in CGRP-like immunostaining and a decrease (30-45%) in [125I]human CGRP alpha binding in laminae I, II and III of the dorsal horn of the spinal cord. These changes coincided with the onset of morphine tolerance and persisted for the 14-day period during which tolerance was present. Similar changes were not observed in the immunostaining or binding of the other neuropeptides studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Picolinic acid protects against quinolinic acid-induced depletion of NADPH diaphorase containing neurons in the rat striatum.

Previous studies in our laboratory have demonstrated that focal injections of picolinic acid (PIC) protect the cholinergic neurons of the nucleus basalis magnocellularis (nbm) against quinolinic acid (QUIN)-induced neurotoxicity. The present study was designed to examine the effects of chronic infusions of QUIN and PIC on nicotinamide adenine dinucleotide (NADPH) diaphorase containing neurons of the rat striatum. Using osmotic minipumps, QUIN (6 nmol/h) and PIC (18 nmol/h) were infused alone or in combination to examine the neurotoxic effects of QUIN and the potential anti-neurotoxic action of PIC. Exposure to QUIN for 7 days severely depleted NADPH diaphorase-positive neurons. When co-infused with this neurotoxic dose of QUIN, PIC attenuated the depletion of NADPH diaphorase neurons induced by QUIN. The infusion of PIC alone did not affect the number of these neurons. These results indicate that PIC itself is not neurotoxic and effectively prevents chronic QUIN-induced neurotoxicity in the rat striatum. Since PIC and QUIN are derived from the same metabolic pathway, a balance between endogenous compounds that produce neurotoxicity and those antagonizing these effects may be important in normal neuronal function.

Amino Acid Oxidoreductases↗

PubMed1994

Basal forebrain injections of the benzodiazepine partial inverse agonist FG 7142 enhance memory of rats in the double Y-maze.

Cholinergic replacement strategies have achieved little success in the treatment of Alzheimer's disease. It has been suggested that the mnemonic function of cholinergic neurons may be enhanced by treatments that reduce GABA-ergic inhibition, while preserving the normal pattern of activity in the cholinergic neurons. Following on these suggestions, the present study investigated the mnemonic effects of intra-nucleus basalis magnocellularis (NBM) injections of the benzodiazepine receptor partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142). Rats were surgically implanted with bilateral cannulae in the NBM prior to training in a double Y-maze. Daily training sessions continued until reference and working memory choice performance stabilized to a criterion of > or = 91% correct. Rats (n = 9) received FG 7142 bilaterally in doses of 0.2, 2.0 and 3.0 micrograms/0.5 microliter per side, muscimol (a GABAA agonist) in a dose of 0.1 microgram/0.5 microliter per side, vehicle (345 micrograms 2-hydroxypropyl-beta-cyclodextrin/0.5 microliter saline per side) or no injection in a counterbalanced order with retraining to criterion between treatments. Muscimol impaired choice accuracy on both the reference and working memory components, but the effect was bigger for working memory, replicating our previous findings. Two doses of FG 7142 (0.2 and 2.0 micrograms/0.5 microliter) enhanced choice accuracy on the working memory component. The present results suggest that benzodiazepine partial inverse agonists may enhance mnemonic function.

Animals↗

PubMed1994

The role of excitatory amino acids in the expression of precipitated acute and chronic clonidine withdrawal: an in vivo voltammetric study in the rat locus coeruleus.

It has been previously shown that activation of excitatory amino acid (EAA) pathways contributes to hyperactivity of the locus coeruleus (LC) in antagonist precipitated opioid withdrawal. In this study, using differential normal pulse voltammetry to monitor catechol oxidation as an index of the activity of the LC, the role of EAA pathways in antagonist precipitated withdrawal after acute and chronic clonidine treatment was examined. Intracerebroventricular clonidine (10 micrograms i.c.v.) significantly reduced LC activity to 54.4 +/- 3.1% of baseline 45 minutes following the injection. Subsequent systemic injection of the selective alpha 2 receptor antagonist atipamezole (0.2 mg/kg i.v.) or yohimbine (0.5 mg/kg i.v.) resulted in a rapid reversal of the depressant effects and a significant increase in LC activity above baseline. Pretreatment with the non-selective EAA receptor antagonist gamma-D-glutamylglycine (DGG) (50 micrograms i.c.v.) attenuated the atipamezole-induced rebound response of the LC but not the reversal of clonidine action. However, both the yohimbine-induced rebound and reversal of clonidine effects were attenuated by DGG treated animals. In chronic clonidine treated animals (2, 5, 7, 10 micrograms/h i.c.v., 5 days), a challenge with atipamezole (0.2 mg/kg i.v.) produced an immediate increase in LC activity, blood pressure and heart rate. The magnitude of these responses was dependent on the dose of clonidine. The atipamezole-induced increase in LC activity and blood pressure was significantly attenuated by pretreatment with DGG (200 micrograms i.c.v.). These findings suggest that LC hyperactivity and blood pressure increases elicited during clonidine withdrawal are mediated in part by activation of EAA receptors. In this regard, the mechanisms underlying clonidine withdrawal closely resembles those underlying opioid withdrawal.

