Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion‐induced dopamine dysregulation

We tested the hypothesis that increased dopaminergic sensitivity induced by olfactory bulbectomy is mediated by dysregulation of endocannabinoid signaling. Bilateral olfactory bulbectomy induces behavioral and neurobiological symptomatology related to increased dopaminergic sensitivity. Rats underwent olfactory bulbectomy or sham operations and were assessed 2 weeks later in two tests of hyperdopaminergic responsivity: locomotor response to novelty and locomotor sensitization to amphetamine. Amphetamine (1 mg/kg i.p.) was administered to rats once daily for 8 consecutive days to induce locomotor sensitization. URB597, an inhibitor of the anandamide hydrolyzing enzyme fatty‐acid amide hydrolase (FAAH), was administered daily (0.3 mg/kg i.p.) to sham and olfactory bulbectomized (OBX) rats to investigate the impact of FAAH inhibition on locomotor sensitization to amphetamine. Pharmacological specificity was evaluated with the CB₁ antagonist/inverse agonist rimonabant (1 mg/kg i.p). OBX rats exhibited heightened locomotor activity in response to exposure either to a novel open field or to amphetamine administration relative to sham‐operated rats. URB597 produced a CB₁‐mediated attenuation of amphetamine‐induced locomotor sensitization in sham‐operated rats. By contrast, URB597 failed to inhibit amphetamine sensitization in OBX rats. The present results demonstrate that enhanced endocannabinoid transmission attenuates development of amphetamine sensitization in intact animals but not in animals with OBX‐induced dopaminergic dysfunction. Our data collectively suggest that the endocannabinoid system is compromised in olfactory bulbectomized rats. Synapse 63:941–950, 2009. © 2009 Wiley‐Liss, Inc.     

Reward related neurotransmitter changes in a model of depression: An in vivo microdialysis study

Objectives: The self-medication hypothesis assumes that symptoms related to potential monoaminergic deficits in depression may be relieved by drug abuse. The aim of this study was to elucidate the neurotransmitter changes in a rat model of depression by measuring their levels in the nucleus accumbens shell, which is typically involved in the drug of abuse acquisition mechanism. Methods: Depression was modelled by the olfactory bulbectomy (OBX) in Wistar male rats. In vivo microdialysis was performed, starting from the baseline and following after a single methamphetamine injection and behaviour was monitored. The determination of neurotransmitters and their metabolites was performed by high-performance liquid chromatography combined with mass spectrometry. Results: OBX animals had lower basal levels of dopamine and serotonin and their metabolites. However, γ-aminobutyric acid (GABA) and glutamate levels were increased. The methamphetamine injection induced stronger dopamine and serotonin release in the OBX rats and lower release of glutamate in comparison with sham-operated rats; GABA levels did not differ significantly. Conclusions: This study provides an evidence of mesolimbic neurotransmitter changes in the rat model of depression which may elucidate mechanisms underlying intravenous self-administration studies in which OBX rats were demonstrated to have higher drug intake in comparison to intact controls.     

Long-term behavioral changes after cessation of chronic antidepressant treatment in olfactory bulbectomized rats.

BACKGROUND: Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical central nervous system changes, reminiscent of symptoms of human depression. Moreover, depression-like behavior after OBX can be reversed with antidepressant drugs. However, the lasting effects of these antidepressant drugs on behavior after cessation of treatment have never been studied. METHODS: Male rats received OBX or sham surgery. After recovery, animals received 14 consecutive daily doses of imipramine (20 mg/kg), escitalopram (5 and 10 mg/kg), or vehicle. Animals were tested in an open field after acute, sub-chronic, and chronic injections, as well as 1, 2, 6, and 10 weeks after cessation of treatment. RESULTS: The OBX-induced hyperactivity was normalized after sub-chronic administration of imipramine and escitalopram. Two weeks after treatment, activity of OBX animals was comparable to sham-treated animals, but after 6 weeks, OBX animals treated with both doses of escitalopram had returned to pre-treatment hyperactivity levels. The OBX animals treated with the high imipramine dose (20 mg/kg) retained activity levels comparable to sham-treated animals until 10 weeks after cessation of treatment. CONCLUSIONS: Chronic but not acute administration of imipramine and escitalopram normalizes OBX-induced hyperactivity. This effect continues for up to 10 weeks after cessation of treatment in a dose dependant manner.     

