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Patients with diabetes display a heightened propensity to use tobacco; however, it is unclear whether they experience enhanced rewarding effects of nicotine. Thus, this study examined the reinforcing effects of nicotine in a rodent model of diabetes involving administration of streptozotocin (STZ), a drug that is toxic to pancreatic insulin-producing cells. The first study compared STZ- and vehicle-treated rats that had 23-hour access to intravenous self-administration (IVSA) of nicotine or saline and concomitant access to food and water. In order to examine the contribution of dopamine to our behavioral effects, dopamine transporter (DAT), D1 and D2 receptor levels were compared in the nucleus accumbens (NAc) following 10 days of nicotine or saline IVSA. Dopamine levels in the NAc were also compared following nicotine administration. Lastly, nicotine metabolism and dose-dependent effects of nicotine IVSA were assessed. The results revealed that STZ-treated rats displayed enhanced nicotine intake and a robust increase in food and water intake relative to controls. Protein analysis revealed an increase in DAT and a decrease in D1 receptor levels in the NAc of STZ- versus vehicle-treated rats regardless of IVSA condition. STZ-treated rats also displayed suppressed NAc dopamine levels during baseline and in response to nicotine. STZ treatment did not alter our assessment of nicotine metabolism. Furthermore, STZ treatment increased nicotine IVSA in a dose-dependent manner. Our findings suggest that STZ-treatment increased the rewarding effects of nicotine. This suggests that strong reinforcing effects of nicotine may contribute to greater tobacco use in patients with diabetes.

Rationale: Repeated psychostimulant treatment has been shown to sensitize the locomotor activity of young rats, but there is conflicting evidence suggesting that this sensitized response will persist across only a few drug abstinence days. Objective: The purpose of the present study was to determine whether: (a) young rats are capable of expressing a sensitized locomotor response after an extended drug abstinence period, and (b) the longevity of the sensitized response is critically affected by either the number of drug pretreatment days or environmental conditioning factors. Methods: Young rats were pretreated with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) for either five or ten consecutive days [i.e., on postnatal days (PD) 16-20 or PD 11-20]. After each daily injection, rats were placed in activity chambers, and locomotion was measured for 30 min. To assess environmental conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. After one or seven abstinence days (i.e., on PD 22 or PD 28), rats received a challenge injection of saline or cocaine (15 mg/kg) in the activity chamber and locomotion was assessed. Results: Young rats exhibit cocaine-induced locomotor sensitization after either a short (1-day) or long (7-day) drug abstinence period. When a long abstinence period was used, locomotor sensitization was only apparent when cocaine pretreatment lasted for 10 days. Conditioning factors were also important for determining whether locomotor sensitization was expressed, because young rats pretreated with cocaine in the home cage did not show a sensitized locomotor response after seven abstinence days. Conclusions: Young rats are capable of showing cocaine-induced locomotor sensitization after an extended abstinence period. Both the number of drug pretreatment days and the environmental context in which cocaine was given (i.e., the activity chamber or home cage) influenced the longevity of cocaine-induced locomotor sensitization.

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Dorsal horn NMDA receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of SP, as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) was initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists AP-5 and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalininduced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin generelated peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP. KeywordsNeurokinin 1 receptor; internalization; dorsal horn; glutamate; C-fiber *Correspondence should be addressed to: Dr. Arbi Nazarian, Department of Pharmaceutical Sciences, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766-1854, Tel: (909) Fax: (909) 469-5600, Email: anazarian@westernu.edu. a These authors have contributed equally to this manuscript. Section Editor: Dr. Richard J. Weinberg, Department of Cell and Developmental Biology, CB7090, University of North Carolina, Chapel Hill, NC, 27599 USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Small diameter primary afferents terminate superficially in lamina I and II and exert frequencydependent depolarizin...

Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.

It appears that D(1)-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D(1A) nor D(1B) receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D(1A)-deficient mice. A possible explanation for these conflicting results is that D(1A)-deficient mice may have a compensatory mechanism (not involving D(1B) receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D(1A) receptor.