Biomedical subjects

C Spyraki

Publications and source records attributed to C Spyraki.

At least 19 recordsLinked to original sources

PubMed2005

Behavioral pharmacological properties of a novel cannabinoid 1',1'-dithiolane delta8-THC analog, AMG-3.

Newly developed cannabinoids may hold the promise of the development of useful and safe drugs. This study aimed to investigate the behavioral effects of the novel 1',1'-dithiolane delta8-HC analogue AMG-3, a cannabinomimetic molecule with high affinity for CB1/CB2 receptors. This analog was chosen for its binding affinity to these receptors, which is higher than that reported for delta8-tetrahydrocannabinol (delta8-THC). Behavioral responses were assessed after the administration of AMG-3 (1, 2, 4, 8 mg/kg, i.p.) in the open field, on the bar test, on the hot plate and in the intracranial self-stimulation procedure. AMG-3 increased the reactivity time on the hot plate in a dose- and time-dependent manner, indicating a long-lasting analgesic effect (at least 24 h). The substance was found dose-dependently to decrease spontaneous motor activity and to induce catalepsy, particularly at the highest dose (8 mg/kg). AMG-3 did not affect the rewarding value of intracranial self-stimulation, except to increase the reward threshold at the highest dose (8 mg/kg). The effects of the highest dose of AMG-3 on spontaneous activity and on the self-stimulation paradigm were completely reversed by pre-treatment with the CB1 receptor antagonist AM-251. These findings indicate that the administration of AMG-3 to rats elicits a specific behavioral profile, most probably associated with the activation of CB1 receptors and without effects indicating abuse potential.

Animals↗

PubMed2001

Chronic desipramine treatment selectively potentiates somatostatin-induced dopamine release in the nucleus accumbens.

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin-14 (10(-4) M) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin-induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Interaction between nandrolone decanoate and calcitonin in bone formation markers (osteocalcin and bone specific alkaline phosphatase) and IGF-I in rats.

Bone tissue has been shown to contain numerous cell-to-cell signaling peptides called growth factors. These growth factors are thought to have important regulating effects for bone remodeling, due to their potent effects on bone cell metabolism. Our investigation was intended to assess the effect of nandrolone decanoate and calcitonin treatment on biochemical markers of bone formation (bone alkaline phosphatase - osteocalcin) and insulin-like growth factor-I in rats. We studied 48 adult male rats. The animals were divided into four groups. Group (A) served as control. Animals in Group (B) were injected with 4 mg/kg/day nandrolone decanoate. Animals in Group (C) were injected with 400mU/rat/day calcitonin and Group (D) received combined therapy for seven days. Nandrolone decanoate and calcitonin have a mild but significant effect on insulin-like growth factor-I without affecting osteocalcin levels, while calcitonin alone decreases the BALP levels. The coadministration of two agents caused notable elevation on insulin-like growth factor-I, followed by a significant increase of osteocalcin and bone alkaline phosphatase.

Journal Article↗

PubMed2000

Effects of methyllycaconitine (MLA), an alpha 7 nicotinic receptor antagonist, on nicotine- and cocaine-induced potentiation of brain stimulation reward.

It has been shown that nicotine facilitates intracranial self-stimulation (ICSS) reward and that nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) are of primary importance for its reinforcing and dependence-producing actions. Recently, we have shown that alpha 7 nicotinic receptors in the VTA contribute to both the acute effects of nicotine on the mesolimbic dopamine system, as well as to nicotine withdrawal reactions. However, it is not yet known whether the same receptor conformation is directly involved in the reinforcing actions of nicotine. Here, using the curve-shift method we studied the effects of methyllycaconitine (MLA), a selective alpha 7 receptor antagonist, microinjected (graded doses: 1, 3, 9 micrograms/microliter per side) into the VTA on the rewarding efficacy of lateral hypothalamic self-stimulation and on the systemic nicotine-induced potentiation of brain stimulation reward. MLA did not affect baseline self-stimulation. Nicotine produced a significant reduction in ICSS threshold, without altering maximal rates of responding, while MLA attenuated the effect of nicotine at the two lower doses. Given the reported interaction between nicotine and cocaine at both the neuronal and the behavioral level, we also examined whether alpha 7 receptor antagonism within the VTA can affect the reinforcing action of cocaine, as measured with ICSS. Interestingly, MLA attenuated the reinforcing effect of cocaine in all doses tested, without altering the maximal rate of responding, i.e. the performance of the animals. These results suggest that alpha 7 nAChRs in the VTA are involved in mediating the reinforcing actions of drugs of abuse, such as nicotine and cocaine, and provide evidence that alpha 7 nAChR antagonists may be clinically useful in attenuating the rewarding effects of addictive drugs.

