Biomedical subjects

N A Darmani

Publications and source records attributed to N A Darmani.

At least 19 recordsLinked to original sources

PubMed2003

Behaviorally active doses of the CB1 receptor antagonist SR 141716A increase brain serotonin and dopamine levels and turnover.

Large doses (10-40 mg/kg) of the selective cannabinoid CB(1) receptor antagonist, SR 141716A, produce the head-twitch response (HTR) and scratching in rodents and vomiting in the least shrew (Cryptotis parva). Agents that increase brain serotonin (5-HT) levels induce the HTR in rodents, whereas enhancements in either brain 5-HT or dopamine concentrations can lead to production of emesis in vomiting species. The present study was undertaken to demonstrate whether large doses of SR 141716A can (1) induce the HTR and scratching in the least shrew and (2) cause concurrent biochemical changes in brain 5-HT and dopamine concentrations. SR 141716A (0, 1, 5, 10, 20 and 40 mg/kg i.p.) administration induced the HTR, scratching and vomiting. The HTR effect was bell shaped with a maximum frequency occurring at the 20 mg/kg SR 141716A dose, whereas the scratching and vomiting behaviors displayed dose-dependent effects. The selective 5-HT(2A/C) receptor antagonist, SR 46349B (0, 0.1, 0.25, 1, 3 and 6 mg/kg i.p.), differentially attenuated all SR 141716A (20 mg/kg)-induced behaviors because the HTR was relatively more potently and completely blocked. In the shrew forebrain, SR 141716A (20 and 40 mg/kg ip) caused dose- and time-dependent increases in the levels of 5-HT and dopamine and the concentrations of their major metabolites [5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA)] and the turnover of both monoamines. Although the effects of SR 141716A on brainstem concentrations of both monoamines and their metabolites were not always consistent, the CB(1) antagonist did increase the turnover of both 5-HT and dopamine. The present findings suggest that the mechanism and the neurochemical substrate for SR 141716A-induced HTR and scratching behaviors is enhancement of 5-HT release, whereas increased release of 5-HT and dopamine probably contributes to the production of emesis.

Animals↗

PubMed2001

The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2.

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

Animals↗

PubMed2001

Cannabinoids of diverse structure inhibit two DOI-induced 5-HT(2A) receptor-mediated behaviors in mice.

We have recently shown that the selective cannabinoid CB(1) receptor antagonist SR 141716A produces robust frequencies of head-twitch response (HTR) and ear-scratch response (ESR) in drug-naive mice. Both behaviors were potently blocked by the selective 5-HT(2A/C) receptor antagonist SR 46349B. Selective 5-HT(2A/C) agonists such as DOI also produce these behaviors in mice. The purpose of the present study was to: (1) investigate whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its analogs [Delta(8)-tetrahydrocannabinol (Delta(8)-THC), HU-210, CP 55,940, and WIN 55,212-2] can prevent the DOI-induced behaviors and (2) to see whether any correlation exists in the ID(50) potency order of these cannabinoids in inhibiting the DOI-induced HTR and ESR relative to their published ED(50) potency profiles in producing the tetrad of behaviors in mice. Thus, at 0 min, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Delta(9)-THC (0.25-20 mg/kg), Delta(8)-THC (2.5-20 mg/kg), HU-210 (0.02-0.5 mg/kg), CP 55,940 (0.004-0.5 mg/kg), and WIN 55,212-2 (0.5-10 mg/kg). Twenty minutes later, each mouse received an intraperitoneal injection of DOI (1 mg/kg) and the frequencies of DOI-induced behaviors (mean +/- S.E.M.) were recorded for the next 20 min. The tested cannabinoids reduced the frequencies of both DOI-induced HTR and ESR in a dose-dependent fashion. HU-210 was the most potent inhibitor of HTR, whereas CP 55,940 was most effective against ESR. The ID(50) potency order of cannabinoids in blocking the HTR is: HU-210 > CP 55,940 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC, which is identical to their published order of potency in producing the tetrad of behaviors in mice. On the other hand, they had the following ID(50) potency order against the ESR: CP 55,940 > HU-210 > WIN 55,212-2 > Delta(9)-THC > Delta(8)-THC. The tested cannabinoids were 3-30 times more potent in preventing the ESR than the HTR. The data show that cannabinoids inhibit 5-HT(2A) receptor-mediated functions in a potent but differential manner.

Amphetamines↗

PubMed2001

Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.

Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS.

Animals↗

PubMed2001

Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB(1) receptor antagonist/inverse agonist SR 141716A.

There is substantial clinical evidence that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB(1) receptor or the cannabinoid CB(2) receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB(1) receptor antagonist) or SR 144528 (CB(2) receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7-15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6-9 per group) administration of SR 141716A caused emesis (ED(50) = 5.52 +/- 1.23 and 20.2 +/- 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB(2) antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Delta(9)-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Delta(9)-THC which is consistent with an action on the CB(1) receptor. These results suggest that the antiemetic activity of Delta(9)-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB(1) receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Delta(9)-THC. On the other hand, blockade of CB(1) receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.

Analgesics, Non-Narcotic↗

PubMed2001

Anatomic and physiologic reference values in least shrews (Cryptotis parva).

BACKGROUND AND PURPOSE: The least shrew is an established animal model for reproductive and pharmacologic research. Biologic reference data are needed to assess animal health status and provide a rationale for use of novel statistical programs to evaluate the effects of orally administered substances in toxicologic and pharmacologic studies. METHODS: Organ weights, blood biochemical and hematologic values, and food and water consumption data were collected from 50-day-old shrews after two weeks' consumption of a standard feline diet. RESULTS: In general, data correlated well with values reported for other mammalian species. Plasma phosphorus concentration was high. There was a significant difference in food and water consumption per gram of body weight between shrews at lower and upper (+/- 1 SD) weight ranges for the study. The 3.2-g animals consumed 27% more food per gram of body weight than did the 5.0-g animals. CONCLUSIONS: The high phosphorus concentration was attributed to hemolysis resulting from the axillary cut method of blood sample collection. The small size of the shrew allowed demonstration of the Kleiber effect within a +/- 1 SD weight range in a single species. The phenomenon necessitates the use of statistical methods other than the typical tests establishing the significance of the differences between the means of groups for oral toxicologic and pharmacologic studies.

Animals↗

PubMed2000

Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice.

The receptor mechanisms by which the selective cannabinoid CB1 receptor antagonist/inverse agonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyraz ole-carboxamide] produces scratching and head-twitch response (HTR) in naive mice were examined. Acute intraperitoneal administration of varying doses of SR 141716A produced both scratchings (ED50 = 3.9 mg/kg) and head-twitches (ED50 = 4.6 mg/kg) in a dose-dependent manner. A dose of 10 mg/kg SR 141716A was used to induce the cited behaviors for drug interaction studies. The selective 5-HT2A/C receptor antagonist, SR 46349B [trans-4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3-(2-fluorophenyl) propen-1-yl] phenol] potently and completely blocked the head-twitches produced by SR 141716A (ID50 = 0.08 mg/kg). The induced scratching behavior was partially (68%) and less potently (ID50 = 0.6 mg/kg) blocked by SR 46349B pretreatment. The AMPA/kainate receptor antagonist, CNQX [6-cyano-7-nitroquinoxaline-2,3-dione], partially attenuated (68-78%) the induced scratching and head-twitching behaviors. On the contrary, the selective NMDA antagonist, AP-3 [(+/-)-2-amino-3-phosphonopropionic acid], had no significant effect on these behaviors. The selective tachykinin NK1 antagonist, CP 94, 994 [(+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], also partially attenuated both the scratching (64%) and the head-twitching (76%) symptoms produced by SR 141716A. Since SR 141716A lacks affinity for the discussed receptors, it appears that the induction of the cited behaviors probably involve indirect activation of their respective neurotransmitter systems.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1999

The role of D2 and D3 dopamine receptors in the mediation of emesis in Cryptotis parva (the least shrew).

