Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats

Abstract

Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague-Dawley rats (n=12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0-10mg/kg) and MDPV (3.2mg/kg) facilitated ICSS. RTI-118 (3.2-32mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25-0.5mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV.

Keywords: Cocaine; Intracranial self-stimulation; Methylenedioxypyrovalerone; Neuropeptide S; RTI-118.

Fig. 1. Effects of cocaine (A), RTI-118 (B) and U69,593 (C) on ICSS

Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: percent maximum control reinforcement rate (%MCR). Drug doses are indicated in legends in units of mg/kg. Filled points represent frequencies at which reinforcement rates were statistically different from vehicle rates as determined by two-way ANOVA followed by Holm-Sidak post hoc test, P<0.05. All data show mean ± S.E.M. for five (RTI-118) or six (cocaine, U69,593) rats.

Fig. 2. Effects of pre-treatment with RTI-118 (A) or U69,593 (B) on cocaine-facilitated ICSS

Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: percent maximum control reinforcement rate (%MCR). Pre-treatment doses of RTI-118 or U69,593 are indicated in legends in units of mg/kg. Filled points represent frequencies at which reinforcement rates were statistically different from vehicle + 10 mg/kg cocaine as determined by two-way ANOVA followed by Holm-Sidak post hoc test, P<0.05. All data show mean ± S.E.M. for five (RTI-118 + cocaine) or six (U69,593 + cocaine) rats.

Fig. 3. Comparison of ICSS after treatment with vehicle + vehicle and either RTI-118 + cocaine (A) or U69,593 + cocaine (B)

Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: percent maximum control reinforcement rate (%MCR). Treatments are indicated in legends, and drug doses are presented in units of mg/kg. Filled points represent frequencies at which ICSS rates after drug treatments were different from vehicle treatment as determined by two-way ANOVA followed by Holm-Sidak post hoc test, P<0.05. All data show mean ± S.E.M. for five (RTI-118 + cocaine) or six (U69,593 + cocaine) rats.

Fig. 4. Effects of RTI-118 on MDPV-facilitated ICSS

Abscissa: frequency of electrical brain stimulation in log Hz. Ordinate: percent maximum control reinforcement rate (%MCR). Filled points represent frequencies at which reinforcement rates were statistically different from vehicle rates as determined by two-way ANOVA followed by Holm-Sidak post hoc test, P<0.05. All data show mean ± S.E.M. for five rats.