Aconitine↗

PubMed1999

AMPA-receptor involvement in c-fos expression in the medial prefrontal cortex and amygdala dissociates neural substrates of conditioned activity and conditioned reward.

Exposure to an environment, previously conditioned to amphetamine (1 mg/kg, i.p.), induced locomotor activity and c-fos expression (a marker for neuronal activation) in the mouse medial prefrontal cortex (mPFC) and amygdala; acute or repeated amphetamine (1 mg/kg, i.p.) administration induced c-fos expression additionally in the nucleus accumbens. An alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor antagonist, 2, 3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)quinoxaline (NBQX), blocked expression of conditioned activity, and prevented the increase in c-fos expression in mPFC, implicating mPFC AMPAergic transmission in the conditioned component of behavioural sensitization to amphetamine. NBQX failed to block the expression of amphetamine-conditioned place preference, a measure of conditioned reward, or conditioned c-fos expression in the amygdala, an area implicated in the expression of conditioned place preference. These findings indicate that the conditioned components of behavioural sensitization depend on AMPA-receptor-mediated activation in mPFC, but that conditioned reward does not.

Amygdala↗

PubMed1998

Involvement of the ventral tegmental area opiate receptors in self-stimulation elicited from the ventral pallidum.

Enkephalinergic and dopaminergic mechanisms have been implicated in the electrical self-stimulation (SS) behavior. The present set of experiments investigated the role of opioid receptors within DA-innervated brain regions (nucleus accumbens and ventral tegmental area) in the ventral pallidum self-stimulation (VP-SS). Forty-one rats used in this study were implanted with a monopolar moveable stimulating electrode in the VP. A rate-frequency curve-shift method was applied to determine the reward (threshold) and motor functions (asymptotic rate) of self stimulation elicited from the VP. One group received systemic treatment of graded doses (vehicle; 1.25; 2.50 mg/kg) of morphine injected IP, 60 min before behavioural testing. The results showed a tendency for increased threshold of VP-SS and of the asymptotic rate of responding. Three additional groups were implanted with guide cannulae in the nucleus accumbens (NAC), the ventral tegmental area (VTA) or dorsally to the VTA and received microinjections of morphine (vehicle: 1.25; 2.50; 5.0; 10.0 microg/0.5 microl per side). Central injections of morphine higher than 1.25 microg/side into the VTA were associated with a significant reduction in VP-SS thresholds, indicating a potentiative effect on reward. Microinjections of morphine either into the NAC or into the dorsal tegmentum did not produce significant alterations on thresholds or responding of VP-SS. In order to investigate the extent to which the VTA-NAC dopamine projection was involved in the SS behavior elicited from the ventral pallidum, we tested SS in animals that suffered NAC 6-hydroxydopamine (6-OHDA) lesions. Rats suffering NAC dopamine depletion along with their corresponding controls showed similar levels of thresholds and responding to the ones exhibited prior to the lesion, revealing that NAC dopamine is not necessary to maintain VP-SS. The results suggest that stimulation of opioid receptor in the VTA increases the rewarding efficacy of VP-SS. This effect might be due to the modulation of VTA-DA neurons projecting to the VP rather than to the NAC.

Animals↗

PubMed1998

Dizocilpine (MK-801) and tetrodotoxin influence accumbal dopamine release evoked by intrapallidal morphine.

