Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists - PubMed (original) (raw)

Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists

Takato Hiranita et al. Neuropsychopharmacology. 2013 Mar.

Abstract

Sigma(1) receptors (σ(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.

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Figures

Figure 1

Figure 1

Lack of the reinforcing effects of the selective _σ_1R agonists in experimentally naive rats compared with the typical acquisition of lever pressing with cocaine injections. (a) When each response on the right lever produced a cocaine injection rates of responding increased whereas rates of responding on the alternate (left) lever, which had no scheduled consequences, remained low. When cocaine injections were available only for responses on the previously inactive (left) lever, responding switched to that lever. Saline substitution decreased responding on both levers to low levels. When cocaine was again available for responses on the left lever, responding increased on that lever. (b, c) Lack of acquisition of (+)-pentazocine or PRE-084 self-administration when each response produced an injection. Response rates on the active lever were not consistently greater than those on the inactive lever throughout the course of 28 experimental sessions. *p<0.05, **p<0.01, ***p<0.001, compared with responding on the inactive lever (_post_-hoc Bonferroni _t_-test).

Figure 2

Figure 2

Substitution of cocaine resulted in the acquisition of self-administration in rats that did not self-administer _σ_1R agonists. (a, b) Acquisition of cocaine (0.32 mg/kg/injection) self-administration when each response produced an injection after extended exposure to PRE-084 (0.32 mg/kg/injection) or after exposure to (+)-pentazocine (0.32 mg/kg/injection). Each point represents the mean ±SEM of six subjects. ***p<0.001, compared with responding on the inactive lever (_post_-hoc Bonferroni _t_-test). (c) Examples of actual self-administration performances of a representative subject in real time. Ordinates, cumulative responses; abscissae, time. Each record is from a single 120-min experimental session. Each response on the active lever incrementally stepped the cumulative curve upward and produced a diagonal mark on the cumulative response curve. Vertical marks on the line below the cumulative curve indicate responses on the left (inactive) lever. The first record is from a previously naive subject in the last session with the opportunity to self-administer 0.32 mg/kg/injection of PRE-084. The second record is from that same subject after 14 sessions with the opportunity to self-administer 0.32 mg/kg/injection of cocaine. The third record is from the immediately following session, the first opportunity to self-administer 0.32 mg/kg/injection of PRE-084 after experience with cocaine. The last record shows stable self-administration of PRE-084.

Figure 3

Figure 3

Selective _σ_1R agonist self-administration after cocaine experience, but not after experience with food reinforcement. Each point represents the mean ±SEM. (a, b) Self-administration of selective _σ_1R agonists when each response produced an injection. Reversal of active and inactive levers, extinction, and reacquisition each had the effects expected for a reinforcing agent. (c) Dose–effect curve for PRE-084 self-administration before and after experience with cocaine self-administration. No dose of PRE-084 was self-administered at rates greater than those for saline in cocaine-naive rats. Following cocaine self-administration, the dose–effect curve of PRE-084 self-administration was typical of those obtained with traditional drugs of abuse. (d) A food reinforcement history was not sufficient to induce reinforcing effects of PRE-084. *p<0.05, ***p<0.001, compared with responding on the inactive lever (_post_-hoc Bonferroni _t_-test). (e) Performances of a representative subject in real time (details of recording as in figure 2c). The first record is from the last session of responding maintained by food reinforcement. The second record is from the immediately following session, the first opportunity to self-administer 0.32 mg/kg/injection of PRE-084 after experience with food reinforcement, showing the extinction of responding previously maintained by food reinforcement. The 10th sessions confirm no acquisition of PRE-084 self-administration.

Figure 4

Figure 4

Sensitivity of cocaine self-administration, and insensitivity of PRE-084 self-administration to dopamine receptor antagonism. Rats were trained to self-administer cocaine (0.032–1.0 mg/kg/injection) under a fixed-ratio five-response schedule of reinforcement with different doses of cocaine available in five components. All antagonists except BD1063 (5 min before sessions) were administered intraperitoneally, 30 min before sessions. Each point represents the mean±SEM of response rates on the active lever. (a–c) Effects of antagonists selective for dopamine D1-like receptors, SCH 39166, D2-like receptors, L-741 626, and the combination of minimally active doses of each. SCH 39166 and L-741 626 shifted the cocaine self-administration dose–effect curve rightward and the combination produced an insurmountable antagonism over the range of tested doses of cocaine. (d) The non-selective dopamine receptor antagonist, haloperidol, produced a dose-related rightward shift in the cocaine self-administration dose–effect curve. (e) The _σ_1R antagonist, BD1063, did not substantially affect cocaine self-administration. (f–h) The dopamine antagonists and their combination did not substantially affect PRE-084 self-administration. (i) Haloperidol dose-dependently decreased maximal PRE-084 self-administration. (j) BD1063 dose-dependently decreased maximal PRE-084 self-administration.

Figure 5

Figure 5

Dose-dependent effects of PRE-084 on extracellular levels of dopamine in the nucleus accumbens shell. Ordinates: extracellular dopamine levels as a percentage of baseline during the 30-min period of time after cumulative drug administration. Abscissae: dose of drug in mg/kg, log scale. Each point represents the mean effect ±SEM determined in four rats. The average basal dopamine values in 10 μl samples of dialysates from the nucleus accumbens shell were 16.2 ±1.46 fmoles (±SEM) and 29.7±2.79 for rats, respectively, with and without cocaine experience, which did not significantly differ in the two groups (_t_=−2.12; _p_=0.08).

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