This study introduces Cryptotis parva (the least shrew) as a new dopaminergic animal model of emesis. The potential emetogenic effects of a nonselective dopamine agonist [apomorphine], two D1 agonists [SKF-38393 and SKF-82958], a D2 preferring agonist [quinpirole], and two D3-preferring agonists [7-(OH) DPAT and PD 128, 907] were investigated. Intraperitoneal administration of D1 agonists failed to induce emesis. However, other agonists caused a dose-dependent increase in the percentage of animals vomiting as well as potentiating the mean frequency of emesis with the following ED50, potency order: 7-(OH) DPAT < apomorphine < quinpirole < PD 128, 907. For antagonist studies a 2 mg/kg dose of these agonists were used to induce emesis. Thus, the inhibitory dose-response effects of a D2-preferring [sulpride], a D3-preferring [U 99194A] and combination of varying doses of these antagonists [sulpride + U 99194A] were evaluated on the ability of the cited agonists to produce vomiting. Sulpride decreased the number of shrews vomiting and the mean vomiting frequency produced by the cited agonists in a dose-dependent fashion with the following ID50 order [apomorphine < PD 128, 907 < 7-(OH) DPAT < quinpirole]. By itself, U 99194A failed to significantly alter the emesis produced by any of the cited agonists, however, it potentiated (3-8 times) the antiemetic effects of sulpride both in reducing the number of shrews vomiting as well as decreasing the mean vomiting frequency with the following ID50 order: PD 128, 907 < 7-(OH) DPAT < quinpirole. However, U 99194A attenuated the potent antiemetic effect of sulpride on the apomorphine-induced emesis. The results suggest that the tested agonists primarily activate dopamine D2 receptors to induce emesis in the least shrew whereas activation of D3 sites potentiate the vomiting action of D2 dopamine receptors.

Analysis of Variance↗

PubMed1999

Inhibition of B16 melanoma metastasis by overexpression of the cysteine proteinase inhibitor cystatin C.

Progression to metastasis has been correlated with increased cysteine proteinase activity for a number of tumour types. One mechanism of cysteine proteinase regulation in normal cells is by natural protease inhibitors, the cystatins. Here we further characterize a transfected cell line showing increased cystatin C transcription driven by cytomegalovirus (CMV) promoter/enhancer sequences. Properties of this cystatin C altered cell line such as growth in vitro, lung colonization after tail vein injection in mice, production of cystatin, and cysteine proteinase inhibitor activities were examined. Although there was no difference between the growth rate of the cystatin transfected cell line and that of the control, there was a substantial difference in metastatic ability. No increase was noted in cystatin C secretion into the media for the cystatin C transfected cell line compared with the control transfected cell line. There was, however, a difference in cysteine protease inhibitor activity in the cell-free extracts. These results show that alteration of cystatin C levels by overexpression in B16 melanoma alters properties associated with metastasis.

Animals↗

PubMed1999

Long-term sequential determination of behavioral ontogeny of 5-HT1A and 5-HT2 receptor functions in the rat.

Activation of 5-hydroxytryptamine1A (5-HT1A) receptors in rats produces hypothermia and a number of behaviors [hindleg abduction (HLA), lateral head-weaving (LHW), forepaw treading (FPT), flat body posture (FBP), rollover (RO), tremor (T), and straub tail (ST)] known collectively as the serotonin syndrome (SS). Stimulation of 5-HT2A receptors produces wet-dog shakes (WDS), whereas 5-HT2C sites induce back muscle contraction (BMC). We investigated the functional ontogeny of the cited receptors in rat pups on postnatal days (PD) 7, 14, 18, 22, 28, 35, 60, and 120 by using (1) the 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin (0, 1.25, and 5 mg/kg) to induce the SS and hypothermia and (2) the 5-HT2A/C agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (0, 0.5, and 4 mg/kg) to produce both WDS and BMC. The age of onset for most symptoms of SS [FBP, HLA, RO, and T] was the first week of life. They attained maximal intensities at ages 7 to 14 days, after which their maxima either reduced or dissipated to zero. Per contra, the onset of LHW and FPT required 14 to 18 days, and their maxima developed later. The onset of (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane-induced WDS occurred after PD 14, and by PD 18, it reached its maximal intensity, which persisted up to PD 60, after which it declined. The onset of BMC was evident on PD 28 and attained its maximal frequency at ages 90 to 120 days. The results show that different components of SS appear within 14 days of birth, but they mature differentially, whereas the hypothermic effect of 5-HT1A receptors remains relatively constant during aging. The times of onset and maturation of WDS were intermediate (between the second and third weeks of life), whereas BMC required 1 to 2 months for its appearance and maturation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Production of serotonin syndrome by 8-OH DPAT in Cryptotis parva.

