Effect of synthetic cathinones: Mephedrone, butylone and 3,4 methylene-dioxypyrovalerone (MDPV) on social separation induced distress vocalization, vigilance and postural control of young domestic chicks

Highlights

• Mephedrone and MDPV enhanced distress calls of socially isolated domestic chicks.

• Butylone caused postural disorder and hyperventilation in chicks.

• MDPV increased wakeful activity and pecking in chicks.

• Closely related cathinones exert different behavioral effects.

Abstract

Designer drugs have become a distinct social problem and health hazard in Europe and US, and their abuse has increased dramatically in the last decade. Selective effects of these agents on animal behavioral parameters may help in better understanding of the potential risks of human drug abuse. In the present study, the effects of three different abusive agents of the cathinone family, mephedrone, butylone and 3,4 methylene-dioxypyrovalerone (MDPV) were tested in young domestic chicks, following administration of single intraperitoneal injections (10 mg/bwt). Early maturing (precocial) birds are particularly suited for investigation of isolation stress-related behavioral response and stereotypic or targeted pecking. Both mephedrone and MDPV increased the frequency of distress calls of socially isolated birds as measured over a period of 10 min. While this effect of mephedrone was only evident in the first half of observation period, an increase with MDPV was more lasting. Though increased non-distress vocalization, butylone failed to enhance distress calls probably due to a general adverse effect on muscle tone. Apart from its effect on distress vocalization, mephedrone did not alter the behavior of chicks. However, both butylone and MDPV showed prominent behavioral changes, which were examined in another set of long term experiments, over a period of 120 min. Butylone caused hyperventilation and a robust impairment of postural control, whereas neither the wakeful activity level, nor the pecking frequency was significantly affected. Conversely, no hyperventilation or postural disorder was observed with MDPV, however, both waking state and pecking were significantly enhanced. The results may be relevant to potentially different and specific effects of cathinone drugs under stress-related conditions, as well as on other physiological and behavioral parameters, even in case of closely related compounds.

Introduction

The term “designer drug” refers to a group of synthetic substances that are pharmacologically and structurally very similar to an illegal substance. These compounds are also known as ‘legal highs’ and they are available on Internet websites,’ head shops’ and local drug suppliers as ‘plant food’ or ‘bath salts’. Many of these agents belong to the family of synthetic cathinones, derivates of the naturally occurring beta-ketone amphetamine analog found in the leaves of the Catha edulis plant [1]. Until 2010, the most commonly available cathinones were mephedrone and methylone [2]. Due to the easy accesibility via the Internet, they spread rapidly among teenage people and young adults. Abuse of mephedrone has increased dramatically and it has become a significant public health problem in Europe, as well as in US. Since mephedrone is banned worldwide, alternative products like butylone (MBDB, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine hydrochloride), methylone (βk-MDMA, 3,4-methylenedioxy-N-methylcathinone; ‘Top Cat’), MDPV (3,4 methylenedioxypyrovalerone) have appeared on the market. Regardless of the fact that more and more experimental studies are being done on these compounds, still relatively little is known about the selective behavioral alterations caused by cathinone compounds.

Butylone and mephedrone are very similar to each other in their chemical structure and both seem to act as psychostimulants like cocaine and MDMA. These compounds are known to increase anxiety, the level of stress and excitement in adult recreational users [3], [4]. Based on observations on human subjects, a limited number of behavioral investigations, including locomotor and novel object discrimination tasks, have been carried out in laboratory rodents [5], [6], [7]. MDPV has a dose-dependent reinforcing effect in a self-administration schedule [8]. In addition, it can stimulate locomotor activity and stereotypies, while it elevates heart rate, blood pressure and body temperature [9], [10], [11].

All synthetic cathinones are beta-keto analogs of amphetamine, which, as evidenced by novel studies, belong to one of three subgroups, according to the relative potencies as inhibitors of serotonin, norepinephrine or dopamine transporter, as well as their releasing actions [12]. Of the drugs investigated in our study, both mephedrone and butylone are members of the same subgroup (cocaine-MDMA mixed cathinones), which are similar to cocaine in their ability to act as nonselective monoamine uptake inhibitor and also as active releasers of 5-HT (like MDMA). Conversely, MDPV belongs to a different subgroup (pyrovalerone–cathinones), whose members are highly potent and selective catecholamine uptake blockers but not substrate releasers.

To investigate the behavioral alterations caused by synthetic cathinones, we chose to apply avian models. Social isolation task is well described in several studies [13], [14]. Newly hatched chicks respond to social isolation with continuous, sharp and loud vocalization, the so called distress call (DC). The number of distress vocalizations [15] can be taken as the measure of the level of fear and anxiety [16].

Domestic chicks are nidifogous (leaving the nest soon after hatching), with a relatively rigid behavioral repertoire, which shows the main behavioral elements of adult birds, not altered by previous experiences. Thus, the experiments based on natural behavioral responses can easily be reproduced. Several studies have utilized the model value of domestic chicks for investigating drug induced behavioral effects of psychoactive drugs [17], [18]. In spite of a vast length of time elapsing since the separation of the ancestry of mammals and sauropsids (including birds), a remarkable degree of homology is still evident in the fundamental neural systems and mechanisms. In particular, the basal ganglia represent a graphic example of such homologies given their neural composition and connectivity [19], [20]. Thus, a great deal of behavioral features such as reward, addiction, learning and decision-making can be analyzed in avian systems with full relevance to comparable mammalian systems and studies. In addition, incomplete development of the blood brain barrier in young posthatch chicks [21], [22], [23] presents a distinct advantage in case of administration of drugs expected to act on the CNS.

The objective of the present study was to provide experimental evidence for the differential behavioral effects of acute systemic administration of two closely related members of the cathinone group (mephedrone and butylone), as compared to the effects of a more distant relative (MDPV), focusing on alterations of wakefulness, pecking, postural control and distress level.