Edmund Przegaliński

The role of nitric oxide in chemically- and electrically-induced seizures in mice

The effect of the nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) on seizures induced by N-methyl-D-aspartate (NMDA), pilocarpine (PIL) and pentylenetetrazol (PTZ), as well as on the electroconvulsive threshold was studied in mice. It was found that L-NAME and 7-NI decreased the dose of NMDA necessary to produce clonic convulsions in 50% of animals (CD50). Such a proconvulsant effect was not observed in mice pretreated with N-nitro-D-arginine methyl ester (D-NAME), an inactive isomer of L-NAME. Neither L-NAME nor 7-NI affected the convulsions induced by PIL (clonic seizures) or PTZ (clonic and tonic seizures), having no effect on their CD50 values. Similarly, neither NOS inhibitor affected the electroshock threshold. These results, together with some literature data, indicate that nitric oxide (NO) may be regarded as an anticonvulsant substance in relation to seizures induced by NMDA and other excitatory amino acids, but not by other agents, in mice.

The role of nitric oxide in the kainate-induced seizures in mice

The effect of L-arginine (L-Arg), D-arginine (D-Arg), N-nitro-L-arginine methyl ester (L-NAME) and N-monomethyl-L-arginine (L-NMMA) on the kainate-induced seizures was studied in mice. It was found that the precursor of nitric oxide (NO) L-Arg (150-600 mg/kg i.p.) increased dose-dependently the dose of kinate necessary to produce clonic convulsions in 50% of the animals (CD50). Such an anticonvulsant effect was not observed in mice pretreated with D-Arg (150-600 mg/kg i.p.), the latter drug not being a substrate for NO formation. The inhibitors of NO synthase L-NAME and L-NMMA, both administered in doses of 30-30 mg/kg i.p., reduced the convulsive threshold by decreasing the CD50 of kainate. Moreover, L-NAME (3 mg/kg) antagonized the anticonvulsant effect of L-Arg (300 mg/kg). These results indicate that NO may play a role of an endogenous anticonvulsant substance in mice.

Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine.

Recent data indicate that cocaine locomotor responses may be influenced by dopamine (DA) neurotransmission and adenosine neuromodulation involving the A2A receptor (A2AR). Male Wistar rats were injected with MSX-3 (1-25 mg/kg; an antagonist of A2AR), CGS 21680 (0.05-0.2 mg/kg; an agonist of A2AR), SCH 23390 (0.125-0.25 mg/kg; an antagonist of DA D1/5R), raclopride (0.1-0.8 mg/kg; an antagonist of DA D2/3R), nafadotride (0.2-0.4 mg/kg; an antagonist of DA D3R) or 7-OH-PIPAT (0.01-1 mg/kg; an agonist of DA D3R) to verify the hypothesis that adenosine A2AR and DA receptors and their antagonistic interactions may control locomotor and sensitizing effects of cocaine. In well-habituated animals, MSX-3 (5 mg/kg) increased, while raclopride (0.4-0.8 mg/kg) decreased basal locomotor activation; the other drugs were inactive. The locomotor hyperactivation induced by acute cocaine (10 mg/kg) was enhanced by MSX-3 (5-25 mg/kg) or nafadotride (0.4 mg/kg), while CGS 21680 (0.2 mg/kg), SCH 23390 (0.25 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (0.1 mg/kg) decreased this effect of cocaine. Given during the development of sensitization (in combination with 5-daily cocaine, 10 mg/kg, injections), MSX-3 (5-25 mg/kg) increased, but CGS 21680 (0.2 mg/kg) and raclopride (0.8 mg/kg) reduced the locomotor response to a cocaine challenge dose (10 mg/kg) on day 10. When injected acutely with a cocaine challenge dose (on day 10), CGS 21680 (0.2 mg/kg), raclopride (0.2-0.8 mg/kg) or 7-OH-PIPAT (1 mg/kg) reduced, while MSX-3 (5 mg/kg) or nafadotride (0.4 mg/kg) enhanced the expression of cocaine sensitization. The present results show that adenosine A2ARs and DA D3Rs exert inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, while DA D2Rs had an opposing role in such effects. Pharmacological stimulation of adenosine A2ARs protected against both the development and expression of cocaine sensitization, which may offer a therapeutic potential of A2AR agonists in the treatment of cocaine dependence. The results suggest an antagonistic role of A2ARs in D2R-mediated cocaine actions based at least in part on the existence of A2A/D2 heteromeric receptor complexes.

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism

The pathophysiology of psychiatric diseases, including depression, anxiety, schizophrenia and autism, is far from being fully elucidated. In recent years, a potential role of the oxidative stress has been highlighted in the pathogenesis of neuropsychiatric disorders. A body of clinical and preclinical evidence indicates that psychiatric diseases are characterized by higher levels of oxidative biomarkers and with lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review current knowledge on the role of the oxidative stress in psychiatric diseases, based on clinical trials and animal studies, in addition, we analyze the effects of drug-induced modulation of oxidative balance and explore pharmacotherapeutic strategies for oxidative stress reduction.

Behavioral evidence for the significance of serotoninergic (5-HT) receptors in cocaine addiction.

Cocaine addiction has somatic, psychological, psychiatric, socio‐economic and legal implications in the developed world. Presently, there is no medication approved for the treatment of cocaine addiction. In recent years, data from the literature (pre‐clinical studies and clinical trials) have provided several lines of evidence that serotonin (5‐HT) and 5‐HT receptors play a modulatory role in the mechanisms of action of cocaine. Here we review the contribution of 5‐HT receptor subtypes to cocaine sensitization, discrimination, conditioned place preference, self‐administration, reinstatement of seeking behavior and withdrawal symptoms in laboratory animals. Additionally, the consequences of chronic cocaine exposure on particular 5‐HT receptor‐assigned functions in pre‐clinical studies are presented.