We have previously shown that the 5-HT2A/C agonist, DOI, potently and in a dose-dependent manner produces the head-twitch response in the least shrew (Cryptotis parva) via the activation of serotonergic 5-HT2A receptors. The purpose of the present study was to determine whether activation of 5-HT1A receptors by its selective agonist, 8-OH DPAT, can induce the serotonin syndrome (SS) in this species. In the rat, the symptoms of SS include: forepaw splaying, hindleg abduction, forepaw treading, flat body posture, tremor, and straub tail. Intraperitoneal (i.p.) administration of 8-OH DPAT produced four classic symptoms (forepaw splaying, hindleg abduction, forepaw treading, and straub tail) of SS in the least shrew in a dose-dependent manner in the 30-min observation period. The mean total cumulative score for all components of SS also significantly increased in intensity in a dose-dependent fashion. Administration of selective 5-HT1A antagonists [S(-)UH 301 or NAN-190] potently blocked the 8-OH DPAT-induced mean total SS score in a dose-dependent manner. Moreover, these antagonists had similar potencies as indicated by their identical ID50 values (0.5 and 0.52 mg/kg respectively). However, unexpectedly and unlike the published findings in the rat, the nonselective 5-HT1A antagonist with b-blocking activity, propranolol, failed to attenuate the induced response in this species. As was expected, the selective 5-HT2A/C antagonist, SR 46349B, did not affect the intensity 8-OH DPAT-induced symptoms. Overall, these data suggest that the SS produced by 8-OH DPAT in the least shrew is mediated via the activation of serotonergic 5-HT1A receptors. In addition, propranolol is not a useful 5-HT1A antagonist in this species.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

The silent and selective 5-HT1A antagonist, WAY 100635, produces via an indirect mechanism, a 5-HT2A receptor-mediated behaviour in mice during the day but not at night. Short communication.

The head-twitch response (HTR) in rodents is considered to be a functional index for the activation of 5-HT2A receptors. Intraperitoneal administration of the silent and selective 5-HT1A receptor antagonist, WAY 100635, produced the HTR in mice in a dose-dependent bell-shaped manner. The induced behaviour followed a diurnal pattern in that WAY 100635 only produced a robust HTR frequency during the light period of the 24h daily cycle. Pretreatment with the selective 5-HT2A/C receptor antagonist, SR 46349B, potently, and in a dose-dependent manner attenuated the induced behaviour. It appears that WAY 100635 produces the HTR indirectly via disinhibition of endogenous serotonergic inhibitory tone operating on the somatodenritic pulse-modulating 5-HT1A autoreceptors. The latter antagonism seems to potentiate endogenous 5-HT release in serotonergic terminal field synapses which subsequently stimulates postsynaptic 5-HT2A receptors to produce the head-twitch behaviour.

Animals↗

PubMed1998

Serotonin 5-HT3 receptor antagonists prevent cisplatin-induced emesis in Cryptotis parva: a new experimental model of emesis.

The aim of this manuscript is to introduce Cryptotis parva (the least shrew) as a new experimental emesis model. The chemotherapeutic agent, cisplatin, caused a dose-dependent increase in the number of animals exhibiting vomiting and retching behaviours with ED50 values of 6.43+/-1 and 7.9+/-1.2 mg/kg, respectively. The frequencies of these parameters were also dose-dependent. Intraperitoneal administration of 5-HT3 receptor antagonists (tropisetron or MDL 72222) prevented cisplatin-induced emesis and retching behaviours in the least shrew by a dose-dependent mechanism with respective ID50 values of 4.28+/-2.8 and 2.05+/-2 for emesis, and 2.71+/-4.5 and 2.52+/-2.59 for retching. Intraperitoneal injection of selective and nonselective 5-HT3 receptor agonists potently, and in a dose-dependent fashion, induced emesis in the least shrew with the following ED50 potency order: 2-methyl 5-HT approximately 5-HT (p > 0.05) <5-HTQ (p < 0.01) <mCPBG (p < 0.001). As with other established experimental animal emesis models, the present data indicate that cisplatin causes emesis by activating 5-HT3 receptors indirectly via release of 5-HT.

Analysis of Variance↗

PubMed1998

Cocaine and selective monoamine uptake blockers (sertraline, nisoxetine, and GBR 12935) prevent the d-fenfluramine-induced head-twitch response in mice.

