Lack of effect of sildenafil on cocaine-induced convulsions in mice

doi:10.1016/S1734-1140(09)70151-3

Pharmacological Reports

Volume 61, Issue 5, September–October 2009, Pages 930-934

https://doi.org/10.1016/S1734-1140(09)70151-3 Get rights and content

Abstract

The convulsant action of cocaine and the proconvulsant effects of sildenafil, a drug which is widely used in the treatment of erectile dysfunction, have been documented both in humans and mice. Since it was reported that sildenafil alone, and in conjunction with cocaine, is used recreationally, the present study was performed to examine the influence of sildenafil on cocaine-induced seizures in mice. We showed that administration of sildenafil (5–20 mg/kg, ip) did not affect latency to clonic seizures induced by ip administration of cocaine at a dose of 85 mg/kg, nor did it influence seizure incidence and mortality. We conclude that sildenafil does not significantly increase the risk of seizures when co-administered with cocaine.

Introduction

Cocaine (benzoylmethyl ecgonine) is a psychostimulatory and highly addictive alkaloid obtained from the leaves of Erythroxylon coca.Cocaine administration in humans causes euphoria, decreased fatigue and hunger, and increased energy and motor activity [6, 9]. However, cocaine overdose can exert deleterious effects on the cardiovascular and central nervous systems [8, 19]. Central hyperexcitation usually leads to a single tonicclonic seizure episode both in naive and heavy cocaine users, but multiple seizures and status epilepticus were also noted [6]. Both single administration of a high dose of cocaine and repetitive administration of sub-convulsive doses (pharmacological kindling) elicit convulsions in animals [8, 12, 13, 20, 23].

Sildenafil is predominantly used in the treatment of erectile dysfunction of various etiologies. The pharmacological action of sildenafil is closely associated with the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Sildenafil competitively inhibits phosphodiesterase 5 (PDE5), which catalyzes the breakdown of cGMP to guanosine monophosphate (GMP). The increase in cGMP levels enhances the effect of NO and leads to relaxation of the smooth muscle in the corpus cavernosum, thus improving blood flow into the penis. The ability of sildenafil to cross the blood-brain barrier and the presence of PDE5 in different brain areas implicates that this drug may affect various central nervous system functions [21, 34]. Sildenafil has been shown to improve memory and learning processes, exhibits prodepressant and anxiogenic activity, and has proaggressive potential [10, 15, 18, 21, 24, 27, 36]. Antinociceptive activity of sildenafil in animals has also been reported [4, 5], and the proconvulsant activity of sildenafil has been reported in humans [14]. Furthermore, sildenafil decreased the threshold for clonic seizures induced by intravenous (iv) administration of pentylenetetrazole (PTZ) and bicuculine and abolished the adenosine-induced increase in threshold for myoclonic jerks and tonic extension in the iv PTZ seizure threshold test in mice [2, 29]. It was reported that the NO/cGMP pathway affects both glutamatergic and GABAergic neurotrans mission so that it may influence seizure susceptibility[26].Interviews with customers of night clubs in North West England documented that sildenafil was used as recreational drug by 3% of responders. Most of them combined sildenafil with illegal or illicit drugs and alcohol. Some of them took sildenafil concomitantly with cocaine [3]. Considering the proconvulsant effects of both cocaine and sildenafil, one could suspect that sildenafil might enhance the risk of seizures after the use of cocaine. Therefore, the aim of the present study was to examine the effect of sildenafil on seizure activity induced by acute cocaine administration in mice.

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Materials and Methods

The experiments were carried out on male Albino Swiss mice weighing 25–30 g. The animals were housed in Makrolon cages under the strictly controlled laboratory conditions (ambient temperature of 22–23°C, relative humidity of 45–55%, 12/12 h light /dark cycle, light on at 6:00 a.m., chow pellets and tap water continuously available). After acclimatization, mice were randomly divided into four experimental groups, each of which consisted of 9–10 mice. The experimental protocol was approved by the

Results

Observation of the animals in test cages showed no grossly observable behavioral changes in the groups that received sildenafil. The chimney test did not indicate any neurotoxic effects of sildenafil at the doses tested (not illustrated).

As shown in Figure 1, cocaine administered at a dose of 85 mg/kg produced seizures in mice, both in control animals and in animals which were pretreated with sildenafil (dosage range 5–20 mg/kg). The treatment with sildenafil slightly prolonged the latency to

Discussion

Proconvulsant activity of cocaine and sildenafil has been previously reported both in humans and in mice [2, 14, 23, 29]. Cocaine-induced seizures are caused mainly by the increase in concentration of monoamines (serotonin, dopamine and noradrenaline) in the synaptic cleft, although participation of other neurotrans mitter systems has also been reported [8, 23, 35]. The mechanism of proconvulsant activity of sildenafil has not been precisely delineated, but it seems to be connected with an

Acknowledgments

The authors wish to thank Prof. Dr. Wtadystaw Lasori (Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland) and Polpharma S.A. (Starogard Gdariski, Poland) for a generous gift of cocaine hydrochloride and sildenafil, respectively.