Oral modafinil facilitates intracranial self-stimulation in rats: comparison with methylphenidate

Abstract

Modafinil is a low-potency inhibitor of dopamine transporters (DAT) approved clinically to promote wakefulness. In most procedures used for abuse-liability assessment, modafinil produces effects similar to those of abused DAT inhibitors like cocaine and methylphenidate, although modafinil often displays lower effectiveness. However, modafinil has failed to maintain drug self-administration or produce conditioned place preferences in rats. The low potency and poor solubility of modafinil complicate its delivery by parenteral routes of administration commonly used in rats, and this may contribute to negative results. This study evaluated effects of orally administered modafinil in rats using an assay of intracranial self-stimulation (ICSS) that has been used to examine effects of other DAT inhibitors. Adult male Sprague-Dawley rats equipped with electrodes in the medial forebrain bundle responded for pulses of brain stimulation that varied across a range of frequencies (158-56 Hz) during daily behavioral sessions. Modafinil (20-600 mg/kg, p.o.) and methylphenidate (1.0 – 10 mg/kg, i.p.; 3.2 – 32 mg/kg, p.o.) produced dose- and time-dependent facilitation of ICSS, an effect produced by abused DAT inhibitors and other classes of abused drugs. These results agree with other evidence for stimulant-like abuse liability of modafinil and demonstrate sensitivity of ICSS to orally administered drug.

Effects of repeated treatment with monoamine-transporter-inhibitor antidepressants on pain-related depression of intracranial self-stimulation in rats

“…When bupropion was administered alone in the absence of the IP acid noxious stimulus, it weakly but significantly increased ICSS. This is consistent with our previous findings with this relatively low dose of 3.2 mg/kg bupropion (Leitl and Negus 2016;Rosenberg et al 2013), and higher bupropion doses produce much larger magnitudes of ICSS facilitation similar to those produced by abused monoamine transporter inhibitors such as cocaine, methylphenidate, and methylenedioxypyrovalerone (MDPV) (Bonano et al 2014;Kornetsky and Esposito 1979;Lazenka and Negus 2017). ICSS facilitation is suggestive of abuse potential (Carlezon and Chartoff 2007;Negus and Miller 2014;Wise 1996), and although bupropion is not currently scheduled by the Drug Enforcement Administration in the United States, it does produce abuserelated effects in other preclinical procedures in laboratory animals (e.g.…”

Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142

“…Abuse-related effects are one limitation of typical DAT inhibitors that restricts their clinical utility; thus, a primary goal of the current study was to assess the abuse potential of SRI-31142 in comparison with the typical DAT inhibitors cocaine and GBR-12935. Consistent with previous studies using these and other typical DAT inhibitors, both GBR-12935 and cocaine produced ICSS facilitation (Rosenberg et al, 2013;Bonano et al, 2014b;Lazenka and Negus, 2017), and cocaine also increased NAc DA levels (Di Chiara and Imperato, 1988;Fig. 6.…”

Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats

“…ICSS is an alternative method for preclinical abuse liability assessment, and in general, there is a high degree of correlation between results from drug self-administration and ICSS procedures (Negus and Miller 2014). ICSS is especially advantageous for some applications, such as assessment of abuse-related effects in drug-naïve subjects, simultaneous assessment of both abuse-related ICSS facilitation and abuse-limiting rate-decreasing effects, assessment of the time course of drug effects, and evaluation of compounds that may be difficult to deliver via the intravenous route of administration commonly used for drug self-administration (Lazenka and Negus 2017; Negus and Miller 2014). Results of the present study provide new data that permit comparison of results from ICSS studies in rats and drug self-administration studies in nonhuman primates.…”