It has been hypothesized that the intrapallidal morphine-induced dopamine release in the nucleus accumbens may be mediated by thalamocorticostriatal or mesolimbic pathways. In order to challenge the above hypothesis, we examined whether changes in accumbal dopamine and its metabolites produced by intrapallidal morphine a) are associated with local excitatory amino acid neurotransmission b) are determined by impulse propagation in dopamine neurons and c) are observed both ipsi- and contralateral to the morphine administration site. In vivo microdialysis was used to assess dopamine release and metabolism in the right and the left nucleus accumbens separately of awake, unrestrained rats. Vehicle or morphine hydrochloride (10 microliters/26.0 mM) was applied unilaterally into the pallidum alone or in combination with ipsilateral application of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) into the nucleus accumbens or the sodium channel blocker tetrodotoxin into the medial forebrain bundle. Drugs' application was performed via reverse dialysis. Concentrations of dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the collected dialysate were measured by high performance liquid chromatography with electrochemical detection. Morphine administration resulted in elevated levels of dopamine in the ipsilateral and of DOPAC and HVA in both the ipsi- and contralateral nucleus accumbens. Dizocilpine (MK-801) (0.3 mM) did not influence the basal levels of dopamine, DOPAC or HVA in the nucleus accumbens. Ipsilaterally, dizocilpine (MK-801) inhibited the effect of morphine on dopamine release, whereas it increased significantly the effect of the drug on DOPAC and HVA. Tetrodotoxin (3 microM) reversed the effect of intrapallidal morphine on dopamine, DOPAC or HVA in the ipsilateral nucleus accumbens. The results show that the intrapallidal morphine-induced dopaminergic activation in the ipsilateral nucleus accumbens is dependent upon both phasic and tonic activation of dopaminergic neurons. They suggest that both the thalamocorticostriatal and the mesolimbic dopamine pathways may mediate the investigated effect of morphine.

Animals↗

PubMed1997

Ventral pallidum self-stimulation induces stimulus dependent increase in c-fos expression in reward-related brain regions.

Neuronal expression of Fos, the protein product of the immediate early gene c-fos has been used as a high resolution metabolic marker for mapping polysynaptic pathways in the brain. We used Fos immunohistochemistry to reveal neuronal activation following self-stimulation of the ventral pallidum. Four groups of rats were allowed to self-stimulate for 30 min with 0.4 s trains of cathodal rectangular pulses of constant intensity (0.4 mA) and duration (0.1 ms). Each group was assigned a different pulse frequency, (3, 17, 24 and 50 pulses/stimulation train). Which was preselected from within each animal's rate-frequency function. The subjects that were assigned three pulses failed to self-stimulate and were considered as controls. The subjects that were assigned 17 pulses self-stimulated at half-maximal rate, whereas those that were assigned 24 and 50 pulses self-stimulated at maximal rates. The animals were sacrificed 90 min after the self-stimulation session and their brains were processed for Fos-like immunoreactivity. Fos-like immunoreactivity was found to increase as a function of pulse frequency in several brain regions known to be involved in drug and/or brain stimulation reward (medial prefrontal cortex, lateral septum, nucleus accumbens; lateral hypothalamus and ventral tegmental area), whereas it was not affected in structures devoid of such involvement (substantia nigra reticulata and dorsolateral striatum). The level of Fos expression induced by trains of 50 pulses was considerably higher than that produced by 24 pulses although both frequencies supported the same (maximal) self-stimulation rate. This finding indicates that Fos expression correlated with reward magnitude (known to increase between these frequencies), not with bar-pressing rate, thus suggesting the presence of a reward-specific effect. The finding of a frequency-dependent Fos expression in a behavioural paradigm can be considered analogous to a pharmacological dose-response curve and, as such, our results may open new avenues for the use of Fos immunohistochemistry in quantitative neurobehavioural studies.

Animals↗

PubMed1996

Dopamine-somatostatin interactions in the rat striatum: an in vivo microdialysis study.

Dopamine-somatostatin interactions were investigated in the rat striatum using in vivo microdialysis. Somatostatin-14 and somatostatin-28 (10(-4), 10(-5), 10(-6) M) were infused, and the levels of dopamine and its metabolites DOPAC and HVA were assessed using high pressure liquid chromatography with electrochemical detection. Somatostatin-14 was more effective than somatostatin-28 in producing a dose-dependent increase in dopamine levels with no significant alterations in the levels of the metabolites. To assess the effect of dopamine on somatostatinergic neurons, dopaminergic agents were administered and somatostatin levels measured using a radioimmunoassay. The nonselective agonist apomorphine was administered subcutaneously (0.00, 0.05, 0.10, 0.50, 1.00 mg/kg) or directly infused (10(-4), 10(-5) M) in the striatum. The selective D1 and D2 dopamine antagonists SCH23390 and sulpiride, respectively, were also infused at concentrations of 10(-4) and 10(-5) M. None of these agents elicited any significant changes in the somatostatin release in the striatum, while altering dopamine release. This study provides for the first time evidence regarding dopamine-somatostatin interactions in the awake and freely moving animal. The results confirm that somatostatin modulates the function of dopaminergic neurons in the striatum and provide new evidence that somatostatin-14 may differentially regulate dopamine release. Furthermore, our findings suggest that dopamine does not play a major role in the regulation of somatostatin neurons.

