Use of intracranial self‐stimulation to evaluate abuse‐related and abuse‐limiting effects of monoamine releasers in rats

Abstract

BACKGROUND AND PURPOSEMonoamine releasers constitute a class of drugs that promote the release of dopamine (DA), serotonin (5-HT) and/or norepinephrine. Although some drugs in this class are well-known drugs of abuse (amphetamine, methamphetamine), others are thought to have reduced (3,4-methylenedioxy-N-methylamphetamine [MDMA]) or no (fenfluramine) abuse potential. The purpose of this study was to further elucidate the role of dopamine versus serotonin selectivity on expression of abuse-related effects produced by monoamine releasers in an assay of intracranial self-stimulation (ICSS) in rats. EXPERIMENTAL APPROACHThis study evaluated effects produced in a frequency-rate ICSS procedure by 11 monoamine releasers that vary in selectivity to release DA versus 5-HT. KEY RESULTSEfficacy of monoamine releasers to facilitate ICSS correlated with DA-selectivity, such that DA-selective releasers exclusively facilitated ICSS, a 5-HT-selective releaser exclusively depressed ICSS, and mixed-action releasers both facilitated low ICSS rates and depressed high ICSS rates. Fixed-proportion mixtures of a DA-selective releaser and a 5-HT-selective releaser recapitulated effects of mixed-action releasers. Efficacy of monoamine releasers to facilitate ICSS also correlated with previously published data on efficacy to maintain self-administration in rhesus monkeys responding under a progressive-ratio schedule of reinforcement. CONCLUSIONS AND IMPLICATIONSThese data support the importance of selectivity for DA versus 5-HT in determining abuse potential of monoamine releasers and demonstrate a novel correlation between rat ICSS and nonhuman primate self-administration measures of abuse-related effects. Taken together, these results support the use of ICSS in rats as an experimental tool to study the expression and pharmacological determinants of abuse-related effects of monoamine releasers.

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

“…Acute administration of psychomotor stimulants such as methamphetamine, MDPV, and mephedrone via i.p. injection has been shown to lower ICSS thresholds in rodents (Bauer et al, 2013;Bonano et al, 2014;Harris et al, 2015;Robinson et al, 2012;Watterson et al, 2014). The relative potencies determined by locomotor stimulant effects in this study and our prior work (Aarde et al, 2013a, b;Huang et al, 2012;Wright et al, 2012) were effective in selecting appropriate doses to alter ICSS thresholds.…”

“…Further experiments were conducted to determine whether intracranial self-stimulation (ICSS) reward thresholds are reduced by vapor exposure to stimulants, as has been reported following intraperitoneal (i.p.) administration of MA (Bauer et al, 2013), MDPV (Bonano et al, 2014), or mephedrone (Robinson et al, 2012). Finally, the effects of i.p.…”

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

“…The k-agonists also tend to be less potent to depress microdialysis measures of NAc DA than ICSS and other behavioral end points (Carlezon et al, 2006;Negus et al, 2010b;Zhang et al, 2005). Moreover, the slower onset, longer duration, and lower potency of these treatments to depress NAc DA levels vs behavior is mirrored by a similar slower onset, longer duration, and lower potency of amphetamine-like drugs to stimulate NAc DA vs behavior (eg, amphetamine; see Bauer et al, 2013;Schad et al, 1995). Taken together, these results suggest that microdialysis measures of NAc DA are slightly less sensitive to, and slower to recover from, experimental manipulations than ICSS or other behavioral measures.…”

Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

“…Rats were trained to respond for ICSS as previously described (Bauer et al, 2013) and are detailed in Supplementary Methods. Test sessions occurred 30 min after CNO (1.5-6 mg/kg, i.p.)…”