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

Abstract

Background and purpose: Monoamine 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 approach: This 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 results: Efficacy 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 implications: These 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.

Figure 1

Effect of PAL-353, amphetamine, phenmetrazine, methamphetamine and PAL-314 on ICSS. Left panels (A, C, E, G, I) show drug effects on full ICSS frequency–rate curves. Abscissae: Frequency of electrical brain stimulation in Log Hz. Ordinates: Percent maximum control reinforcement rate (%MCR). Drug name and doses are indicated in legends. Filled points represent frequencies at which reinforcement rates were statistically different from vehicle rates as determined by a two-way anova followed by a Holm–Sidak post hoc test, P < 0.05. Right panels (B, D, F, H, J) show summary ICSS data expressed as percent pre-drug baseline number of reinforcers delivered across all frequencies of brain stimulation. Abscissae: drug dose in mg kg⁻¹. Ordinates: Percent pre-drug baseline number of reinforcers. The drug and pretreatment time are shown for each panel. Upward/downward arrows indicate significant drug-induced increase/decrease in ICSS relative to vehicle for at least one brain stimulation frequency as determined by analysis of full frequency–rate curves. All data show mean ± SEM for five to seven rats (except for 3.2 mg kg⁻¹ PAL-353, n = 4). Statistical results for data in left panels are as follows: (A) PAL-353 0.1–1.0 mg kg⁻¹ (n = 7): significant main effect of frequency [F_(9,54) = 88.6, P < 0.001], dose [F_(3,18) = 38.8, P < 0.001] and significant interaction [F_(27,162) = 7.9, P = < 0.001]. PAL-353 3.2 mg kg⁻¹ (n = 4): significant main effect of frequency [F_(9,27) = 17.1, P < 0.001], dose [F_(1,3) = 12.0, P = 0.04] and significant interaction [F_(9,27) = 18.8, P < 0.001]. (C) Amphetamine (n = 6): significant main effect of frequency [F_(9,45) = 144.2, P < 0.001], dose [F_(4,20) = 55.4, P < 0.001] and significant interaction [F_(36,180) = 10.5, P = < 0.001]. (E) Phenmetrazine (n = 5): significant main effect of frequency [F_(9,36) = 22.8, P < 0.001], dose [F_(4,16) = 4.9, P < 0.009] and significant interaction [F_(36,144) = 3.8, P = < 0.001]. (G) Effect of methamphetamine (n = 5): significant main effect of frequency [F_(9,36) = 56.2, P < 0.001], dose [F_(4,16) = 40.4, P < 0.001] and significant interaction [F_(36,144) = 6.6, P = < 0.001]. (I) PAL-314 (n = 6): significant main effect of frequency [F_(9,45) = 67.9, P < 0.001], dose [F_(4,20) = 6.0, P = 0.003] and significant interaction [F_(36,180) = 11.8, P = < 0.001].

Figure 2

Time courses of PAL-353, amphetamine, phenmetrazine, methamphetamine and PAL-314. Left panels (A, C, E, G, I) show drug effects on full ICSS frequency-rate curves. Right panels (B, D, F, H, J) show summary ICSS data expressed as percent pre-drug baseline number of reinforcers delivered across all frequencies. Other details as in Figure 1. All data show mean ± SEM for five to seven rats. Statistical results for data in left panels are as follows: (A) PAL-353 (n = 7): significant main effect of frequency [F_(9,54) = 40.6, P < 0.001], time [F_(5,30) = 29.5, P < 0.001] and significant interaction [F_(45,270) = 3.3, P < 0.001]. (C) Amphetamine (n = 5): significant main effect of frequency [F_(9,36) = 63.9, P < 0.001], time [F_(4,16) = 48.2, P < 0.001] and significant interaction [F_(36,144) = 3.5, P < 0.001]. (E) Phenmetrazine (n = 5): significant main effect of frequency [F_(9,36) = 23.4, P < 0.001], time [F_(3,12) = 18.6, P < 0.001] and significant interaction [F_(27,108) = 4.5, P < 0.001]. (G) Methamphetamine (n = 5): significant main effect of frequency [F_(9,36) = 36.4, P < 0.001], time [F_(4,16) = 14.9, P < 0.001] and significant interaction [F_(36,144) = 10.0, P < 0.001]. I. PAL-314 (n = 5): significant main effect of frequency [F_(9,36) = 47.8, P < 0.001], time [F_(4,16) = 14.9, P < 0.001] and significant interaction [F_(36,144) = 9.5, P < 0.001].