The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats

There is evidence that indicates that tonic activation of cannabinoid CB1 receptors plays a role in extinction/reinstatement of cocaine seeking-behavior but is not involved in the maintenance of cocaine self-administration. To further explore the importance of other endocannabinoid-related receptors in an animal model of cocaine addiction, the present paper examines cannabinoid CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and the transient receptor potential vanilloid type-1 (TRPV1) receptor antagonist N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) on intravenous (i.v.) cocaine self-administration and extinction/reinstatement of cocaine-seeking behavior in rats. For comparison and reference purposes, the effect of the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was also examined. Moreover, for comparison effects of those drugs on operant lever responding for artificial (cocaine) vs. natural (food) reward, food self-administration was also evaluated. Our findings show that AM251 (1-3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.3-1mg/kg) did not affect cocaine self-administration. However, AM251 (0.1-1mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) decreased cocaine-induced reinstatement of cocaine-seeking behavior, and AM251 (0.3-1mg/kg) decreased cue-induced reinstatement. Moreover, AM251 (3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) slightly decreased food self-administration behavior, but only AM251 (3mg/kg) reduced food reward. In conclusion, our results indicate for the first time, that tonic activation of CB2 or TRPV1 receptors is involved in cocaine-induced reinstatement of cocaine-seeking behavior, but their activity is not necessary for the rewarding effect of this psychostimulant. In contrast to CB1 receptors, neither CB2 nor TRPV1 receptors play a role in cue-induced reinstatement of cocaine-seeking behavior.

The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression

Abstract Antidepressant properties of 5-HT 1A receptor ligands (the full agonist 8-OH-DPAT, the partial agonists ipsapirone and buspirone, and the selective antagonist WAY 100135) were studied in a chronic mild stress model of depression. In this model, rats subjected to a variety of mild Stressors for a prolonged period of time show a substantial decrease in the consumption of a 1 % sucrose solution (anhedonia), an effect being sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in the sucrose intake was gradually reversed by chronic (3–5 weeks) administration of buspirone (2.5 and 5 mg/kg, i.p., b.i.d.) or WAY 100135 (10 mg/kg, s.c., b.i.d.), but not 8-OH-DPAT (0.5 mg/kg, s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effect of buspirone and WAY 100135 was comparable to that observed following similar administration of the antidepressant drugs imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). Increases in the sucrose intake following chronic treatment with buspirone, WAY 100135, imipramine and citalopram were specific to the stressed animals; the behaviour of control non-stressed animals was unchanged by any drug. These results suggest that buspirone and WAY 100135 may have antidepressant properties. Possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HT 1A receptors and/or the dopamine system are discussed.

The behavioural, but not the hypothermic or corticosterone, response to 8-hydroxy-2-(di-n-propylamino)-tetralin, is antagonized by nan-190 in the rat

The 5-HT1A receptor antagonistic properties of 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl] piperazine (NAN-190) were studied in rats: its effect on the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced behavioural syndrome (flat body posture and reciprocal forepaw treading), hypothermia and secretion of corticosterone, i.e. responses mediated by 5-HT1A receptors, were examined. The drug NAN-190 (1-8 mg/kg) antagonized dose-dependently behavioural effects of 8-OH-DPAT (in both non-reserpinized and reserpine-pretreated animals); however, when administered in doses of 0.5-4 mg/kg, it did not affect the hypothermic or the hormonal response to 8-OH-DPAT. However, NAN-190 (1-8 mg/kg) given alone, produced hypothermia and increased the concentration of corticosterone in serum. The latter effects of NAN-190 were not reduced by (-)pindolol or spiperone. Moreover, the NAN-190-induced secretion of corticosterone was not affected by ketanserin, prazosin or yohimbine. The above results indicate that NAN-190 acts as a 5-HT1A receptor antagonist, only in the model of the 8-OH-DPAT-induced behavioural syndrome. The lack of effect of NAN-190 on the hypothermic or corticosterone response to 8-OH-DPAT most probably results from its own action which mimics the effects of 8-OH-DPAT. The mechanisms responsible for the NAN-190-induced hypothermia and secretion of corticosterone are still unknown, though stimulation of 5-HT1A receptors (either effect), 5-HT2 receptors and alpha 1- and alpha 2-adrenoceptors (corticosterone response) seems to be excluded.

Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats

The antidepressant-like activity of gepirone, a drug with a high and selective affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the forced swimming test in rats. The drug, administered intraperitoneally in single doses of 2.5-20 mg/kg, potently and dose-dependently shortened the immobility time. The anti-immobility effect of gepirone (10 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist, NAN-190 (0.25 and 0.5 mg/kg), the beta-adrenoceptor blocker with the affinity for 5-HT1A and 5-HT1B receptors, pindolol (2 and 4 mg/kg), the 5-HT1A, 5-HT2 and dopamine receptor blocker spiperone (0.01 and 0.03 mg/kg) and by the dopamine receptor antagonist, haloperidol (0.125 and 0.25 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the selective 5-HT2 receptor antagonist, ketanserin (1 and 2 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25 and 0.5 mg/kg) and the beta-blockers with no affinity for 5-HT receptors, betaxolol (4 and 8 mg/kg) and ICI 118,551 (4 and 8 mg/kg), did not affect the anti-immobility effect of gepirone. The effect of gepirone was not modified, either, in animals with a lesion of the 5-HT system, produced by p-chloroamphetamine (PCA, 2 x 10 mg/kg) or p-chlorophenylalanine (PCPA, 3 x 300 mg/kg). The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action.

GABAB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators

γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted.