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     

Infusion of Nicotine in the Ventral Tegmental Area or the Nucleus Accumbens of the Rat Differentially Affects Accumbal Dopamine Release

Abstract: The present study examined the effects of acute, continuous infusion of nicotine in either the ventral tegmental area or the nucleus accumbens on extracellular concentrations of dopamine in the nucleus accumbens by applying in vivo microdialysis in freely moving rats. Nicotine (1000 μM) infusion for 80 min. in the ventral tegmental area produced a long-lasting increase in accumbal dopamine, whereas similar nicotine infusion in the nucleus accumbens increased dopamine levels only within the first 20 min. of administration. This effect was blocked by systemic pretreatment with the nicotinic receptor antagonist mecamylamine (1 mg/kg, subcutaneously). In contrast to the effects of nicotine, N-methyl-D-aspartate infusion in the ventral tegmental area as well as in the nucleus accumbens produced a long-lasting increase in accumbal dopamine levels. The more procounced effect of infusion of nicotine in the ventral tegmental area as compared to the nucleus accumbens on accumbal dopamine release may be due to a lower rate or even lack of tolerance to nicotine's stimulatory action in the ventral tegmental area. These results support the notion that nicotinic receptors in the ventral tegmental area may be of greater importance than those located in the nucleus accumbens for mediating some of the stimulatory effects of nicotine on the reward-related mesoaccumbens dopamine system.     

Repeated d-amphetamine enhances stimulated mesoamygdaloid dopamine transmission

The mesoaccumbens dopamine pathway exhibits an enhanced dopaminergic response to a challenge injection of d-amphetamine or cocaine after repeated intermittent exposure to that drug. Much research has focused on the potential role of this sensitised response in the enhanced propensity of drug-associated stimuli to elicit relapse. However, the amygdala is acknowledged to play a critical role in stimulus-reward learning, and recent work suggests that the mesoamygdaloid dopamine pathway exerts a significant influence upon amygdala function. In the present study, rats were administered d-amphetamine (1 mg/kg, IP) or vehicle once per day, for 14 days. After 11 untreated days, a locomotor assay showed that prior repeated administration of d-amphetamine led to a markedly enhanced locomotor response to 0.5 mg/kg d-amphetamine. There was no effect of d-amphetamine pretreatment upon the response to a novel environment, or to injection with vehicle. Following a total of 14 days in the home cage, subjects were implanted with microdialysis probes within the amygdala, and for comparison also within the nucleus accumbens. Baseline and d-amphetamine-stimulated (0.5 mg/kg) levels of extracellular dopamine were assessed for each brain region. Results showed that baseline levels of dopamine were very similar in sensitised and control animals. By contrast, prior treatment with d-amphetamine enhanced dopamine overflow in response to a challenge with d-amphetamine both in the nucleus accumbens and amygdala. These results indicate that changes in the pattern of dopamine transmission both in the nucleus accumbens, and the amygdala, accompany the behavioural sensitisation observed after repeated exposure to d-amphetamine. Hence, an enhanced propensity of drug-associated stimuli to elicit relapse may not depend solely upon changes relating to the mesoaccumbens dopamine projection. Received: 24 October 1996/Final version: 28 February 1997     

Pre- and postsynaptic dopamine mechanisms after repeated nicotine: effects of adrenalectomy

The reinforcing properties of nicotine may be related to its ability to release dopamine in the nucleus accumbens and to increase locomotor activity in experimental animals. Both these effects are sensitized following repeated drug exposure, a phenomenon that may underlie important aspects of addiction. Adrenal steroids may be involved both in positive reinforcement and in sensitization. Adrenalectomy hampers, e.g., the induction of locomotor sensitization to nicotine, and cross-sensitization between stress and psychostimulants may develop. Here, the effect of adrenalectomy on postsynaptic and presynaptic changes of the mesolimbic dopamine system in association with nicotine sensitization was examined. Adrenalectomy or sham-operated rats received daily nicotine (0.4 mg/kg s.c.) or vehicle for 15 days, after which the locomotor responses to nicotine (0.2 mg/kg s.c.) and the dopamine D1/D2 receptor agonist apomorphine (1.0 mg/kg s.c. or 100 microM in the nucleus accumbens by reversed microdialysis) were recorded. In addition, accumbal dopamine output was monitored by in vivo microdialysis after nicotine challenge. Sham/nicotine animals showed a sensitized locomotor response to systemic and local apomorphine compared to all other groups, including the adrenalectomized/nicotine group. Nicotine increased accumbal dopamine output in all animals. In contrast, nicotine induced a pronounced increase in locomotor activity in the sham/nicotine animals compared to the other vehicle group and the adrenalectomized animals. These results indicate that adrenal steroids are involved in the induction of the postsynaptic component of nicotine sensitization, whereas their involvement in tentative presynaptic changes remains unclear.     

