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J De Vry

Publications and source records attributed to J De Vry.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of nimodipine on extracellular dopamine levels in the rat nucleus accumbens in ethanol withdrawal.

Withdrawal from chronic ethanol intoxication is associated with a reduction of dopamine neurotransmission. However, the mechanisms of dopamine depletion, a putative neurochemical correlate of the dysphoric symptomatology, are not yet understood. To assess the role of L-type calcium channels in the inhibition of the dopaminergic system in the withdrawal state, the effects of the dihydropyridine calcium channel antagonist nimodipine on the extracellular levels of dopamine were studied in the nucleus accumbens shell of awake rats 10 h after withdrawal from chronic ethanol intoxication. In control, chronic sucrose-withdrawn rats, nimodipine did not change extracellular dopamine levels. However, in ethanol-withdrawn rats nimodipine (5 or 10 mg/kg s.c.) increased extracellular dopamine to 136 +/- 16 and 305 +/- 19% of pre-administration values, respectively, the latter dose elevating levels above those of controls. The elevations of extracellular DA by nimodipine (10 mg/kg) were associated with a significant reduction (-17%) of the overall behavioural score of the withdrawal symptomatology, as evaluated for 11 behavioural items. Significant reductions of the score for convulsions (-47%) and, to a lesser extent, for catatonia (-30%) and tremors (-15%) contributed to the overall effect. It is suggested that overactivity of L-type calcium channels is involved in the mechanisms of dopamine depletion as well as in certain behavioural/neurological signs associated with ethanol withdrawal. By restoring depleted dopamine levels, dihydropyridines might ameliorate the dysphoric symptoms of ethanol abstinence.

Alcoholism↗
PubMed1999

5-HT2A and 5-HT2C/5-HT1B receptors are differentially involved in alcohol preference and consummatory behavior in cAA rats.

The present study aimed to investigate the role of serotonin 5-HT2A and 5-HT2C receptors in the control of alcohol preference and consummatory behavior in alcohol-preferring cAA rats. Effects of the 5-HT(2A/2C) receptor agonist, DOI, the 5-HT(2C/1B) receptor agonist, mCPP, the 5-HT(2A/2C) receptor antagonist, ritanserin, and the 5-HT2A receptor antagonist, MDL 100,907, on ethanol (EtOH, 10% v/v) preference and intake, as well as total fluid and food intake were evaluated in a 12-h limited-access two-bottle paradigm. DOI (0.3-3 mg/kg, i.p.) reduced EtOH intake and preference, but not total fluid or food intake; whereas mCPP (1-10 mg/kg, s.c.) reduced EtOH, total fluid, and food intake. Therefore, it is concluded that DOI induces a specific and selective antialcohol effect, whereas mCPP rather induces a general suppressive effect on consummatory behavior. Ritanserin (1-10 mg/kg, i.p.) did not affect EtOH intake and preference, nor total fluid and food consumption. MDL 100,907 (0.1-1 mg/kg, i.p.) induced only a small reduction of food intake at the highest dose tested. Pretreatment with ritanserin (3 mg/kg, i.p.) and MDL 100,907 (0.3 mg/kg, i.p.) blocked the effects of DOI (3 mg/kg, i.p.), but not those of mCPP (10 mg/kg, i.p.). It is suggested that activation of 5-HT2C and/or 5-HT1B receptors results in a general decrease of consummatory behavior, whereas activation of 5-HT2A receptors selectively decreases EtOH intake and preference, as assessed in the cAA rat model of alcoholism.

Alcohol Drinking↗
PubMed1999

Discriminative and affective stimulus effects of dihydropyridine calcium channel modulators: relationship to antialcohol effects.

Voltage-operated calcium channels (VOCCs) have been implicated in alcoholism. Thus, dihydropyridine (DHP) VOCC antagonists, such as nimodipine, reduce ethanol (EtOH) intake and preference in a variety of animal models of alcoholism. Paradoxically, the DHP VOCC agonist BAY k 8644 also demonstrates antialcohol effects in such models. The antialcohol effects of BAY k 8644 are stereoselective [the "agonistic" (-)-enantiomer being more potent than the "antagonistic" (+)-enantiomer], and are not blocked by pretreatment with nimodipine. The present review summarizes studies on the effects of DHPs in drug discrimination (DD), conditioned taste aversion (CTA), and conditioned place preference (CPP) paradigms, and discusses the possibility that the apparent antialcohol effect of these compounds is related to their discriminative and/or affective stimulus effects. In rats trained to discriminate nimodipine from vehicle, (-)-BAY k 8644 completely generalizes to the nimodipine cue; whereas, in rats trained to discriminate (-)-BAY k 8644, nimodipine completely generalizes to, and is unable to block, the (-)-BAY k 8644 cue. The same stereoselectivity is obtained for BAY k 8644 in DD paradigms and models of alcoholism. The apparent similarity of these profiles of activity suggests that a common neurobiological mechanism underlies the discriminative stimulus and antialcohol effects of DHPs. It appears unlikely, however, that the antialcohol effects of DHPs are based on substitution for, or blockade of, the EtOH cue, as these compounds were not found to generalize to, or block, the EtOH cue. Comparison of the effects of DHPs in CTA and CPP paradigms suggests that the affective stimulus effects of these compounds are dissimilar, and that the mechanism underlying the latter effects is probably not related to the mechanism underlying the antialcohol effects of DHP VOCC modulators.