Serotonin release subsequent to 5-HT precursor loading mainly occurs via exocytosis. Acute cocaine or sertraline administration promote the ability of 5-HT precursors (e.g. L-tryptophan) to induce the 5-HT2A receptor-mediated head-twitch response (HTR) in rodents. The 5-HT releaser, d-fenfluramine, at behaviorally active doses, can induce the head-twitch response in rodents by releasing cytoplasmic 5-HT via the serotonin uptake carrier working in reverse. The purpose of the present study was to utilize the d-fenfluramine-induced HTR to determine the serotonergic and nonserotonergic components of cocaine's actions on the d-fenfluramine-sensitive pool of cytoplasmic 5-HT. Because a dramatic differential potentiation in HTR frequency is obtained when cocaine is administered prior relative to after L-tryptophan injection, the effects of varying doses of cocaine and the selective serotonin (sertraline), dopamine (DA) (GBR 12935), and norepinephrine (NE) (nisoxetine) uptake blockers were investigated on the d-fenfluramine-induced behavior in two experimental protocols. Thus, each uptake inhibitor was administered either 10 min following (protocol 1) or 10 min prior to (protocol 2) d-fenfluramine injection. All the tested uptake inhibitors attenuated the d-fenfluramine-induced HTR in a dose-dependent manner in both experimental protocols. However, their order of potency in either protocol 1 (nisoxetine > GBR 12935 > cocaine > sertraline) or protocol 2 (cocaine > GBR 12935 > nisoxetine = sertraline) does not agree with in vitro affinity of these drugs for the 5-HT transporter. In addition, the potency order for cocaine and nisoxetine in protocol 1 was significantly reversed in protocol 2. The inhibitory effects of the cited drugs on the d-fenfluramine-induced HTR are discussed in terms of: 1) high doses of selective monoamine uptake blockers may not exhibit as much selectivity for their target uptake sites as indicated by in vitro tests; and 2) possible pharmacokinetic interactions between d-fenfluramine and the monoamine uptake blockers.

1-Naphthylamine↗

PubMed1997

Prolonged deficits in presynaptic serotonin function following withdrawal from chronic cocaine exposure as revealed by 5-HTP-induced head-twitch response in mice.

Recent in vivo microdialysis studies have indicated that presynaptic deficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch response (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the dose- and time-response effects of this deficit. The HTR is considered to be a sensitive model for activation of central postsynaptic 5-HT2A receptors in rodents. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing, at 24 h following last injection, the treated mice received either 1) no cocaine; 2) their corresponding daily dose as challenge injection; or 3) a 10 mg/kg challenge dose. In a second series of experiments, extended abstinence studies were performed under the conditions of experimental protocols 1 and 2 for both 7- and 13-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 24, 48, 72 and 96 h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied following prolonged withdrawal from chronic cocaine exposure (0, 0.5, 5 and 10 mg/kg, twice daily for 7 and 13 days) at 24, 96 and 240 h abstinence. In experimental protocol 1 at 24 h abstinence in the 7 day exposure group, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenuated the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72 h abstinence. Although in the 13 day cocaine exposure groups (experimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96 h abstinence. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) in their corresponding pretreatment groups significantly reduced the behavior at diverse abstinence intervals in both 7- and 13-day exposure regimens relative to their chronically vehicle-treated controls which had received a vehicle challenge injection during HTR testing. Unlike small doses of cocaine, larger challenge doses (5-10 mg/kg) of the stimulant potentiated the HTR score at various abstinence periods. However, the degree of the potentiations are considerably less than the ability of acute cocaine administration in enhancing the 5-HTP-induced HTR. The 10 mg/kg challenge injection in experimental protocol 3 at 24 h abstinence in the 7-day exposed mice attenuated the 5-HTP-induced HTR in 0.5, 5 and 10 mg/kg cocaine-treated groups relative to their chronic vehicle-treated controls receiving a 10 mg/kg challenge cocaine injection. The deficit in chronic 10 mg/kg cocaine-exposed mice persisted up to 240 h postcocaine abstinence. On the other hand, in the 13-day regimen, the challenge 10 mg/kg dose exhibited significant potentiations at 24 h and at 96 h for 5 and 0.5 mg/kg chronic cocaine doses respectively, but it also produced significant deficits in 0.5 and 10 mg/kg chronic doses of cocaine at 240 h abstinence. Overall, the present results suggest that enduring deficits occur in presynaptic serotonin neurochemistry and serotonergic adaptive mechanisms are exquisitely sensitive to chronic administration of low- and high-doses of cocaine.

5-Hydroxytryptophan↗

PubMed1997

Withdrawal from chronic cocaine administration causes prolonged deficits in L-tryptophan-induced head-twitch response in mice.