Investigating the actions of bupropion on dependence-related effects of nicotine in rats

Abstract Rationale. The clinical success of the antidepressant bupropion, marketed as Zyban in smoking cessation, presents an ideal opportunity to unravel its mechanism of action utilising animal models of nicotine dependence. Objective. The present experiments utilise bupropion as a reference compound to examine putative interactions with stimulus properties of nicotine in rats. Methods and results. In male hooded Lister rats, bupropion (10 and 30 mg/kg IP) administered 30 min prior to each intravenous nicotine (0.03 mg/kg per infusion) self-administration session failed to attenuate rates of nicotine intake. Moreover, following the large dose of bupropion, nicotine intake was enhanced and response rates remained elevated throughout the 28-day course of treatment. To examine interactions with subjective effects of nicotine, rats trained to discriminate nicotine (0.2 mg/kg SC) from vehicle were tested with bupropion (1, 3, 10 and 30 mg/kg IP). Bupropion pre-treatment failed to exert a "nicotine-like" action and also failed to attenuate the orderly dose-related discrimination function of nicotine (0.05–0.4 mg/kg SC) in rats. Using the conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake, bupropion (3, 10 and 30 mg/kg IP) pre-treatment failed to modify the aversive effects produced by a threshold dose of nicotine (0.2 mg/kg SC). Conclusions. The results obtained with bupropion in these animal models of dependence suggest this antidepressant may not directly interact with stimulus properties of nicotine; rather its clinical efficacy may be exposed in animal models that are based upon chronic exposure to nicotine and upon abstinence effects. Electronic Publication     

Repeated nicotine treatment in rats with high versus low rearing activity: analyses of behavioural sensitisation and place preference

Rationale Repeated treatment with the cholinergic agonist nicotine can sensitise rats to its psychomotor stimulant effects, which is largely due to changes within the mesolimbic and mesostriatal dopamine system. Since this brain system also plays a critical role in motivational processes, changes of motivational functions may also be expected with repeated nicotine experiences.Objective 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) differed from those with low rearing activity (LRA) with respect to dopaminergic and cholinergic brain activity. In this study, we asked whether HRA and LRA rats might respond differentially to repeated nicotine treatment, which we tested in terms of behavioural sensitisation and place preference.Methods Nicotine hydrogen tartrate (0.4 mg/kg) or saline was administered on eight alternate days (drug treatment). After each injection, the rats had access to one specific quadrant of a circular unbiased place preference apparatus. Sensitisation to nicotine was assessed by measuring locomotion and rearing during drug treatment. On the days after each drug treatment, rats had free access to the entire apparatus without prior drug treatment. Here, we tested for preference for the previously drug-paired quadrant. One week after this procedure, all animals were tested again for sensitisation and place preference after injection of saline or nicotine.Results Overall, sensitisation occurred earlier during locomotor than rearing activity. Both, HRA and LRA rats treated with nicotine showed sensitisation, but with different profiles. Rearing sensitised earlier in HRA than LRA rats, and a sensitised locomotor response to nicotine was observed only in HRA rats when compared with baseline. When re-tested again 1 week later, expression of sensitisation to nicotine was detected in rearing and locomotor activity in both HRA and in LRA rats. In the place preference tests, nicotine-treated and saline-treated rats spent more time in the treatment quadrant, but nicotine did not lead to place preference compared to saline. Furthermore, there was no substantial evidence that nicotine might lead to place preference in only HRA or LRA rats. However, we obtained other evidence that HRA versus LRA rats responded differently to the procedure of place preference testing.Conclusions These data supplement previous findings that different levels of psychomotor activity can affect the reactivity to psychostimulant drugs and add new evidence with respect to nicotine.     

Effects of nicotine and epibatidine on locomotor activity and conditioned place preference in rats

We studied the effects of nicotine and epibatidine given s.c. acutely and repeatedly, on locomotor activity and conditioned place preference (CPP) in rats. Nicotine at 0.5 mg/kg immediately and at 0.8 mg/kg after a delay increased the locomotor activity and its locomotor stimulant effects were greatly sensitized (about fourfold) when it was given repeatedly. Acute epibatidine at 0.6 and 3.0 microg/kg increased the activity modestly after a delay. When given repeatedly epibatidine's stimulant effects, mainly those at 3.0 microg/kg, were somewhat sensitized (less than twofold). Nicotine at 0.5 and 0.8 mg/kg produced CPP in rats in a biased paradigm. Epibatidine elicited CPP at very low dose (0.1 microg/kg), but at 0.3 or 0.6 microg/kg it induced neither preference nor aversion and at the 3.0 microg/kg dose it was aversive. Both acutely and after the repeated administration, epibatidine enhanced the locomotor activity of rats clearly less than nicotine agreeing with its previously reported lesser effects on accumbal dopamine output. Thus, while nicotine elicits CPP at doses (0.5 and 0.8 mg/kg) equal to those that increase accumbal dopamine output and locomotor activity, epibatidine seems to be aversive at the dose (3.0 microg/kg) that enhances accumbal dopamine output and increases locomotor activity.     

Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats.

Methylphenidate, a dopamine reuptake inhibitor, is the most common treatment for attention-deficit hyperactivity disorder and may be prescribed for years, despite little evidence of any long-term benefit, nor knowledge of potential chronic side-effects. Therefore, this study examined the acute and longer-term behavioural effects and assessed striatal dopamine function following subchronic methylphenidate administration to adolescent rats. Male hooded Lister rats received methylphenidate (4 mg/kg i.p. twice daily for 4 days) or saline (1 ml/kg) and the acute locomotor and stereotype behaviour was monitored on days 1 and 4, novel object exploration on day 2 and, following 12 days drug withdrawal, the long-term effect examined on social interaction on day 16. Ex-vivo K+ (20 mM)- and methylphenidate (0.1 mM)-induced [3H]dopamine release from striatal slices and striatal monoamine content were measured on day 18. Compared with saline, methylphenidate induced mild hyperactivity without stereotypy but did not alter novel object exploration and, following withdrawal, had no long-term effect on social interaction. In striatal slices from controls, both K+ and methylphenidate elevated [3H]dopamine release (p < 0.01) while only combined treatment elevated release in methylphenidate pretreated rats, although striatal monoamine content was unaltered compared with control rats. In summary, a repeated dose of methylphenidate that had acute behavioural effects produced no long-term alteration in social interaction but attenuated presynaptic striatal dopamine function.     

Effect of quinpirole on striatal dopamine release and locomotor activity in nicotine-treated mice

The effect of chronic oral nicotine treatment which in its intermittent delivery resembles human smoking was studied on the sensitivity of dopamine autoreceptors in mice. On the 50th day of nicotine administration in the drinking water or after 23-25 h withdrawal quinpirole (D2/D3 agonist, 0.01-0.1 mg/kg s.c.) was given, and accumbal and dorsal striatal dopamine outflow, locomotor activity and body temperature were measured. Dorsal striatal extracellular dopamine concentration and locomotor activity were found to be elevated during nicotine administration. Chronic nicotine did not alter the effects of small, autoreceptor preferring doses of quinpirole on accumbal or dorsal striatal dopamine, locomotor activity or body temperature. However, quinpirole's locomotor activity reducing effect was slightly diminished in mice treated repeatedly with nicotine (0.4 mg/kg twice daily for 10 days s.c.). Thus, although repeated nicotine treatment for 5-14 days decreases dopamine autoreceptor sensitivity, after long-term oral nicotine treatment such a decrease is not seen. Thus, the changes occurring in the sensitivity of D2-like dopamine receptors probably play a minor role in regulating the dopaminergic transmission during long-term nicotine administration.     

Nicotine and epibatidine alter differently nomifensine-elevated dopamine output in the rat dorsal and ventral striatum

We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 microg/kg but not 3.0 microg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 microg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 microg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic dopaminergic pathways.     

Effects of atypical antipsychotic drugs on intralipid intake and cocaine-induced hyperactivity in rats.

Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo. Olanzapine (0.1-1 mg/kg) stimulated Intralipid intake to an equal extent in male and female rats. Quetiapine (10 mg/kg) also stimulated Intralipid intake whereas ziprasidone (0.3-10 mg/kg) or risperidone (0.03-0.3 mg/kg) did not have this effect. All of the compounds, except quetiapine, reduced cocaine-stimulated locomotor activity but the relationship to the degree of Intralipid hyperphagia was variable. Since there was a positive relationship between Intralipid hyperphagia and the reported extent of human body weight gain, we conclude that Intralipid hyperphagia may have predictive value for this drug-associated side effect and is not related to the dopamine antagonist properties of these agents.     

Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats

Rats were pretreated with saline or nicotine (1.5 mg/kg per day) by subcutaneously implanting each animal with an Alzet osmotic mini-pump which continuously released saline or nicotine for 1, 5 and 14 days. At the end of each pretreatment period, animals were used for (i) determining their locomotor response to acutely injected nicotine (0.2 mg/kg, s.c.) and (ii) measuring the density of L-[3H]nicotine and [3H]spiperone binding sites in the striatum. We observed no changes in nicotine-induced locomotor response, striatal L-[3H]nicotine and [3H]spiperone binding in the animals pretreated with nicotine for 1 day. In rats which were pretreated with nicotine for 5 days, there was a significant increase in the nicotine-stimulated locomotor response which was associated with an increase in the number of L-[3H]nicotine binding sites and also with an elevated dopamine (DA) level in the striatum. The number of striatal [3H]spiperone binding sites was not affected. In animals pretreated with nicotine for 14 days, the nicotine-induced locomotor response remained to be potentiated. However, this response was correlated with an elevated number of striatal [3H]spiperone binding sites, whereas the number of striatal L-[3H]nicotine binding sites and the striatal DA level were normal. These results suggest that chronic nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of nicotinic receptors and DA concentration, followed by inducing DA receptor supersensitivity in the striatum.     

Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats

Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.     

Conditioned Place Preference and Self-Administration Induced by Nicotine in Adolescent and Adult Rats

Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.     

Adrenalectomy attenuates nicotine-induced dopamine release and locomotor activity in rats

Adrenalectomy (ADX) in mice can potentiate several physiological and behavioural responses to nicotine. The present experiments sought to examine this issue in the rat by characterising the influence of ADX upon the locomotor depressant, activating and dopamine-releasing properties of nicotine. Nicotine (0.8–1.2 mg/kg SC) dose-dependently depressed locomotor activity, an effect that was potentiated by ADX, while the locomotor activating effects of a smaller dose (0.4 mg/kg) were attenuated by ADX. In both SHAM and ADX rats chronically treated with nicotine for 5 days (daily injections of 0.4 mg/kg SC), the locomotor depressant effects of nicotine did not differ from saline-treated controls. Nicotine (0.4 mg/kg SC) increased extracellular levels of dopamine in the nucleus accumbens. This response was unaffected in rats pretreated with nicotine for 5 days (daily injections of 0.4 mg/kg SC). However, both ADX groups of rats showed smaller increases in dopamine following administration of nicotine. The results suggest that depletion of circulating corticosteroids can modulate sensitivity to nicotine in rats. The suppressant effects of ADX on nicotine-induced locomotor activity may be due to its effects on dopamine release in the nucleus accumbens. Received: 13 July 1995/Final version: 28 July 1996     

Effects of environmental conditioning on the development of nicotine sensitization: behavioral and neurochemical analysis

We have investigated the effects of environmental conditioning on the induction of nicotine sensitization of locomotion, stereotypy and nucleus accumbens dopamine release. Sprague-Dawley rats, some of which had been previously implanted with a microdialysis guide cannula over the nucleus accumbens, were sensitized with 5 days of repeated nicotine (0.6 mg/kg per day, SC) or saline injections (1 ml/kg per day). During nicotine treatment the drug administration was either paired with the microdialysis/activity monitor testing chamber (conditioned) (n=6) or with the animal's home cage (unconditioned) (n=6) and after 60 min the animal was returned to home cage and received a second injection of saline 15 min later. A third group received saline in the testing apparatus followed by nicotine in the home cage (pseudo-conditioned) (n=6). In the guide cannulated animals, 2 mm microdialysis probes were inserted after completing day 5 of treatment and all animals were tested for their response to nicotine (0.6 mg/kg, SC) on day 6. Both locomotor activity and nucleus accumbens dopamine release showed a larger response subsequent to nicotine challenge in the nicotine versus saline pretreated animals in the conditioned group, but not in the unconditioned group. In the pseudo-conditioned group there was an increase in the stereotypy responses to nicotine, however the locomotor and dopamine release responses were not significantly enhanced. The results from the conditioned group were confirmed in animals which were tested for behavioral activation and dopamine release simultaneously (n=5). These findings indicate that nicotine sensitization of locomotor activity and nucleus accumbens dopamine release (using a 5-day pretreatment protocol) is dependent on conditioning the animal to the testing environment during nicotine pretreatment.     

Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence

The development of nicotine dependence is related to stimulation of the dopamine projections to the nucleus accumbens. This review considers the evidence that the addictive potential of nicotine depends upon its ability to elicit burst firing of these neurones and, thereby, evoke a large and sustained increase in the dopamine concentration in the extracellular space between the cells. This dopamine, it is argued, stimulates extra-synaptic dopamine receptors that mediate the responses underling the development of dependence. The review also considers the hypothesis that the two principal subdivisions of the structure, the core and shell, play different roles in the development of dependence. It proposes that the projections to the shell signal the presence of a rewarding stimulus and facilitate the acquisition of behaviours related to obtaining the reward. In contrast, the projections to the core, which are sensitised selectively by repeated exposure to the drug, mediate the transition to habit or Pavlovian responding to cues repetitively paired with the positive reinforcing properties of nicotine. Nicotine withdrawal, following a period of chronic exposure, diminishes the activity of the dopamine projections to the accumbal shell, a response that is thought to be the neural correlate of the anhedonia experienced by many abstinent smokers. The data suggest that plasticity within the principal mesoaccumbens dopamine projections play a central role in the development of nicotine dependence and that the mechanisms underlying the plasticity may provide putative targets for the treatment of tobacco dependence.     

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.     

Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens

The extent to which repeated administration produces tolerance to nicotine-induced increases in dopamine transmission in the nucleus accumbens was investigated in rats. In vivo microdialysis was used to sample extracellular dopamine and metabolites after a nicotine challenge (0.35 mg/kg) in (1) naive rats, (2) acutely pretreated rats (1 prior nicotine injection), and (3) chronically pretreated rats (12-15 prior daily nicotine injections, 0.35 mg/kg per injection). Nicotine increased extracellular DA and its metabolites, and these increases were not significantly altered by either acute or chronic prior exposure to the drug. The failure to find evidence of tolerance is compatible with the hypothesis that the mesolimbic dopaminergic system is a substrate for the reinforcing properties of chronically administered nicotine.     

Differences between three rat strains in sensitivity to prepulse inhibition of an acoustic startle response: influence of apomorphine and phencyclidine pretreatment

In the present study we have examined the effect of varying three prepulse parameters (prepulse intensity, prepulse duration, prepulse-pulse interval) on the level of prepulse inhibition (PPI) in Lister hooded, Wistar and Sprague-Dawley rats. The results indicate that each strain showed subtle differences in sensitivity to the prepulse. For instance, Sprague-Dawley and Lister hooded rats showed PPI to prepulses of lower saliency compared to Wistar rats. Optimal prepulse parameters were selected for each strain to examine the effects of apomorphine and phencyclidine on PPI. Further inter-strain differences were noted; apomorphine (0.1-1 mg/kg) increased startle amplitude in Lister hooded and Sprague-Dawley, but not Wistar rats. PPI was attenuated in each strain by apomorphine pretreatment. In a final series of experiments, phencyclidine disrupted PPI in each strain, although with greater potency in the Lister hooded rats. A marked behavioural syndrome was seen at phencyclidine doses that disrupted PPI. It is concluded that rat strain and prepulse parameters are important variables in studying drug effects on PPI.