Affect↗
PubMed1999

Comparison of the effects of the selective serotonin-reuptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats.

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

Alcohol Drinking↗
PubMed1999

Effects of calcium channel blockade on intravenous self-administration of ethanol in rats.

In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5-4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5-20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5-5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose-response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.

Animals↗
PubMed1999

Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism.

Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John's wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. In addition, hypericum extracts, as well as standard antidepressants such as the tricyclic, impramine, and the selective serotonin reuptake inhibitor, fluoxetine, have been reported to be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients. It was the aim of the present study to compare the effects of hypericum extracts with those of imipramine and fluoxetine in the rat forced swimming test (RFST), a model of depression, as well as in cAA rats, a genetic model of alcoholism. In the RFST, triple i.p. administration of imipramine (3-30 mg/kg) and fluoxetine (3-30 mg/kg) induced a dose-dependent reduction in immobility: the minimal effective dose (MED) being 30 and 10 mg/kg, and the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. In this test, the hypericum extracts Ze 117 (Remotiv) and LI 160 (Jarsin) also induced a statistically significant reduction of immobility when administered under the same application schedule (5-40 mg/kg, i.p., triple application). In the case of the hypericum extracts the dose-response relationship was inverted U-shaped with a MED value of 20 mg/kg and a maximal effect of 41% and 32% immobility reduction, for Ze 117 and LI 160, respectively. Interestingly, the anti-immobility effects tended to be more pronounced after subacute (1 week, B.I.D.) treatment with 10 mg/kg of imipramine, fluoxetine, or Ze 117, as compared with acute treatment. This phenomenon is in accordance with clinical experience and suggests that repeated treatment is required for full development of antidepressive effects. In the alcohol-preferring cAA rats, acute i.p. administration of imipramine (3-30 mg/kg), fluoxetine (1-10 mg/kg) and Ze 117 (10-40 mg/kg) dose-dependently reduced alcohol intake in a 12-h limited access two-bottle [ethanol 10% (v/v) versus water] choice procedure: with MED values of 30, 5 and 20 mg/kg, respectively. The anti-alcohol effects of fluoxetine and Ze 1-17 appeared to be specific, as reductions in alcohol intake coincided with reductions in alcohol preference. The present study suggests that hypericum extracts have antidepressant-like properties which resemble those of clinically established antidepressants, and that Remotiv may be an interesting adjunct for the treatment of alcoholism.

Alcoholism↗
PubMed1999

Effects of the 5-HT1A receptor agonist ipsapirone on operant self-administration of ethanol in the rat.

Although the serotonin (5-HT)1A receptor agonist ipsapirone reduces ethanol intake in a variety of animal models of alcoholism, such effects have only been reported in models based on nonoperant behavior (e.g., two-bottle choice procedures). It was the aim of the present study to characterize the effects of ipsapirone in an operant model of alcohol self-administration. Rats were trained during daily 30-min sessions to respond for oral delivery of an ethanol solution (10% w/v) or water in a two-lever, fixed-ratio:1, saccharin-fading procedure. After establishment of stable responding, ipsapirone (0, 2.5-20 mg/kg, intraperitoneal) was tested in combination with different ethanol unit doses (0, 1.25-20%). Ethanol-reinforced responding was related to the ethanol unit dose in an inverted U-shaped manner. Ipsapirone dose-dependently decreased the number of ethanol- and water-reinforced lever responses, irrespective of the ethanol unit dose, and failed to affect ethanol preference. As there was only a minor difference between the minimal effective dose which reduced operant responding for ethanol and water (i.e., 10 and 20 mg/kg, respectively), and there was no evidence for a drug-induced left- or rightward shift of the ethanol unit dose-response curve, the effects of ipsapirone are considered to be nonselective. It is suggested that the ethanol intake-reducing effects of ipsapirone are not the result of a drug-induced interference (either of an attenuating, or potentiating, nature) with the positive reinforcing stimulus properties of alcohol.

