Assessment of reinforcement enhancing effects of toluene vapor and nitrous oxide in intracranial self-stimulation

Abstract

Rationale Despite widespread abuse there are few validated methods to study the rewarding effects of inhalants. One model that that may have utility for this purpose is intracranial self-stimulation (ICSS). Objectives We wished to compare and contrast the ICSS reward-facilitating effects of abused inhalants to other classes of abused drugs. Compounds were examined using two different ICSS procedures in mice to determine the generality of each drug's effects on ICSS and the sensitivity of the procedures. Methods Male C57BL/6J mice with electrodes implanted in the medial forebrain bundle were trained under a three component rate-frequency as well as a progressive ratio (PR) ICSS procedure. The effects of nitrous oxide, toluene vapor, cocaine and diazepam on ICSS were then examined. Results Concentrations of 1360-2900 ppm inhaled toluene vapor significantly facilitated ICSS in the rate frequency procedure and 1360 ppm increased PR breakpoint. A concentration of 40% nitrous oxide facilitated ICSS in the rate-frequency procedure but reduced PR breakpoint. Doses of 3-18 mg/kg cocaine facilitated ICSS in the rate frequency procedure and 10 and 18 mg/kg increased PR breakpoint. Doses of 1 and 3 mg/kg diazepam facilitated ICSS in the rate frequency procedure and 3 mg/kg increased PR breakpoint. Conclusions The reinforcement facilitating effect of toluene in ICSS is at least as great as diazepam. In contrast, nitrous oxide weakly enhances ICSS in only the rate frequency procedure. The data suggest that the rate frequency procedure may be more sensitive than the PR schedule to the reward facilitating effects of abused inhalants.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Other drugs acting at GABA receptors have a more varied profile of effects. For example, ethanol typically produces a modest but significant facilitation of ICSS, as do some abused solvents like toluene (Kornetsky et al, 1988;Bespalov et al, 1999;Bespalov et al, 2003;Chan et al, 2012;Fish ICSS in Abuse Potential Testing et al, 2010;Tracy et al, 2014) (Fig. 13D).…”

“…For example, FR schedules can use ratio values .1 (e.g., under an FR 10 schedule, brain stimulation is delivered after completion of 10 responses) (West et al, 1983;Neill et al, 2002). Alternatively, under fixed-interval schedules, stimulation is delivered upon the first response after expiration of a designated temporal interval (Elder et al, 1965;Hunt and Atrens, 1992;Schaefer and Michael, 1992), and under progressive-ratio schedules, the number of responses required to produce stimulation increases as successive stimulations are earned (Easterling et al, 2000;Tracy et al, 2014).…”

“…This is consistent with other evidence to suggest that maximal ICSS rates can be reduced by manipulations that increase the difficulty of the response (e.g., by weighting the lever so that it is more difficult to press) ( . However, drug effects on ICSS are generally similar across manipulanda and schedules of reinforcement, and prevailing evidence suggests that ICSS maintained under an FR 1 schedule is either as sensitive or more sensitive to abuse-related drug effects than ICSS maintained under other schedules (Schaefer and Michael, 1992;Tracy et al, 2014).…”

“…Filled points show drug effects significantly different from vehicle as determined by two-way ANOVA and the Holm-Sidak post hoc test (P , 0.05). Data sets are published for diazepam and toluene (Tracy et al, 2014) and for MK801 and ketamine (Hillhouse et al, 2014). Results with nicotine and caffeine are unpublished but collected with identical procedures.…”

“…In general, ICSS is facilitated by barbiturates including phenobarbital and pentobarbital, although the magnitude of this facilitation is generally small relative to effects of stimulants like amphetamine (Reid et al, 1964;Seeger et al, 1981a;Bossert and Franklin, 2003). ICSS is also typically facilitated by benzodiazepines including midazolam, diazepam, and chlordiazepoxide (Olds, 1966;Ichimaru et al, 1985;Straub et al, 2010;Tracy et al, 2014;Engin et al, 2014). For example, Fig.…”