Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment

Abstract

'Rate dependency' in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, predrug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an intracranial self-stimulation assay. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in-vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (P<0.025, R=0.50). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (P<0.05, R=0.64). Overall, these results extend the rate-dependent effects of monoamine releasers to behavior maintained under intracranial self-stimulation and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate-dependency plots might be a useful metric of drug reward and predictor of drug self-administration measures of drug reinforcement.

Figure 1. Rate-dependent effects of amphetamine on ICSS

A. Previously published figure (Bauer, 2012) showing the effects of amphetamine on ICSS frequency-rate curves. Abscissa: Frequency of stimulation expressed at Log Hz. Ordinate: ICSS rate expressed as % Maximum Control Rate (%MCR). B. Transformation of data from Panel A into rate-dependency plots showing linear regression lines drawn through points generated by vehicle and 4 doses of amphetamine. Abscissa: Log (baseline rate). Ordinate: Log (% baseline rate). Line at Y=2.0 indicates no change from baseline rates, while line at X=1.0 indicates the position of the Y-intercept values used in Panel C. C. -slope and Y-intercept values generated by regression lines in Panel B are plotted against dose of amphetamine. Abscissa: Dose of amphetamine in mg/kg (log scale). Left ordinate: -Slope. Right ordinate: Y-intercept.

Figure 2. Rate-dependent effects of selected doses of PAL-353, PAL-287, and fenfluramine on ICSS

A–C. Effects of 1.0 mg/kg PAL-353, 3.2 mg/kg PAL-287 and 3.2 mg/kg fenfluramine on ICSS frequency-rates curve compared to the pre-drug baselines. Abscissae: Brain stimulation frequency expressed as Log Hz. Ordinates: ICSS rate expressed as % Maximum Control Rate (%MCR). D. Transformation of data from Panels A–C into rate-dependency plots showing linear regression lines drawn through points generated by the three drugs. Abscissa: Log (baseline rate). Ordinate: Log (% baseline rate).

Figure 3. Rate-dependency plot parameters as a function of dose for nine of the monoamine releasers tested

Abscissae: dose in mg/kg (log scale). Left ordinates: -Slope. Right ordinates: Y-intercept. Amphetamine (shown previously in Fig. 1) and rMDMA are omitted.

Figure 4. Rate-dependency plot parameters as a function of pharmacological selectivity to release dopamine vs. serotonin

Abscissae: Pharmacological selectivity expressed as log (in vitro potency to release serotonin ÷ in vitro potency to release dopamine) as shown in Table 2. Ordinate (panel A): Peak –slope for any dose of each drug as shown in Table 2. Ordinate (panel B): Peak Y-intercept for any dose of each drug as shown in Table 2. *Asterisk indicates that fenfluramine data were not included in the correlation because its in vitro potency to release dopamine has not been precisely quantified.

Figure 5. Rate-dependent effects of selected doses of PAL-353/fenfluramine mixtures on ICSS

A–C. Effects of 1:1, 1:3, and 1:10 mixtures of PAL-353/fenfluramine on ICSS frequency-rate curves compared to the pre-drug baselines. Abscissae: Brain stimulation frequency in log Hz. Ordinate: ICSS rate expressed as % Maximum Control Rate (%MCR). D. Transformation of data from Panels A–C into rate-dependency plots showing linear regression lines drawn through points generated by the mixtures. Abscissa: Log (baseline rate). Ordinate: Log (% baseline rate).

Figure 6. Rate-dependency plot parameters as a function of dose for 1:1, 1:3 and 1:10 mixtures of PAL-353 and fenfluramine

Abscissae: dose of PAL-353 in the mixture (log scale). The corresponding fenfluramine dose was determined by the mixture ratio. Left ordinates: -Slope. Right ordinates: Y-intercept.

Figure 7. Correlation between breakpoint in monkey self-administration and Y-intercept data generated by rate-dependency analysis of ICSS data from rats

Abscissa: Maximum breakpoint maintained by any drug dose under a progressive-ratio schedule of drug self-administration in rhesus monkeys. Ordinate: Peak Y-intercept produced by linear regressions of data on a rate-dependency plot. *-MDMA and fenfluramine did not reliably maintain self-administration in all monkeys under this paradigm. Monkey self-administration data taken from Wee et al., 2005; Wang and Woolverton, 2007; unpublished observations (fenfluramine).