Alcoholism↗
PubMed1998

Long-term alcohol self-administration and alcohol withdrawal differentially modulate microtubule-associated protein 2 (MAP2) gene expression in the rat brain.

Chronic alcohol intoxication is known to produce neuronal degeneration in the central and peripheral nervous system of experimental animals and of humans. It is suggested that various components of the cytoskeleton undergo profound changes following chronic alcohol use and misuse. Here we studied the expression of the neuronal cytoskeletal microtubule-associated protein 2 (MAP2) following long-term alcohol consumption and subsequent alcohol withdrawal. Alcohol-preferring AA (Alko Alkohol) rats with a high voluntary alcohol consumption for a period of 16 months were compared with age-matched control rats without prior experience with alcohol. For comparison, in a second experiment, heterogeneous Wistar rats that also had voluntary access to alcohol for 8 months were examined following alcohol consumption and withdrawal. In situ hybridization and subsequent dot blot and Northern blot analysis for further quantification revealed that chronically alcoholized animals exhibit markedly decreased MAP2 mRNA levels in several parts of the extrapyramidal system (mainly in the caudate putamen, the substantia nigra pars compacta and the globus pallidus), the mesolimbic system, in several hypothalamic nuclei and in the nucleus inferior colliculus. Other areas such as the hippocampus, frontoparietal cortex and cerebellum were less affected by chronic alcohol intake, however, in these regions the MAP2 mRNA levels were increased during alcohol withdrawal. These results suggest that long-term alcohol self-administration affects central neurons involved in motor control via the influence on the integrity of the cytoskeleton and may thus induce motor dysfunction.

Alcohol Withdrawal Delirium↗
PubMed1998

Discriminative stimulus properties of the 5-HT1A receptor agonist BAY x 3702 in the rat.

The aminomethylchroman derivative BAY x 3702 (R-(-)-2-¿4-[(chroman-2-ylmethyl)-amino]-butyl¿-1,1-dioxo-benzo[d] isothiazolone HCl) has recently been characterized as a relatively selective, high affinity 5-HT1A receptor agonist with neuroprotective, anxiolytic- and antidepressant-like effects in animal models. It was the aim of the present study to further confirm its receptor binding profile in an in vivo assay. Rats were trained to discriminate BAY x 3702 (0.1 mg/kg, i.p.) from vehicle in a standard two-lever fixed ratio 10 food-reinforced procedure. All rats learned the discrimination, the median number of sessions to reach criterion being 38 (range: 22-58 sessions). Generalization tests with BAY x 3702 showed dose-dependent and complete generalization after different routes of administration; the ED50 values being: 0.030, 0.007 and 0.36 mg/kg, after i.p., i.v. and p.o. administration, respectively. Assessment of the duration of action after administration of 0.1 mg/kg BAY x 3702, i.p., resulted in a T1/2 of 65 min. Dose-dependent and complete generalization was also obtained with the 5-HT1A receptor agonists 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin, ED50 in mg/kg, i.p.: 0.086), flesinoxan (0.30), SR 57746A ((4-(3-trifluoromethylphenyl)-N-(2-(naphth-2-yl)ethyl)-1,2,3,6-tet rahydropyridine HCl, 1.0), the (+)-enantiomer of BAY x 3702 (1.3) and ipsapirone (1.8); the ED50 values being closely correlated with their respective affinities for the 5-HT1A receptor. Pretreatment with the selective 5-HT1A receptor antagonist WAY-100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N(2-pyridinyl) cyclohexane carboxamide trihydrochloride) dose-dependently and completely blocked the discriminative effects of 0.1 mg/kg BAY x 3702 (ID50: 0.013 mg/kg, i.p.). WAY-100635, prazosin, idazoxan, raclopride, paroxetine, (-)-BAY k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-p yridine-5-carboxylate), ethanol, and the putative neuroprotectants MK-801 ((+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e), CNS 1102 (N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methyl-guanidine), CGS 19755 (cis-4-(phosphonomethyl) piperidine-2-carboxylic acid) and nimodipine did not induce more than 20% generalization. It is concluded that the BAY x 3702 cue is mediated by its agonistic activity at 5-HT1A receptors.

Administration, Oral↗
PubMed1998

The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test.

We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (> 30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.

Animals↗
PubMed1998

Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat.

