Effect of methamphetamine self-administration on neurotensin systems of the basal ganglia

Abstract

Methamphetamine (METH) dependence causes alarming personal and social damage. Even though many of the problems associated with abuse of METH are related to its profound actions on dopamine (DA) basal ganglia systems, there currently are no approved medications to treat METH addiction. For this reason, we and others have examined the METH-induced responses of neurotensin (NT) systems in the basal ganglia. This neuropeptide is associated with inhibitory feedback pathways to nigrostriatal DA projections, and NT tissue levels are elevated in response to high doses of noncontingent METH because of its increased synthesis in the striatonigral pathway. The present study reports the contingent responses of NT in the basal ganglia to self-administration of METH (SAM). Intravenous infusions of METH linked to appropriate lever-pressing behavior by rats significantly elevated NT content in both dorsal striatum (210%) and substantia nigra (202%). In these same structures, NT levels were also elevated in yoked METH animals (160 and 146%, respectively) but not as much as in the SAM rats. These effects were blocked by a D1, but not D2, antagonist. A NT agonist administered before the day 5 of operant behavior blocked lever-pressing behavior in responding rats, but a NT antagonist had no significant effect on this behavior. These are the first reports that NT systems associated with striatonigral pathway are significantly altered during METH self-administration, and our findings suggest that activation of NT receptors during maintenance of operant responding reduces the associated lever-pressing behavior.

Fig. 1.

METH-induced increases in the NT levels of the striatum after both noncontingent and contingent drug treatment. The noncontingent rats received one METH injection (10 mg/kg/injection of METH or saline s.c.) and were sacrificed 12 h after treatment. In contrast, the contingent SAM and YM rats received >3.0 mg i.v. of METH over five sessions in the operant chambers and were killed 6 h after the final session. Values represent the mean percentages of respective controls (Saline or YS) ± S.E.M. (n = 7–10). *, P < 0.05 versus respective saline or YS and YM. **, P < 0.05 versus YS.

Fig. 2.

METH-induced increases in striatal NT content of YM versus YS rats were blocked by pretreatment with the D1 (SCH, SCH23390), but not D2 (Etic, eticlopride), antagonist. Exposure to patterns of intravenous infusions of METH (YM), identical to that determined by a yoked SAM, significantly elevated the NT content but not as much as in the corresponding SAM animals. The eticlopride treatment in YS rats elevated NT levels in this brain region. These two treatments together had an additive effect on the NT response (YM+Etic). n = 7–17. Values represent mean percentages of YS ±S.E.M. *, P < 0.05 versus all other groups and each other.

Fig. 3.

METH-induced increases in nigral NT of YM versus YS rats were blocked by pretreatment with the D1 (SCH, SCH23390), but not D2 (Etic, eticlopride), antagonist. Exposure to patterns of intravenous infusions of METH (YM), identical to that determined by a yoked SAM, significantly elevated the nigral NT content but not as much as in the corresponding SAM animals. Values represent mean percentages of YS ±S.E.M (n = 7–16). *, P < 0.05 versus all other groups. **, P < 0.05 versus all other groups but not each other.

Fig. 4.

Effect of pretreatment with the NT agonist PD149163 (PD) or antagonist SR48692 (SR) on lever-pressing behavior in SAM rats. The PD compound was administered 15 min before the fifth session (n = 7), whereas the SR compound was administered 15 min before each of sessions 5–7 (n = 8). Activation of NT receptors significantly, but temporarily, reduced lever-pressing behavior versus that occurred on the day 4 of self-administration (*, P < 0.05) (n = 15); however, blockade of NT receptors had no significant impact.

Fig. 5.

Effect of METH self-administration on striatal and nigral dynorphin levels. Increases in striatal and nigral DYN were observed in SAM rats, but in YM animals, a significant elevation only occurred in the substantia nigra. *, P < 0.05 versus YS and YM in the striatum and versus YS in the substantia nigra (n = 9–10).