The effect of sazetidine-A and other nicotinic ligands on nicotine controlled goal-tracking in female and male rats.

Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by human and non-human animals. Previous research with rodents directly investigating the nature of the nicotine stimulus has been limited to males. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session. On interspersed saline session, sucrose was not available. Both sexes acquired the discrimination as evidenced by increased head entries into sucrose receptacle (goal-tracking) evoked by nicotine; the nicotine generalization curves were also similar between females and males. The pharmacological profile of the nicotine stimulus was assessed using substitution and targeted combination tests with the following ligands: sazetidine-A, PHA-543613, PNU-120596, bupropion, nornicotine, and cytisine. For females and males, nornicotine fully substituted for the nicotine stimulus, whereas sazetidine-A, bupropion, and cytisine all evoked partial substitution. Female and male rats responded in a similar manner to interaction tests where a combination of 1 mg/kg of sazetidine-A plus nicotine or nornicotine shifted the nicotine dose-effect curve to the left. The combination of sazetidine-A plus bupropion or cytisine failed to do so. These findings begin to fill a significant gap the in scientific literature by studying the nature of the nicotine stimulus and response to therapeutically interesting combinations using a model that includes both sexes.

Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine.

Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4ß2-containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.01 mg/kg/infusion) [Dosage error corrected]. Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and a better understanding of its action could contribute to medication development.

Dopamine receptor inactivation in the caudate-putamen differentially affects the behavior of preweanling and adult rats.

The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in young and adult rats. Most notably, systemic administration of EEDQ blocks the DA agonist-induced behaviors of adult rats, while leaving the behavior of preweanling rats unaffected. The purpose of the present study was to: (a) determine whether the age-dependent actions of EEDQ involve receptors located in the dorsal caudate-putamen (CPu) and (b) confirm that EEDQ's behavioral effects result from the inactivation of DA receptors rather than some other receptor type. In Experiment 1, EEDQ or DMSO was bilaterally infused into the CPu on PD 17 or PD 84. After 24h, rats were given bilateral microinjections of the full DA agonist R(-)-propylnorapomorphine (NPA) or vehicle into the dorsal CPu and behavior was assessed for 40 min. In Experiment 2, preweanling rats were treated as just described, except that DA receptors were protected from EEDQ-induced alkylation by administering systemic injections of D1 (SCH23390) and D2 (sulpiride) receptor antagonists. As predicted, microinjecting EEDQ into the dorsal CPu attenuated the NPA-induced locomotor activity and stereotypy of adult rats. In contrast, rats given bilateral EEDQ infusions on PD 17 exhibited a potentiated locomotor response when treated with NPA. Experiment 2 showed that DA receptor inactivation was responsible for NPA's actions. A likely explanation for these results is that EEDQ inactivates a sizable percentage of DA receptors on PD 17, but leaves the remaining receptors in a supersensitive state. This receptor supersensitivity, which probably involves alterations in G protein coupling, could account for NPA-induced locomotor potentiation. It is likely that adult rats to not show a similar EEDQ-induced change in receptor dynamics or DA receptor inactivation was more complete in older animals and effectively eliminated the expression of DA agonist-induced behaviors.

Importance of D1 and D2 receptors in the dorsal caudate-putamen for the locomotor activity and stereotyped behaviors of preweanling rats.

Dopaminergic compounds often affect the unlearned behaviors of preweanling and adult rats differently, although the brain regions underlying these age-dependent behavioral effects have not been specified. A candidate brain region is the dorsal caudate-putamen (CPu); thus, a goal of the present study was to determine whether D1 and D2 receptors in the dorsal CPu are capable of modulating the unlearned behaviors of preweanling rats. In Experiments 1 and 2, selective and nonselective dopamine agonists were bilaterally microinjected into the dorsal CPu on postnatal day (PD) 18 and both locomotor activity and stereotypy were measured. In Experiment 3, the functional coupling of D1 and D2 receptors was assessed by microinjecting the D1 agonist SKF-82958 and the D2/D3 agonist quinpirole either alone or in combination. In Experiments 4 and 5, quinpirole and the D1 receptor antagonist SCH-23390, or SKF-82958 and the D2 receptor antagonist raclopride, were co-administered into the dorsal CPu to further assess whether a functional D1 or D2 receptor system is necessary for the expression of quinpirole- or SKF-82958-induced behaviors. Results showed that selective stimulation of D1 or D2 receptors in the dorsal CPu increased both the locomotor activity and stereotypy of preweanling rats. Receptor coupling was evident on PD 18 because co-administration of a subthreshold dose of SKF-82958 and quinpirole produced more locomotor activity than either agonist alone. Lastly, the dopamine antagonist experiments showed that both D1 and D2 receptor systems must be functional for SKF-82958- or quinpirole-induced locomotor activity to be fully manifested. When the present data are compared to results from non-ontogenetic studies, it appears that pharmacological manipulation of D1 and D2 receptors in the dorsal CPu affects the behavior of preweanling and adult rats in a generally similar manner, although some important age-dependent differences are apparent. For example, D1 and/or D2 agonists preferentially induce locomotor activity, and not intense stereotypy, in younger animals.

Age-dependent effects of kappa-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate-putamen: an in vivo microdialysis study.

kappa-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because kappa-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether kappa-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 microg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying kappa-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why kappa-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.

Effects of dorsal striatal infusions of R(-)-propylnorapomorphine on kappa-opioid-mediated locomotor activity in the young rat: possible role of the indirect pathway.

Stimulation of kappa-opioid receptors in the substantia nigra pars reticulata (SNPR) increases the locomotor activity of young rats: an effect blocked by systemic administration of a D2-like receptor agonist. Based on these initial findings, we proposed that: (a) D2-like receptors in the dorsal striatum are responsible for attenuating kappa-opioid-induced locomotor activity, and (b) the effects of D2-like receptor stimulation are mediated by the indirect pathway, which extends from the dorsal striatum to the SNPR via the globus pallidus (GP) and subthalamic nucleus (STN). To test the first hypothesis, young rats were given a systemic injection (i.p.) of saline or the kappa-opioid receptor agonist (+/-)-trans-U50,488 methanesulfonate salt (U50,488) on postnatal day (PD) 18. Later in the testing session, rats received bilateral infusions of vehicle or the D2-like receptor agonist R(-)-propylnorapomorphine (NPA) into the dorsal striatum, and the ability of NPA to block U50,488-induced locomotor activity was determined. To test the second hypothesis, rats were given sham or bilateral electrolytic lesions of the GP or STN on PD 16. Two days later, saline- and U50,488-induced locomotor activity was measured after systemic (i.p.) administration of vehicle or NPA. As predicted, dorsal striatal infusions of NPA attenuated the U50,488-induced locomotor activity of young rats. Contrary to our expectations, bilateral lesions of the GP or STN did not impair NPA's ability to block U50,488-induced locomotor activity. When considered together, these results suggest that: (a) stimulation of D2-like receptors in the dorsal striatum is sufficient to attenuate the kappa-opioid-mediated locomotor activity of young rats; and (b) the indirect pathway does not mediate the effects of D2-like receptor stimulation in this behavioral model.