Although accumulating evidence suggests that serotonergic drugs are able to substitute for the ethanol (EtOH) cue in rats, it is still unclear which 5-HT receptor subtypes are responsible for this phenomenon, and whether these receptors are critically involved in the EtOH cue. In the present study, rats were trained to discriminate EtOH (1000 mg/kg, i.p., t-15 min) from saline in a two-lever food-reinforced procedure, and it was investigated to which extent serotonergic compounds with a certain level of specificity for either 5-HT1B, 5-HT2A or 5-HT2C receptors generalized to the EtOH cue. Subsequently, the involvement of these receptor subtypes was ascertained by the use of selected 5-HT receptor antagonists. The 5-HT1B receptor agonist CP 94,253 (0.3-5 mg/kg, i.p.) and the mixed 5-HT(2C/1B) receptor agonist mCPP (0.1-1 mg/kg, i.p.), but not the preferential 5-HT2A receptor agonist DOI (0.3-1 mg/kg, i.p.), completely generalized to the EtOH cue. Complete generalization of the former two compounds coincided with a decrease in response rate. In antagonism studies, it was shown that the 5-HT1B receptor antagonist GR 127935 (10 mg/kg, i.p.) completely blocked generalization of CP 94,253 to the EtOH cue, suggesting that stimulation of 5-HT1B receptors produces discriminative stimulus effects which are similar to those of EtOH. GR 127935 (10 mg/kg, i.p.), as well as the mixed 5-HT(1B/2C) receptor antagonist metergoline (1 mg/kg, i.p.), and the 5-HT2C receptor antagonist SB 206,553 (1 mg/kg, i.p.) completely blocked generalization of mCPP to the EtOH cue. This suggests that 5-HT1B and 5-HT2C receptors are required for the generalization of mCPP to the EtOH cue. The present findings indicate that activation of 5-HT1B and 5-HT2C, but not of 5-HT2A receptors, mimics the EtOH cue. However, the finding that neither metergoline, nor the 5-HT2A receptor antagonist MDL 100,907 blocked the EtOH cue, suggests that these receptors play only a minor role in the discriminative stimulus effects of a moderately low dose of EtOH.

Alcohol Drinking↗
PubMed1998

Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist.

The aminomethylchroman derivative BAY x 3702 (R-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d] isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT)1A receptor ligand [calf hippocampus: Ki: 0.19 nM; reference compounds 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT1A receptors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relatively high to moderate affinity to the following receptors: alpha-1 and alpha-2 adrenergic (Ki: 6 and 7 nM, respectively); 5-HT7- and 5-HT1D (7 and 36 nM); dopamine D2- and D4 (48 and 91 nM); sigma sites (176 nM) and 5-HT2C (310 nM); others: > 10 microM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonist (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide trihydrochloride (WAY-100635). At those receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D receptors) or an antagonist (alpha-1, alpha-2 and D2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY x 3702 (0.5 microgram/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY x 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY x 3702 (ED50: 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY x 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED50: 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with high potency and intrinsic activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Effect of repeated ipsapirone treatment on hippocampal excitatory synaptic transmission in the freely behaving rat: role of 5-HT1A receptors and relationship to anxiolytic effect.

The effects of acute and repeated treatment with the 5-HT1A receptor ligand ipsapirone on hippocampal excitatory synaptic transmission and in an ultrasonic vocalization anxiety test were investigated in the rat. Synaptic responses in the CA1 region of the dorsal hippocampus of alert, freely behaving male Wistar rats were reduced after acute injection of ipsapirone (1 or 2 mg/kg, i.p.). This effect was prevented by pretreatment with the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride, 0.25 or 0.5 mg/kg, i.p.) but not by the 5-HT-depleting agent para-chlorophenylalanine (300 mg/kg per day for 3 days, i.p.). WAY-100635 (0.1-0.3 mg/kg, i.p.) also blocked the acute anti-aversive effects of ipsapirone (3 mg/kg, i.p.) in the anxiety test. Repeated administration of ipsapirone (1 or 2 mg/kg per day for 7-8 days, i.p.) produced a gradual reduction in baseline synaptic transmission which was transiently reversed by WAY-100635 (0.25 mg/kg, i.p.). Ipsapirone (1 mg/kg per day for 7 days) produced a gradual and sustained reduction in the duration of vocalizations in the anxiety test which paralleled the reduction in baseline synaptic responses in the same animals. The data indicate that with repeated administration of ipsapirone, a prolongation and enhancement of the 5-HT1A receptor-mediated reduction in hippocampal excitatory synaptic transmission occurs. This delayed effect may contribute to the sustained anxiolytic and/or antidepressant effect of ipsapirone.