Figure 3

Effect of PAL-313, (+)MDMA, PAL-287, (–)MDMA and fenfluramine on ICSS. Left panels (A, C, E, G, I) show drug effects on full ICSS frequency–rate curves. Right panels (B, D, F, H, J) show summary ICSS data expressed as percent pre-drug baseline number of reinforcers delivered across all frequencies. Other details as in Figure 1. All data show mean ± SEM for five to seven rats (except for 10.0 mg kg⁻¹ PAL-287, n = 3). Statistical results for data in left panels are as follows: (A) PAL-313 (n = 5): significant main effect of frequency [F_(9,36) = 44.9, P < 0.001] but not dose [F_(3,12) = 2.9, P = 0.079]. There was a significant interaction [F_(27,108) = 3.8, P = < 0.001]. C. (+)MDMA: significant main effect of frequency [F_(9,36) = 51.0, P < 0.001], dose [F_(4,16) = 3.6, P = 0.028] and significant interaction [F_(36,144) = 4.0, P < 0.001]. (E) PAL-287 0.32–3.2 mg kg⁻¹ (n = 5): significant main effect of frequency [F_(9,36) = 71.6, P < 0.001], dose [F_(3,12) = 4.7, P < 0.021] and significant interaction [F_(27,108) = 3.9, P = < 0.001]. PAL-287 10.0 mg kg⁻¹ (n = 3): significant main effect of frequency [F_(9,18) = 27.0, P < 0.001] but not dose [F_(1,2) = 3.1, P = 0.222]. There was a significant interaction [F_(9,18) = 21.7, P = < 0.001]. Additional rats were not tested at 10 mg kg⁻¹ due to lethality. (G) (–)MDMA: significant main effect of frequency [F_(9,36) = 72.4, P < 0.001] but not dose [F_(3,12) = 3.4, P = 0.052]. There was a significant interaction [F_(27,108) = 3.8, P < 0.001]. (I) Fenfluramine (n = 7): significant main effect of frequency [F_(9,54) = 70.3, P < 0.001], dose [F_(3,18) = 33.5, P < 0.001] and significant interaction [F_(27,162) = 9.1, P = < 0.001].

Figure 4

Time courses of PAL-313, (+)MDMA, PAL-287, (–)MDMA and fenfluramine. Left panels (A, C, E, G) show time course of drug effects on full ICSS frequency–rate curves. Right panels (B, D, F, H) show summary ICSS data expressed as percent pre-drug baseline number of reinforcers delivered across all frequencies. Other details as in Figure 1. All data show mean ± SEM for five to seven rats. Statistical results for data in left panels are as follows: (A) PAL-313 (n = 6): significant main effect of frequency [F_(9,45) = 62.9, P < 0.001], time [F_(4,20) = 3.6, P < 0.001] and significant interaction [F_(36,180) = 8.0, P < 0.001]. C. (+)MDMA (n = 5): significant main effect of frequency [F_(9,36) = 36.6, P < 0.001], time [F_(4,16) = 3.733, P = 0.025] and significant interaction [F_(36,144) = 7.803, P < 0.001]. (E) PAL-287 (n = 5): significant main effect of frequency [F_(9,36) = 85.0, P < 0.001], time [F_(5,20) = 6.5, P < 0.001] and significant interaction [F_(45,180) = 11.0, P < 0.001]. (G) (–)MDMA (n = 6): significant main effect of frequency [F_(9,45) = 24.2, P < 0.001], time [F_(4,20) = 5.5, P = 0.004] and significant interaction [F_(36,180) = 3.6, P < 0.001]. (I) Fenfluramine (n = 7): significant main effect of frequency [F_(9,54) = 41.1, P < 0.001], time [F_(5,30) = 14.5, P < 0.001] and significant interaction [F_(45,270) = 3.8, P < 0.001].

Figure 5

Effect of PAL-353/fenfluramine mixtures on ICSS. Left panels (A, C, E) show drug effects on full ICSS frequency–rate curves. Right panels (B, D, F) show summary ICSS data expressed as percent pre-drug baseline number of reinforcers delivered across all frequencies. Other details as in Figure 1. All data show mean ± SEM for five to six rats. Statistical results for data in left panels are as follows: (A) 1:1 PAL-353/Fenfluramine (n = 5): significant main effect of frequency [F_(9,36) = 66.5, P < 0.001], dose [F_(3,12) = 43.2, P < 0.001] and significant interaction [F_(27,108) = 10.4, P < 0.001]. (C) 1:3 PAL-353/Fenfluramine (n = 6): significant main effect of frequency [F_(9,45) = 65.8, P < 0.001], dose [F_(3,15) = 7.0, P < 0.001] and significant interaction [F_(27,135) = 8.1, P < 0.001]. (E) 1:10 PAL-353/Fenfluramine (n = 6): significant main effect of frequency [F_(9,45) = 54.2, P < 0.001], dose [F_(3,15) = 21.6, P < 0.001] and significant interaction [F_(27,135) = 10.3, P < 0.001].

Figure 6

Correlation of ICSS facilitation in rats with (A) in vitro selectivity to promote DA versus 5-HT release and (B) break points maintained under a progressive-ratio schedule of drug self-administration in rhesus monkeys. (A) Abscissa: Log selectivity to release DA versus 5-HT expressed as the log of selectivity values shown in Table 1. Ordinate: Maximum facilitation of ICSS expressed as the maximum increase produced by any drug dose in percent pre-drug baseline number of reinforcers delivered across all brain stimulation frequencies (from Figures 1 and 3, right panels). Fenfluramine was excluded from this figure because it did not facilitate ICSS at any dose or time and because precise selectivity could not be quantified due to low potency to release dopamine. (B) Abscissa: Maximum break point maintained by any drug dose under a progressive-ratio schedule of drug self-administration in rhesus monkeys. Ordinate. Maximum facilitation of ICSS as in panel A. (–)MDMA and fenfluramine were excluded from the correlation because they did not facilitate ICSS in rats and/or did not reliably maintain self-administration in monkeys (self-administration by <50% of monkeys tested). PAL-287 and phenmetrazine were also excluded, because they have not been tested by Woolverton and colleagues under the progressive-ratio schedule of drug self-administration in rhesus monkeys.