Withdrawal from chronic cocaine exposure potentiates the ability of direct 5-HT2A agonists to induce the head-twitch response (HTR) in rodents. This supersensitivity is assumed to be a consequence of cocaine-induced deficits in presynaptic serotonin neurochemistry. The present study utilized the HTR produced by L-tryptophan (TP) to investigate the dose- and time-response effects of cocaine-induced 5-HT deficit. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing procedure, at 24 h after last chronic injection, treated-mice received either: 1) no cocaine; 2) their corresponding daily dose; or 3) a 10 mg/kg dose. In paradigm 1, the frequency of TP-induced HTR was attenuated in a dose-dependent manner in both chronic cocaine regimens. In paradigm 2, small challenge doses (0.1-2.5 mg/kg) of cocaine in their respective pretreatment groups failed to alter HTR, but larger challenge doses (5 and 10 mg/kg) potentiated the behavior. In paradigm 3, the 10 mg/kg challenge dose potentiated the HTR to a similar degree in both chronically exposed vehicle and various cocaine-treated groups in both treatment regimens. Extended withdrawal studies from cocaine exposure (0, 0.5 and 5 mg/kg twice daily for 7 or 13 days) indicated attenuations in HTR persisted up to 96 h postcocaine abstinence in paradigm 1, whereas paradigm 2 revealed significant attenuations between 48-72 h for 0.5 mg/kg dose; and potentiations for the 5 mg/kg dose persisted throughout the 96 h abstinence. In paradigm 3, no significant effect was observed at 96 h abstinence, but the 10 mg/kg challenge dose significantly potentiated HTR in chronically exposed 10 mg/kg cocaine group 10 days following cocaine abstinence in both exposure regimens. Overall, these results support the notion that chronic cocaine exposure produces prolonged deficits in presynaptic serotonin neurochemistry. Furthermore, serotonergic mechanisms appear to be exquisitely sensitive to chronic administration of both low and high doses of cocaine.

Analysis of Variance↗

PubMed1997

Deficits in D-fenfluramine-sensitive pool of brain 5-HT following withdrawal from chronic cocaine exposure.

Recent head-twitch response (HTR) studies in mice have indicated that withdrawal from chronic cocaine exposure produces deficits in CNS conversion of L-tryptophan to 5-HT. In the present study, the ability of 5-HT releaser, d-fenfluramine, was utilized to induce the HTR in mice following abstinence from chronic cocaine exposure. d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for either 7 or 13 days. At 24 h after last cocaine injection, the treated mice received d-fenfluramine (5 mg/kg, i.p.) and the induced HTR (mean+/-SEM) was recorded for the next 30 min. Cocaine attenuated the d-fenfluramine-induced HTR frequency by 30-37% in the 13-day regimen and significant effects were observed from 0.5 mg/kg dose. At 24 h withdrawal in the 7-day cocaine exposure group, the mean HTR frequencies were attenuated, however, they did not achieve statistical significance. Extended abstinence studies (i.e. 24, 48, 72 and 96 h postwithdrawal) from chronic cocaine exposure (0, 0.5 and 5 mg/kg/day for either 7 or 13 days) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h following withdrawal from 0.5 mg/kg cocaine, whereas its 5 mg/kg dose failed to induce a significant effect. In the 13-day exposure group significant reductions in HTR frequency were observed at 24 h abstinence (27%) for the 0.5 mg/kg cocaine dose and at 24 and 48 h for the 5 mg/kg. Overall, these results indicate that abstinence from chronic exposure to cocaine produces enduring deficits in basal 5-HT concentration. Lastly, serotonergic function appears to be uniquely sensitive to chronic administration of low doses of cocaine.

Animals↗

PubMed1997

Clobenzorex: evidence for amphetamine-like behavioral actions.

Clobenzorex, an optically active N-substituted derivative of (+)amphetamine, has been identified on the illicit market. Because so little is known regarding the pharmacology or abuse potential of this agent, it was examined in tests of stimulus generalization in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle to determine if it would produce amphetamine-appropriate responding. Clobenzorex (ED50 = 6.6 mg/kg) substituted for (+)amphetamine (ED50 = 0.3 mg/kg) but was approximately twenty times less potent than the training drug. Clobenzorex was also compared with (+)amphetamine and cocaine for its ability to induce locomotor stimulation and rearing frequency in mice. Clobenzorex was active in both assays but was less potent than either (+)amphetamine or cocaine. It is concluded that, although weaker than (+)amphetamine, clobenzorex constitutes an agent with amphetamine-like central stimulant behavioral properties.

Amphetamine↗