Object preference and nicotine consumption in rats with high vs. low rearing activity in a novel open field

Our previous work has shown that normal male wistar rats can differ systematically with respect to rearing activity in a novel open field: animals with high rearing activity (HRA rats) differed from those with low rearing activity (LRA rats) in dopaminergic and cholinergic brain activity, as well as in their behavioral responsiveness to a cholinergic antagonist, but not in measures of anxiety in the elevated plus-maze. Here, we tested (a) whether HRA vs. LRA reflects responsiveness to novelty, (b) whether such rats voluntarily consume different amounts of the cholinergic agonist nicotine and (c) whether these measures are related to those of anxiety in the plus-maze. Using a novel object test, we found that HRA showed a trend for more object exploration than LRA rats when confronted with two identical novel objects in a familiar open field. When subsequently confronted with a familiar vs. a new object, HRA rats showed substantially more exploration of the new but not of the familiar object than LRA rats. In a subsequent test, HRA vs. LRA rats did not differ in voluntary or forced consumption of oral nicotine, or water. In contrast to rearing activity in a novel open field, measures of anxiety in the plus-maze were neither related to behavior in the novel object test nor to voluntary oral consumption of nicotine, or water. Among others, these data are discussed with respect to dopaminergic and cholinergic forebrain mechanisms, which have previously been found to differ between HRA and LRA rats. Since forebrain dopamine and acetylcholine functions are critical for novelty processing, we suggest that they are also important for the differential behavioral patterns of HRA and LRA rats in the open field, and in the novel object test.     

Post-trial treatment with the nicotinic agonist metanicotine: Differential effects in Wistar rats with high versus low rearing activity

Laboratory rats, although identical in strain, sex, age and housing conditions, can differ considerably in behavior and physiology. When screened in an open-field, for example, Wistar rats can be assigned to subgroups, based on the measure of rearing activity (high, low rearing activity; HRA/LRA). Such rats have previously been found to differ in dopaminergic and cholinergic brain mechanisms, reactivity to cholinergic drugs, and in tests of learning and memory. Here, we asked whether HRA and LRA rats might respond differently to nicotinic treatment, when given during the consolidation of an aversive experience. Therefore, we tested them for performance in an inhibitory avoidance task where they received post-trial injections of either saline, or the nicotinic agonist metanicotine (RJR-2403, 0.017–1.7 mg/kg, i.p.). In support of previous findings, saline-treated LRA rats showed a trend for higher step-in latencies than HRA rats after shock experience. Furthermore, metanicotine was effective only in LRA rats: Compared to their respective saline-treated controls, the retention scores of LRA rats were decreased after post-trial treatment with the highest dose (1.7 mg/kg). Thus, the nicotinic agonist had an amnestic-like effect dependent on dose and subject-dependent factors (HRA/LRA). These findings are discussed with respect to possible drug actions on mnestic and non-mnestic mechanisms, and the importance of taking subject-dependent variability into account when analysing drug effects.     

Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain

RATIONALE: Sensitisation of the mesoaccumbens dopamine response to nicotine has been implicated in the development of nicotine dependence. This study explored the doses of nicotine that elicit the response in two strains of rats that differ in their baseline levels of activity. METHODS: Male Sprague-Dawley and Lister hooded rats were pretreated with daily subcutaneous injections of (-)-nicotine for 7 days at doses ranging from 0.03 mg/kg to 0.90 mg/kg. Microdialysis studies were performed on day 9 in conscious freely moving rats, placed in an activity box and challenged with 0.4 mg/kg nicotine. RESULTS: The acute administration of nicotine to drug-naive rats stimulated dopamine overflow in the accumbal shell but not the core. Sprague-Dawley rats, pretreated with nicotine (0.03 mg/kg/day and 0.10 mg/kg/day) showed increased basal overflow of dopamine in the accumbal core. Pretreatment with 0.10 mg/kg/day or 0.30 mg/kg/day, but not 0.03 mg/kg/day or 0.90 mg/kg/day, also caused sensitisation of the response to a nicotine challenge on the test day. Sensitisation of the locomotor response to nicotine exhibited a simple dose-response relationship, with the largest sensitisation being observed in animals pretreated with 0.90 mg/kg/day. In Lister hooded rats, pretreatment with nicotine reduced basal dopamine overflow in the accumbal core and did not cause sensitisation to a subsequent challenge with nicotine. CONCLUSIONS: Sensitisation of the mesoaccumbens dopamine response to nicotine is influenced by pre-treatment dose and the strain of rats used. It is not related directly to the expression of sensitised locomotor responses to the drug and, therefore, may be implicated in other psychopharmacological properties of the drug, including dependence.     

Immediate and long-term behavioral effects of a single nicotine injection in adolescent and adult rats

We examined the acute rewarding as well as the long-term psychomotor altering effects of nicotine in early adolescent and adult male Sprague-Dawley rats. Place conditioning was used to examine nicotine-induced reward after a single drug pairing. A single pairing of nicotine with the initially non-preferred side of the place conditioning apparatus produced a conditioned place preference (CPP) in early adolescent but not adult animals. One month later, animals were given a nicotine challenge and locomotor activity observed in the open field to characterize age differences in the lasting alterations resulting from this single injection. Adult rats showed tolerance to the locomotor depressant effects of a low dose of nicotine whereas adolescent rats showed tolerance to a higher dose. Regardless of treatment group, animals tested during adolescence responded to the nicotine challenge with less hypoactivity when compared with animals tested as adults. The present results are in agreement with previous studies showing that early adolescent rats are more sensitive to nicotine's rewarding effects and are in accord with studies showing a unique profile of neurobehavioral alterations following nicotine exposure when compared with adults. Such findings are extended here by showing that these differences are seen following only a single pretreatment dose and persist for at least one month after pretreatment.     

Procedural examination of behavioural sensitisation to morphine: lack of blockade by MK-801, occurrence of sensitised sniffing, and evidence for cross-sensitisation between morphine and MK-801

Rats were tested in an open field, a "sniffing box" and an eight-arm maze, to examine in detail the behavioural changes induced by morphine (10mg/kg, i.p.) and MK-801 (0.1mg/kg, i.p.), either alone or in combination, during a 10 day treatment and subsequent drug challenges. In addition to locomotion, a number of other behaviours such as sniffing, rearing and exploration were examined. After morphine challenge, sensitised locomotion and rearing were found in the open field, and sensitised sniffing and turning were observed in the sniffing box. In addition, in the sniffing box, saline challenge produced significant conditioned sniffing and turning, and after a challenge with MK-801, sensitised sniffing and turning were seen in the group pretreated with morphine, suggesting a cross-sensitisation between morphine and MK-801 (but not vice versa). In the eight-arm maze, sensitised locomotion was found after morphine challenge. Morphine and MK-801 changed the preference for particular angles run during trials in a characteristic manner. In none of the behavioural measures was MK-801 able to block the development (and expression) of sensitisation to morphine. In several cases, rather, MK-801 enhanced the acute morphine effects. Sensitisation of sniffing suggests that sensitisation has also developed within the nigrostriatal dopamine system and not only within the mesolimbic dopamine system, as is generally discussed in the context of the most commonly assessed behaviour, locomotion. This finding argues for the additional use of the sniffing box in sensitisation experiments.     

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine

The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.     

The role of mu opioid receptors in psychomotor stimulation and conditioned place preference induced by morphine-6-glucuronide

Previous studies have shown that morphine-6-glucuronide (M6G), a metabolite of morphine, induces reward and psychomotor stimulation but the role of the mu opioid receptor in these actions of the drug is not fully characterized. Thus, using mice lacking exon-2 of the mu opioid receptor and their wild-type littermates/controls, we determined the role of this receptor in psychomotor stimulation, sensitization, and conditioned place preference (CPP) induced by M6G. For comparison, we also assessed the role of the mu opioid receptor in the rewarding action of morphine. For the measurement of locomotor activity and sensitization, mice were habituated to motor activity chambers for 1h, then injected with M6G (10mg/kg) and locomotor activity was recorded for an additional 1h. The same treatment was given for five days and mice were tested for sensitization a week later. For the CPP experiments, mice were tested for baseline place preference on day 1, then received single or repeated alternate-day saline/drug or drug/saline conditioning and tested for CPP the following day. Mice were also tested for CPP under a drugged state. M6G induced psychomotor stimulation, a response that was enhanced upon repeated administration of the drug, showing that locomotor sensitization developed to the motor stimulatory action of M6G. However, M6G induced a weaker CPP response compared to morphine. None of these actions of M6G was detected in mice lacking the mu opioid receptor. Together, the current results suggest that M6G induces psychomotor stimulation and a weaker rewarding action via the mu opioid receptor.     

Effects of voluntary alcohol intake on nicotine-induced behavioural sensitisation in rats

Behavioural sensitisation has been suggested to play a role in the acquisition and maintenance of addictive behaviour. The aim of the present study was to assess nicotine-induced behavioural sensitisation in chronic voluntary alcohol drinking rats. Subjects had free access to alcohol/water or glucose/water solutions since weaning. Rats were pretreated after 2 months of voluntary alcohol drinking. Pretreatment consisted of once-daily intraperitoneal injection of nicotine (0.5 mg/kg) or saline administered for five consecutive days. The nicotine-induced behavioural sensitisation of locomotor activity was tested 3 weeks latter. Horizontal motor activity was monitored for 30 min and expressed as distance travelled (in centimetres). During all the experimental procedure, the animals were maintained under 1-h limited access to alcohol. In glucose-drinking animals, results indicated that nicotine induced locomotor activity sensitization: The locomotor effects of nicotine challenge in the nicotine-pretreated group of rats were significantly enhanced as compared with the saline-pretreated group (Duncan, P<.01). Instead, in the alcohol-drinking animals, no significant differences were observed between the nicotine- and saline-pretreated groups. Thus, chronic alcohol consumption at mild doses prevented the development and/or the long-term expression of the nicotine-induced sensitisation at the doses tested.     

Loss of nicotine-induced effects on locomotor activity in fetal alcohol-exposed rats

Previous evidence from our laboratory showed that systemic injection of nicotine enhanced attention and memory in control rats, but not fetal alcohol–exposed (FAE) rats. The present study examined the effects of nicotine on two measures of locomotor activity in FAE rats. Subjects were 2-month-old male offspring of Sprague–Dawley rats fed a 35% ethanol-derived caloric diet, a pair-fed sucrose diet, or a chow-fed diet during the last 2 weeks of gestation. The two experiments examined the effects of intraperitoneal injection of saline or nicotine (0.25 or 0.75 mg/kg) on rearing in an operant chamber and locomotor activity in an open field for 60 min. The high dose of nicotine produced a decrease in rearing in the first 10-min period, followed by a later increase in rearing in the pair-fed and chow-fed groups, but not the FAE group. Nicotine also produced an elevation of locomotor activity in the open field in only the two control groups. These findings provide additional evidence that FAE rats show less behavioral responsiveness to nicotine.     

Effects of nicotine, caffeine, and their combination on locomotor activity in rats.

The interactive effect of caffeine and nicotine on spontaneous locomotor activity in a tunnel maze was determined in nicotine-naive and nicotine-tolerant rats. Rats were daily injected subcutaneously for 12 days with nicotine (0.4 mg/kg) to induce nicotine tolerance. Nicotine-naive rats were injected with saline. During the next two days, they were exposed to a tunnel maze for two 6-min trials. On the third day, locomotor activity was measured (30-min trial) in the tunnel maze 15 minutes after subcutaneous injection of saline, nicotine (0.2 mg/kg), caffeine (8 mg/kg), or nicotine (0.2 mg/kg) and caffeine (8 mg/kg) in combination. Acute exposure to nicotine decreased locomotor activity in nicotine-naive rats. This decrease was antagonized by simultaneous injection of caffeine. Chronic nicotine exposure induced the development of tolerance to the acute behavioral depressive effects of nicotine. In nicotine-tolerant rats, caffeine and nicotine in combination significantly increased locomotor activity above saline level, whereas given alone they had no significant stimulant effect. Neither chronic nicotine treatment nor acute drug treatments affected exploratory efficiency of rats.     

The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine

Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg SC daily for 5 days) caused sensitisation of the locomotor responses to D-amphetamine (0.1–0.5 mg/kg SC) but not cocaine (15 mg/kg IP). Nicotine pretreatment did not influence the increase in DA overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg IP) but decreased the overflow evoked by the administration of D-amphetamine (1 × 10^–6M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the NAcc may be pharmacologically specific to nicotinic drugs. Received: 23 July 1997/Final version: 19 March 1998     

Morphine-induced place conditioning is not confounded by drug-induced alterations in locomotor activity

The influence of locomotor activity and environmental familiarity upon the reinforcing effects of morphine was examined in an unbiased place preference conditioning procedure. Groups of rats were trained to associate one distinctive environment with morphine and another with saline. One group was made tolerant to the locomotor activity effects of morphine by the SC administration of morphine (5.0 mg/kg/12 hr) for four days prior to conditioning. The other group received injections of saline. Administration of morphine, at doses which decreased locomotor activity, resulted in marked preferences for the drug-associated place in saline-treated rats. In contrast, chronic morphine treatment resulted in tolerance to the sedative effects of morphine and an abolition of the morphine-induced place preference. These results indicate that in the place conditioning procedure, measures of reinforcement are not confounded by drug-induced increases in activity.     

Genetic differences in the rewarding and activating effects of morphine and ethanol

The influence of genotype on the rewarding and locomotor activating effects of morphine and ethanol was examined in the place conditioning paradigm. Two inbred mouse strains (C57BL/6J and DBA/2J) were exposed to a differential conditioning procedure in which each mouse received four pairings of a distinctive floor stimulus with IP injection of morphine (0, 2.5, 5 or 10 mg/kg) or ethanol (0, 1, 2, 3 or 4 g/kg). A different floor stimulus was paired with saline. Conditioning trials lasted 30 min and each experiment concluded with a floor preference test in the absence of drug. In accord with previous studies, morphine evoked a dose-dependent increase in activity during conditioning that was greater in C57BL/6J mice than in DBA/2J mice. In contrast, ethanol produced a dose-dependent increase in activity that was greater in DBA/2J than in C57BL/6J mice. Both strains showed conditioned place preference with morphine, but only the DBA/2J strain showed conditioned place preference with ethanol. No conditioned place aversion was seen. With both drugs, stronger place preference conditioning was obtained in DBA/2J mice, supporting the general conclusion that sensitivity to drug reward is influenced by genotype. The fact that the same genotype is more sensitive to the rewarding effects of two different drugs supports theories postulating commonality in the biological mechanisms of drug reward. Although the outcome of the ethanol study supports predictions of the psychomotor stimulant theory of addiction concerning the relationship between drug-induced activation and reward, the outcome of the morphine study does not. The direction of the strain difference in conditioned place preference is opposite to what might be predicted on the basis of strain differences previously reported in drug consumption and preference studies, suggesting that genetic differences in drug consumption may not accurately reflect postabsorptive motivational effects of drug.     

Accentuated behavioral sensitization to nicotine in the neonatal ventral hippocampal lesion model of schizophrenia

The prevalence of smoking in schizophrenia patients far exceeds that in the general population. Increased vulnerability to nicotine and other drug addictions in schizophrenia may reflect the impact of developmental limbic abnormalities on cortical-striatal mediation of behavioral changes associated with drug use. Rats with neonatal ventral hippocampal lesions (NVHLs), a neurodevelopmental model of schizophrenia, have previously been shown to exhibit altered patterns of behavioral sensitization to both cocaine and ethanol. This study explored nicotine sensitization in NVHLs by testing locomotor activity of NVHL vs. SHAM-operated controls over 3 weeks in response to nicotine (0.5 mg/kg) or saline injections (s.c.) followed by a nicotine challenge delivered to all rats 2 weeks later. At the beginning of the initial injection series, post-injection locomotor activation was indistinguishable among all treatment groups. However, nicotine but not saline injections produced a progressive sensitization effect that was greater in NVHLs compared to SHAMs. In the challenge session, rats with previous nicotine history showed enhanced locomotor activation to nicotine when compared to drug na?ve rats, with NVHL-nicotine rats showing the greatest degree of activity overall. These results demonstrate that NVHLs exhibit altered short- and long-term sensitization profiles to nicotine, similar to altered long-term sensitization profiles produced by cocaine and ethanol. Collectively, these findings suggest the neurodevelopmental underpinnings of schizophrenia produce enhanced behavioral sensitization to addictive drugs as an involuntary and progressive neurobehavioral process, independent of the acute psychoactive properties uniquely attributed to nicotine, cocaine, or alcohol.     