Animals↗

PubMed1996

Neuropharmacological evidence for the role of dopamine in ventral pallidum self-stimulation.

The present study examines the role of dopaminergic neurotransmission in modulating the reinforcing effect of ventral pallidum (VP) intracranial self-stimulation (ICSS). Fifty four adult rats were implanted with a monopolar moveable stimulating electrode in the VP. Rate-frequency functions were determined by logarithmically decreasing the number of pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After the ICSS thresholds stabilized, the animals received treatments with several doses of cocaine and of various selective drugs acting at the level of DA receptor subtypes. Their effects on threshold and asymptotic rate were analyzed. Cocaine produced a significant decrease in ICSS threshold but had no significant effect on the asymptotic rate. A significant decrease in ICSS threshold was also seen with the D3 agonist 7-OH-DPAT. This was associated with a decrease rather than an increase in performance. D1 and D2 DA receptor blockers (haloperidol, SCH-23390, raclopride and sulpiride) produced a dose dependent increase in ICSS threshold and a decrease in the maximal rate. The results suggest that DA plays a modulatory role in VP intracranial self-stimulation, and that D1, D2 and D3 receptors are involved in the mediation of this effect, although to different extents.

Animals↗

PubMed1995

Ventral pallidum self-stimulation: a moveable electrode mapping study.

The distribution of electrical self-stimulation (ESS) foci within the ventral pallidum (VP) was mapped using moveable electrodes in rats. The function relating ESS bar-pressing rate to the frequency of cathodal rectangular pulses (0.4 mA and 0.1 ms) was obtained for several positions of a moveable electrode in the VP and in the various adjacent to VP nuclei. The rate-frequency functions were fitted to a sigmoid model to obtain the asymptotic rate and threshold frequency. ESS was found in almost all (98%) VP sites tested and to a lesser degree (66%) in the surrounding areas (namely globus pallidus and caudate). Depending on the VP site, maximum rates varied from 14 to 85 bar presses/min, whereas threshold frequencies varied from 10.2 to 36.4 pulses/train; no correlation between these two aspects of ESS was found. Extra-pallidal areas contained less low-frequency threshold sites compared to VP. The lowest threshold found in the VP was slightly higher than that usually obtained for the most rewarding brain areas (VTA, dorsal raphé, LH, amygdala), which suggests that the VP represents an important structure for reward. Furthermore the threshold frequencies were found to decline along the rostrocaudal axis of the VP which supports the view that the VP is heterogeneous in regard to reward related functions.

Amygdala↗

PubMed1995

Poststimulation excitability of ventral pallidum self-stimulation neurons.

The degree of neural recovery from refractoriness was inferred in rats self-stimulating with pairs of pulses in the ventral pallidum. The prerecovery intrapair interval varied from 0.5 to 1.0 ms, depending on brain site. At some sites, recovery reached its maximum within less than 1.6 ms whereas, at the majority of sites, a substantial amount of recovery occurred at delays longer than 1.2 ms. The shortest recovery estimates were not fundamentally different from those obtained from sites lying along the medial forebrain bundle. The longest recovery estimates were similar to those obtained from cortical and basal forebrain sites. The differences in recovery noted between sites and the presence of step-like patterns in the recovery curves suggest the presence of neural heterogeneity within the ventral pallidal substrates of reward.

Animals↗

PubMed1994

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens.

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was performed through microdialysis probes into the rat ventral pallidum (10 microliters of 0, 2.6, 4.0, 13.0, and 26.0 mM) or globus pallidus (10 microliters of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Regulation of dopamine D2 receptor mRNA expression in the olfactory tubercle by cocaine.

The influence of acute and chronic cocaine treatment on the expression of dopamine D2 receptor (D2R) mRNA was examined in the rat basal ganglia by in situ hybridization histochemistry. No significant alterations in D2R mRNA levels were observed in the striatum or the nucleus accumbens following acute or chronic cocaine. In the olfactory tubercle, acute cocaine (20 and 40 mg/kg, i.p.) was found to decrease D2R mRNA expression. Chronic cocaine (20 mg/kg, i.p. x 15 days), however, produced an increase in D2R mRNA levels in this region which was detected 24 h, but not 7 days after withdrawal. Acute and chronic cocaine have different effects on the regulation of D2R gene expression in the olfactory tubercle.

Animals↗

PubMed1993

Neuronal release of somatostatin in the rat striatum: an in vivo microdialysis study.