Animals↗
PubMed1997

Substitution of the selective serotonin reuptake inhibitors fluoxetine and paroxetine for the discriminative stimulus effects of ethanol in rats.

Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs.

Animals↗
PubMed1997

The management of coexisting depression in patients with dementia: potential of calcium channel antagonists.

Depression frequently coexists with dementia, although in many cases the depression is not recognized clinically. Depression represents a major additional burden in dementia, not only for the patients but also for families, caregivers, and, economically, society as a whole. However, depression in patients with dementia does respond to treatment, and appropriate therapy can significantly improve the well-being of these patients. Depression in patients with dementia is currently treated with a variety of standard antidepressive agents (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), but none is free from significant side effects. Moreover, the use of these drugs is often complicated by a number of age-related factors or effects on the cholinergic neurotransmitter system. Consequently, an antidementia treatment with concomitant antidepressive properties and an acceptable benefit/risk ratio would represent an attractive therapeutic option. The pathogenesis of depression in patients with dementia is not well understood, but may be related to increased intracellular calcium ions in the CNS, the so-called "calcium hypothesis." This hypothesis may explain why some calcium antagonists exert psychotropic effects, including putative antidepressant activity. Animal models and clinical data provide support for the use of calcium channel antagonists for the treatment of depression, with the potential for good tolerability. The latter aspect is especially important for elderly patients with dementia. Although antidepressive effects have been seen with a number of calcium channel antagonists, the dihydropyridine derivative nimodipine shows particular potential for clinical use, perhaps because nimodipine is one of the most lipophilic of these drugs and therefore achieves high concentrations in the CNS, and because of the unique biochemical properties of the dihydropyridine compounds compared with other L type calcium channel blockers. Nimodipine also increases somatostatin levels in CSF, one of the cardinal biochemical deficits in Alzheimer's disease. Data obtained incidentally from the use of nimodipine in the treatment of elderly demented patients clearly demonstrate significant antidepressant activity by the drug in this patient group. Formal clinical evaluation is therefore recommended to establish more clearly the therapeutic benefits offered by nimodipine in patients who suffer from both dementia and depression.

Aged↗
PubMed1996

Comparison of the stimulus properties of ethanol and the Ca2+ channel antagonist nimodipine in rats.

A variety of L-type Ca2+ channel antagonists, including the dihydropyridine derivative nimodipine, have been shown to be effective in reducing ethanol intake and preference in animal models of alcoholism. The behavioral mechanism involved in the anti-alcohol effects of nimodipine are, however, not clear yet. The aim of the present study was to investigate the possibility that the effects of nimodipine on ethanol intake are based on stimulus substitution. Therefore, rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (dose range of ethanol tested: 125-1000 mg/kg i.p., ED50 value: 488 mg/kg). In cross-generalization tests with nimodipine (0.15-15 mg/kg i.p.), stimulus substitution was not noted. In addition, a cross-familiarization conditioned taste aversion paradigm was utilized. In rats, 1000 mg/kg i.p. ethanol was used as the reference drug producing a conditioned taste aversion. Effects of preexposure to ethanol (500-1500 mg/kg i.p.) and nimodipine (7.5-30 mg/kg i.p.) on the magnitude of the ethanol-induced conditioned taste aversion were investigated as an index for stimulus similarity between preexposure and reference drug. Preexposure to both ethanol and nimodipine prevented the development of a conditioned taste aversion. Contrary to the drug discrimination results, these latter findings suggest that there may be similarities between the stimulus properties of nimodipine and ethanol. Moreover, the apparent discrepancy between the results obtained in drug discrimination and cross-familiarization conditioned taste aversion suggests that different stimulus properties of ethanol control behavior in both procedures. The finding that, under particular conditions, ethanol and nimodipine appear to share common stimulus properties needs to be further evaluated, as this may be related to the reported anti-alcohol effects of nimodipine and other Ca2+ channel antagonists.

Analysis of Variance↗
PubMed1996

Somatodendritic 5-HT1A receptors are critically involved in the anxiolytic effects of 8-OH-DPAT.

In the rat shock-induced ultrasonic vocalization test, the anxiolytic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) obtained after systemic (IP) and intracerebral injection into the dorsal raphe nucleus (DRN) were selectively abolished by pretreatment with the 5-HT1A receptor antagonist WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexane-carboxamide trihydrochloride]. This blockade was demonstrated both after systemic and DRN application of WAY-100635. Therefore, it is concluded that the anxiolytic effects of 8-OH-DPAT are mediated by activation of somatodendritic 5-HT1A receptors.

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