Acute and chronic nicotine effects on measures of activity in rats: a multivariate analysis

Nicotine has been reported to increase or decrease measures of activity in rats, including locomotor activity and rearing. Nicotine dose and repeated exposure to nicotine are known to be important factors in determining the effects on locomotor behavior. Less information has been gathered on rearing and other measures of activity. Rats were tested repeatedly, once per day, in Digiscan automated activity analyzers that reported 19 measures of activity. Each rat was given the same drug and dose each day, either saline or 0.1, 0.2, or 0.4 mg/kg nicotine. The 19 measures were combined or modified to produce 14 measures that were examined using factor analysis to help select the most independent measures. Four measures were selected to describe the effects of dose and to compare day 1 results with day 5 results. Total distance moved was increased in a dose-related fashion and was greater on day 5 than on day 1. Rearing was increased at low doses and decreased at high doses on both days. Stereotypy was increased approximately the same amount by all three doses, and was greater on day 5 than on day 1. Center time was increased by the highest dose on both days. These results once again point out the influences of repeated testing and repeated nicotine exposure on behavior. They may also help to clarify why some studies have reported that both ambulation and rearing are increased after nicotine whereas others find opposite effects.     

The α4β2 agonist SIB 1765F, but not the α7 agonist AR-R 17779, cross-sensitises to the psychostimulant effects of nicotine

RATIONALE: Repeated administration of nicotine leads to an augmentation of its locomotor activating effects. Although studies have begun to identify the nicotinic receptor subtype(s) mediating the psychostimulant properties of nicotine, none as yet have investigated the subtypes which contribute to the process of sensitisation. OBJECTIVES: We therefore investigated cross-sensitisation to nicotine using subjects chronically treated with two nicotine subtype-selective agonists in an attempt to identify the relative contribution of each to the sensitisation process. METHODS: Rats received ten daily injections of either vehicle, nicotine (0.4 mg/kg), the alpha7-agonist AR-R 17779 (20 mg/kg), or the alpha4beta2-agonist SIB 1765F (3 mg/kg), and their subsequent locomotor response to acute challenge with each of these compounds was assessed. RESULTS: Chronic administration of both nicotine and SIB 1765F, but not AR-R 17779, resulted in an enhanced locomotor response to acute challenge with either nicotine or SIB 1765F but not AR-R 17779. CONCLUSIONS: These data support a role for the alpha4beta2 receptor in both the initiation and expression of sensitisation to the psychomotor stimulant effects of nicotine.     

Behavioral and neurochemical components of nicotine sensitization following 15-day pretreatment: studies on contextual conditioning

The effects of contextual conditioning on the induction of nicotine sensitization of locomotor activity, stereotypy and nucleus accumbens dopamine release were studied using a 15-day pretreatment regimen. Six groups of Sprague-Dawley rats were employed to test for the effects of drug pretreatment, conditioning and novelty. Groups 1-4 were treated with daily nicotine (0.6 mg/kg, s.c.) or saline injections that were either paired with the test chamber or given in the home cage, followed by saline injections in the home cage. Group 5 received saline in the test chamber followed by nicotine in the home cage (unpaired). Group 6 was naive to handling and drug treatment. Pretreated animals were implanted with 2 mm microdialysis probes, via chronic guide cannulae, after completing the 15th day of treatment, and were tested for their response to nicotine (0.6 mg/kg, s.c) or saline on day 16. Naive animals were implanted with microdialysis probes and tested in a similar manner. Nicotine-stimulated locomotor activity was sensitized in the paired, unpaired and homecage pretreatment groups whereas nicotine-stimulated stereotypy was sensitized only in the paired pretreatment group. Nicotine-stimulated nucleus accumbens dopamine release was sensitized in the paired and unpaired pretreatment groups. Saline-stimulated nucleus accumbens dopamine release, but not locomotor activity or stereotypy, was also found in the nicotine-pretreated, paired group. These findings demonstrate the development of sensitization to nicotine-induced locomotor activity, stereotypy and nucleus accumbens dopamine release after a 15-day pretreatment regimen. Each of these responses to nicotine were differentially modulated by contextual conditioning. It is suggested that nicotine-stimulated dopamine release in sensitized animals represents the conditioned component of nicotine sensitization.     

Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice

Rationale. Studies have reported that chronic exposure to nicotine does not alter the effects of cocaine on locomotor activity, and vice versa. However, the apparent lack of effect of one drug on the behavioural response to the other may be due to an exclusive focus on locomotor activity as the target behaviour. Objective. To test whether repeated pretreatment with nicotine causes tolerance or sensitization to cocaine's effects on diverse behaviours: locomotion, rearing, grooming, and immobility. Similarly, the effects of repeated cocaine treatment on the acute response to nicotine were also tested. Methods. Mice were pretreated with 14 injections of nicotine (0.3 mg/kg), cocaine (5 mg/kg) or saline, the injections being given once daily, except for three breaks of two days each. Two days after the final pretreatment injection, mice were given a challenge injection of saline, cocaine (3 or 5 mg/kg) or nicotine (0.3 or 1 mg/kg), and observed in a large test cage for 40 min using a time-sampling procedure. Results. Repeated administration of either drug produced some tolerance to subsequent challenge with the same dose of the drug. Prior nicotine exposure significantly attenuated cocaine-induced decreases in grooming and increases in rearing, but did not significantly affect other behaviours. In contrast, prior cocaine exposure failed to alter nicotine's effects on any behaviour. Conclusions. Cross-tolerance between nicotine and cocaine (but not vice-versa) can be demonstrated if several behaviours are observed; measures of locomotor activity are less sensitive to the effect. The asymmetrical pattern of cross-tolerance may be due to differential inhibition of dopamine uptake by the two drugs. Electronic Publication     

Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine

Rationale Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults.Objectives This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. We also examined age differences in locomotor responses to nicotine.Methods In the CPP paradigm, male periadolescent and adult Wistar rats received nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle prior to place conditioning trials. In the CTA paradigm, in separate groups of rats, periadolescents and adults were exposed to a 0.1% saccharin solution, followed by the administration of nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle. Four saccharin–nicotine pairings were followed by a preference test and three extinction sessions.Results In the CPP paradigm, nicotine produced a dose-dependent place preference in periadolescent, but not in adult, rats. In the CTA paradigm, adult rats expressed a dose-dependent avoidance of saccharin after pairings with nicotine, whereas periadolescents were resistant to CTA formation. With regard to locomotor activity, adults and periadolescents showed comparable locomotor responses to nicotine.Conclusions These results suggest that periadolescent rats find nicotine more rewarding and less aversive, compared to adult rats. This shift in the balance between the rewarding and aversive effects of nicotine may make adolescents more susceptible to continued nicotine use.     

The 5-HT₆ serotonin receptor antagonist SB-271046 attenuates the development and expression of nicotine-induced locomotor sensitisation in Wistar rats

5-HT(6) receptors are almost exclusively expressed in the central nervous system, particularly in areas relevant for addictive behaviour. Based on this, together with other data, this receptor may be a viable target for the control of drug abuse. The present study tested the ability of the 5-HT(6) receptor antagonist SB-271046 to attenuate the development and expression of nicotine-induced behavioural sensitisation. Rats were habituated to the test apparatus prior to experimentation (day 0) and locomotor activity recorded. On days 1 and 5, animals were placed in locomotor test apparatus and after 30?min injected with SB-271046 (1, 3, and 6?mg/kg, intraperitoneally IP) or vehicle. Thirty minutes later, nicotine (0.4?mg/kg, subcutaneously SC) or saline were administered and activity recorded for 60?min. On days 2, 3 and 4 treatments were performed in the home cage. After 17 days of withdrawal (day 23), a challenge test was performed with nicotine (0.4?mg/kg SC) or saline. In a separate experiment of similar design the effects of SB-271046 (1, 3, and 6?mg/kg IP) was tested for its ability to reduce the expression of behavioural sensitisation (day 23). SB-271046 dose dependently reduced the development and expression of nicotine sensitisation vs respective controls. In conclusion, the 5-HT(6) receptor antagonist SB-271046 reduced both the development and expression of nicotine sensitisation, suggesting that the 5-HT(6) receptor may be a viable target for the control of nicotine abuse. Further studies are warranted to substantiate this conclusion and further understand the role of 5-HT(6) receptors in addiction.