Extracellular levels of somatostatin in the rat striatum were studied using in vivo microdialysis and radioimmunoassay. In vitro studies were performed using three different dialysis membranes at various flow rates and temperatures to assess the optimal recovery of somatostatin. The best results were obtained when a cellulose fibre membrane was utilized at 37 degrees C with a flow rate of 0.5 microliters/min. For the in vivo studies, transcerebral cellulose probes were implanted in the striatum of chloryl hydrate-anaesthetized rats. Basal levels of somatostatin were detected in the striatum of the freely moving animals and found to be 5-15 fmol. Stimulation with 100 mM KCl increased the recovered somatostatin by 138% (P < 0.05). A second stimulation following a 3-h interval increased the somatostatin levels by approximately 60%. The addition of veratridine (100 microM) in the perfusion medium increased the somatostatin levels recovered from the striatum by 85% (P < 0.01). Following a 3-h interval, a second stimulation by veratridine also increased somatostatin levels (43%). The increases observed after the second depolarizing stimulus (KCl and veratridine) were not found to be significantly different from basal levels. Both EGTA and the sodium channel blocker tetrodotoxin attenuated the effect of KCl and veratridine, respectively. However, neither EGTA nor tetrodotoxin had an effect on the basal levels of somatostatin recovered. These results indicate that (i) the somatostatin measured is neuronally released in the striatum and (ii) microdialysis is a useful tool for examining the regulation of somatostatin release in the brain.

Analysis of Variance↗

PubMed1992

Analgesia induced by morphine injected into the pallidum.

Bilateral microinjections of morphine hydrochloride (10; 20; 30 micrograms/0.5 microliter/side) or saline were aimed at three different regions of the rat globus pallidus: dorsal, medial, ventral. Before and at various intervals after intrapallidal morphine (15; 30; 60; 90; 180 min), estimation of pain threshold was made by the hot plate procedure. Dose-dependent morphine analgesia was elicited from all three regions injected. Differences between the pallidal areas as to the intensity and duration of the drug's effect were noticed. Pretreatment with subcutaneous naloxone (1 mg/kg, s.c.) inhibited the morphine (20 micrograms) analgesia elicited from the medial and dorsal pallidum; it decreased and delayed the effect of morphine injected into the ventral pallidum. The results suggest that the three pallidal areas tested are involved to a different degree (medial/dorsal greater than ventral) in the morphine analgesia mediated by opiate receptors.

Animals↗

PubMed1992

Effects of acute and chronic desipramine treatment on somatostatin receptors in brain.

The effects of acute (5 mg/kg, IP twice daily for 2 days) and chronic (5 mg/kg IP twice daily for 21 days) administration of desipramine (DMI) on [125I]-Tyr11-somatostatin binding sites in brain were examined. There was no change in [125I]Tyr11-somatostatin binding in membranes prepared from the frontal cortex, striatum, and hippocampus of rats acutely or chronically treated with DMI as compared to non treated animals. [125I]Tyr11-somatostatin binding was increased in membranes prepared from the rat nucleus accumbens only after chronic DMI administration. Scatchard analysis of the binding data from the nucleus accumbens showed that [125I]Tyr11-somatostatin labels a single population of somatostatin binding sites with an affinity constant, Kd, of 1.8 +/- 0.60 nM and a Bmax of 330 +/- 90 fmol/mg protein. Chronic treatment with DMI increased the Bmax (500 +/- 140 fmol/mg protein) but had no effect on the Kd. This finding shows a regional effect of DMI on [125I]Tyr11-somatostatin binding sites in rat brain and suggests that somatostatin may play a role in the pathophysiology of depression.

Animals↗

PubMed1992

Pallidal substrate of morphine-induced locomotion.

Bilateral microinjections of morphine hydrochloride (5.0; 7.5; 10.0 micrograms/0.5 microliters/side) or saline were infused into 3 different regions (dorsal, medial, ventral) of the rat globus pallidus, to examine their effects on locomotor activity. Locomotor activity of each rat was measured 45 min before and 90 min after saline or morphine pallidal microinjections. Morphine induced a dose-dependent increase in locomotion. This increase in locomotion was also significantly different between the 3 pallidal regions. Pretreatment with naloxone (1 mg/kg, sc) inhibited the morphine (7.5 micrograms) hyperlocomotion elicited from all three pallidal areas. The results suggest that the entire pallidum serves as substrate of morphine hyperlocomotion mediated by opiate receptors.

Animals↗