Acute Disease↗

PubMed1994

Stimulation of GABAB receptors in the basal forebrain selectively impairs working memory of rats in the double Y-maze.

The present experiments were conducted to evaluate the possible contribution of GABAergic inputs to the basal forebrain in the region of the nucleus basalis magnocellularis (nbm) to memory. In two experiments, rats implanted with bilateral intra-nbm guide cannulae were trained in the double Y-maze task to perform working- and reference-memory components. Animals were placed in one of two start arms of the first "Y" and the reference-memory component required travelling to its central stem for food. Access to the second "Y" then was given and the working-memory component for Expt. 1 required travelling to the goal arm diagonally opposite the start arm in the first "Y" of that trial. In Expt. 2, the working-memory component required travelling to the goal arm opposite to the goal arm entered in the second "Y" on the preceding trial, with 0- and 15-s delays between trials. In Expt. 1, pretrained rats (n = 8) received the GABAA agonist, muscimol (0.1 microgram in 0.5 microliter), the GABAB agonist, R(+)-baclofen (0.01, 0.05 and 0.1 microgram), and its less active enantiomer, S(-)-baclofen (0.1 microgram), in a counterbalanced order with retraining to criterion between injections. In Expt. 2, pretrained rats (n = 9) received saline (0.5 microliter), R(+)-baclofen (0.1 microgram), the GABAB antagonist, phaclofen (1 microgram), and R(+)-baclofen+phaclofen. Results of Expt. 1 revealed that intra-nbm muscimol and, in a dose-dependent manner, R(+)-baclofen differentially affected working but not reference memory. In Expt. 2, the differential mnemonic impairment produced by R(+)-baclofen was replicated and co-injection with phaclofen reversed this effect. A 15-s delay between trials significantly impaired working but not reference memory. Results suggest that both GABAA and GABAB receptors may be involved in modulating the possible mnemonic functions of nbm cholinergic neurons.

Animals↗

PubMed1994

Potentiation of NMDA-mediated toxicity on nigrostriatal neurons by a low dose of 7-nitro indazole.

Recent evidence suggests that an excitotoxic mechanism may play a role in the etiology of Parkinson's disease. Previously, we have shown that the nigrostriatal dopaminergic neurons are sensitive to focal infusions of an N-methyl-D-aspartate (NMDA) receptor agonist; this toxicity was potentiated by systemic administration of the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester. The present investigation was undertaken to assess the role of the selective neuronal NOS inhibitor, 7-nitro indazole (7-NI) on the neurotoxicity elicited by NMDA receptor activation in vivo. Single injections of 7-NI (0-125 mg/kg, i.p.) into male Sprague-Dawley rats resulted in a dose-dependent decrease in both nigral and cerebellar NOS activity measured 30 min post-injection. Maximal NOS inhibition was obtained with 20 mg/kg 7-NI (nigra: 90.2 +/- 3.7%, cerebellum: 86.7 +/- 6.3%). In addition, it was found that 7-NI (80 mg/kg, i.p.) did not cause an increase in mean arterial blood pressure over a 48 hr period. Vehicle pretreatment of animals prior to stereotaxic infusion of NMDA (15 nmol) into the substantia nigra compacta resulted in a 56.1 +/- 5.1% decrease in striatal tyrosine hydroxylase (TH) activity from the contralateral side. Pretreatment with 7-NI (5 and 80 mg/kg) produced a 76.9 +/- 3.2% and 49.8 +/- 5.6% decrease, respectively, in striatal TH activity. Thus, a significant increase in NMDA toxicity was observed at the lower but not higher dose of 7-NI. It was also observed that 7-NI (20 and 80 mg/kg) produced a decrease in locomotor activity over a 2 hr period.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