Response of limbic neurotensin systems to methamphetamine self-administration.

Methamphetamine (METH) abuse is personally and socially devastating. Although effects of METH on dopamine (DA) systems likely contribute to its highly addictive nature, no medications are approved to treat METH dependence. Thus, we and others have studied the METH-induced responses of neurotensin (NT) systems. NT is associated with inhibitory feedback action on DA projections, and NT levels are elevated in both the nucleus accumbens and dorsal striatum after noncontingent treatment with high doses of METH. In the present study, we used a METH self-administration (SA) model (linked to lever pressing) to demonstrate that substitution of an NT agonist for METH, while not significantly affecting motor activity, dramatically reduced lever pressing but was not self-administered per se. We also found that nucleus accumbens NT levels were elevated via a D1 mechanism after five sessions in rats self-administering METH (SAM), with a lesser effect in corresponding yoked rats. Extended (15 daily sessions) exposure to METH SA manifested similar NT responses; however, more detailed analyses revealed (i) 15 days of METH SA significantly elevated NT levels in the nucleus accumbens shell and dorsal striatum, but not the nucleus accumbens core, with a lesser effect in the corresponding yoked METH rats; (ii) the elevation of NT in both the nucleus accumbens shell and dorsal striatum significantly correlated with the total amount of METH received in the self-administering, but not the corresponding yoked METH rats; and (iii) an NT agonist blocked, but an NT antagonist did not alter, lever-pressing behavior on day 15 in SAM rats. After 5 days in SAM animals, NT levels were also elevated in the ventral tegmental area, but not frontal cortex of rats self-administering METH.

Role of the dorsal raphe nucleus in morphine-induced immediate early gene expression in the rat striatum.

Serotonin (5-HT) is thought to be involved in morphine action in the brain. To determine if the periaqueductal gray (PAG) and the dorsal raphe nucleus (DRN) are involved in morphine-induced c-Fos and JunB expression in the caudate-putamen (CPu), the mu receptor antagonist, beta-funaltrexamine (beta-FNA), was unilaterally infused into the PAG adjacent to DRN prior to morphine. Behaviorally, beta-FNA prevented morphine-induced loss of righting and Straub tail. In the CPu of beta-FNA treated rats, morphine-induced c-Fos and JunB were attenuated compared to vehicle-infused rats. These results suggest that morphine acts within the PAG-DRN to exert rapid behavioral effects and to induce c-Fos and JunB in the striatum.

Infusion of beta-FNA into the thalamus attenuates morphine-induced c-Fos induction in the rat caudate putamen.

The medial thalamus contains mu opioid receptors and sends a glutamatergic projection to the caudate putamen (CPu) in rat. Morphine-induced c-Fos expression in the CPu has been shown to be blocked by pretreatment with antagonists to N-methyl-D-aspartate receptors, indicating the involvement of glutamate in this morphine-induced response. The importance of the glutamatergic projections from the thalamus was assessed by infusing the mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), prior to systemic morphine injection. Infusion of beta-FNA near specific medial thalamic nuclei attenuated morphine-induced c-Fos expression in the CPu.

Chronic administration of morphine alters immediate-early gene expression in the forebrain of post-dependent rats.

Previous studies from this laboratory have demonstrated that acute, systemic administration of morphine results in an induction of the immediate-early gene (IEG) proteins, c-Fos and Jun-B, in the dorsomedial portion of the rat caudate-putamen (CPu). These studies have also shown that morphine can induce c-Fos in the central medial nucleus of the thalamus (CM). To determine whether this response is altered in post-dependent rats, twice-daily injections of an ascending dose of morphine were administered for 5 days, followed by a withdrawal period of 7 or 14 days. A challenge injection of morphine (10 mg/kg) was administered on the last day of withdrawal. As compared to an acute dose of morphine in a naive animal, the induction of c-Fos was increased in the dorsolateral CPu following challenge injection at 7 days, but not at 14 days. Induction of c-Fos in the CM following the challenge injection was blunted following 7 day, but not at 14 days, of withdrawal. An increase in the IEG protein, Jun-B, was also seen following 7 but not 14 days of withdrawal in both the dorsomedial and dorsolateral CPu. These findings demonstrate that a chronic treatment of morphine can result in altered patterns of IEG expression upon challenge with acute morphine, in a time-dependent manner, within the rat CPu and CM.

The 5-HT3 receptor antagonist, MDL 72222, dose-dependently potentiates morphine-induced immediate-early gene expression in the rat caudate putamen.

Previous studies from this laboratory have demonstrated that acute administration of morphine induces the immediate-early genes (IEGs) c-Fos and JunB in the rat caudate putamen (CPu). In the present study, we tested the hypothesis that the serotonin-3 receptor (5-HT3R) is involved in morphine-induced IEG expression, using the selective antagonist to the 5-HT3R, MDL 72222. Rats were divided into three pretreatment groups: MDL 72222, 1 mg/kg or 10 mg/kg; or vehicle (DMSO). Thirty minutes following the pretreatment, the rats were administered either morphine (10 mg/kg) or vehicle. Morphine significantly induced c-Fos expression in the dorsomedial CPu, as we have reported previously. Whereas MDL 72222 alone did not induce c-Fos, it potentiated the morphine-induced c-Fos expression. Morphine also induced JunB expression in the same region of the dorsomedial CPu. At 1 mg/kg, MDL 72222 both induced JunB expression and potentiated the response induced by morphine. At 10 mg/kg, MDL 72222 had no effect on basal JunB levels, but augmented the response to morphine. These findings demonstrate that the 5-HT3R antagonist, MDL 72222, can positively modulate morphine-induced IEG expression in the rat CPu in a dose dependent manner, in contrast to the reported suppressive effect observed when this antagonist is administered prior to amphetamine.

Transmural myocardial infarction with normal coronary angiograms and with single vessel coronary obstruction. Clinical-angiographic features and five-year follow-up.

Angiographic, clinical, and five-year follow-up study of 20 cases of myocardial infarction with normal coronary angiograms (MI-NCA) and 20 cases of myocardial infarction with single vessel obstruction (MI-SVO) are presented. MI-SVO patients differed from MI-NCA in being older (53.7 vs 44.5 years, p = 0.025), predominantly male (90 percent vs 40 percent, p = 0.001), frequently having large left ventricular akinetic segments (50 percent vs 15 percent, p = 0.01), and frequently having antecedent typical angina (55 percent). MI-NCA was more frequently associated with definite mitral valve prolapse (25 percent vs 10 percent, NS); migraine, or Raynaud's phenomenon (45 percent vs 5 percent, p = 0.001); birth control pill ingestion in women (33 percent vs 0 percent, p = 0.05); paroxysmal atrial flutter (25 percent vs 0 percent, p = 0.01); and antecedent atypical angina (25 percent). Frequency of cigarette smoking and hypertension and the mean serum cholesterol levels were similar in both groups. On follow-up, MI-NCA patients more commonly had neurologic events (25 percent vs 5 percent, p = 0.05) and second myocardial infarction (15 percent vs 0 percent, p = 0.02), but deaths occurred infrequently in both groups. These data suggest a variety of pathophysiologic causes for MI-NCA.