The opioid receptor antagonist naltrexone attenuates reinstatement of amphetamine drug-seeking in the rat

Amphetamine produces its rewarding effects by enhancing dopamine transmission in the mesocorticolimbic pathway. Several studies have also suggested the involvement of the endogenous opioid system in mediating the neurochemical and behavioural effects of amphetamine. The aim of this study was to investigate the effect of the unselective opioid receptor antagonist naltrexone (NTX) on reinstatement of amphetamine self-administration in the rat. Animals were trained to self-administer amphetamine under a fixed ratio 1 (FR1) schedule (0.1mg/kg/infusion). After receiving a stable drug intake the amphetamine was replaced with saline and the animals went through an extinction period. After reaching the extinction criteria, animals were pre-treated with NTX (0, 0.3, 1.0 and 3.0mg/kg, s.c.) 30min before giving a priming dose of amphetamine (0.5mg/kg s.c). To study the effects of NTX on operant behaviour, animals were trained to lever press for food pellets under a FR1 schedule of reinforcement. Results from the present study shows that a single injection of amphetamine reinstated self-administration behaviour. NTX (0.3 and 1.0mg/kg) significantly attenuated the amphetamine-induced reinstatement but NTX had no effect at any dose studied on food taking behaviour. These results show that NTX attenuates reinstatement of amphetamine self-administration in rats without suppressing general behaviour, implicating a functional role for opioid receptors in modulating amphetamine seeking behaviour.     

Permanent deficits in serotonergic functioning of olfactory bulbectomized rats: an in vivo microdialysis study.

BACKGROUND: Bilateral removal of the olfactory bulbs (OBX) in rats results in a complex constellation of behavioral, neurochemical, neuroendocrine, and neuroimmune alterations, many of which are also reported in patients with major depressive disorder (MDD). Drawing on clinical findings, there has been considerable interest in the role of serotonin in the mechanism of action of OBX. However, to date, there has been no report of direct measurement of serotonergic functioning of bulbectomized animals using microdialysis. The present study describes the effects of olfactory bulbectomy on functioning of the serotonergic system. METHODS: In vivo microdialysis was performed in conscious rats that underwent OBX or sham surgery. Alterations in the functioning of the serotonergic system were assessed by administration of fluvoxamine, fenfluramine, and 3-hydroxybenzylhydrazine (NSD-1015). Animals were also repeatedly tested in an open field. RESULTS: Bilateral removal of the olfactory bulbs decreased basal extracellular levels by decreasing the releasable pool of serotonin (5-HT) in the basolateral amygdala 2 weeks after surgery and in the dorsal hippocampus 2 weeks and 5 months after surgery. Olfactory bulbectomized animals showed a lower rate of 5-HT synthesis under basal conditions. However, the capacity of the system to synthesize 5-HT was not affected. Olfactory bulbectomized rats were hyperactive in the open field. This hyperactivity remained after successive testing, indicating permanent behavioral changes. CONCLUSIONS: This microdialysis study shows that OBX has profound and long-lasting effects on serotonergic functioning and on activity levels and is therefore considered an intriguing and promising animal model for affective processes in the brain.     

Olfactory bulbectomy increases food intake and hypothalamic neuropeptide Y in obesity-prone but not obesity-resistant rats

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.     

Chronic buspirone treatment normalizes open field behavior in olfactory bulbectomized rats: assessment with a quantitative autoradiographic evaluation of the 5-HT1A binding sites

The olfactory bulbectomized (OBX) rat model of depression has been widely used in studies on the behavioral and neurochemical aspects of human depression. The objective of the present investigation was to assess open field (OF) activity and the brain regional 5-HT(1A) receptor densities of the sham operated (SHX) and OBX rats treated with saline (SHX-SAL, OBX-SAL), and either 10 mg/(kg day) (SHX-B10, OBX-B10) or 20 mg/(kg day) (SHX-B20, OBX-B20) of buspirone for 14 days, delivered by a subcutaneous osmotic minipump. Adult Sprague-Dawley rats were used for this experiment. The surgery was performed on the first day of the experiment and the rats were randomly assigned to either the SHX or OBX groups. The results of the OF tests were organized in eight groups. Following 14 days of treatment and the final OF tests, the rats were sacrificed and the brains were used for 5-HT(1A) receptor autoradiography using [(3)H]8-OH-DPAT. The data showed that the OF activities, 14 days following surgery, in the OBX rats were significantly elevated when compared to the SHX rats. In the OBX rats, only the 14-day treatment with 20mg/(kgday) of buspirone normalized the elevated OF activity, the same dose shown previously to be needed for the normalization of the regional 5-HT synthesis. A significant reduction in the number of 5-HT(1A) receptor sites was found in most brain regions in the OBX rats when compared to the SHX rats. Data also show that the regional density of the 5-HT(1A) receptors in OBX-SAL treated rats is lower than that of the SHX-SAL rats. The 14-day treatment with either 10 or 20 mg/(kg day) of buspirone reduced the 5-HT(1A) receptors in most brain regions of the SHX rats, without an obvious dose-dependent effect of the buspirone. The comparison between the OBX-B20 and control (SHX-B20) rats suggests that the buspirone treatment resulted in a regional balance in the 5-HT(1A) sites. A dose dependent reduction in the density of 5-HT(1A) sites was observed in the sham rats, but the buspirone treatment had very little effect on the density of the 5-HT(1A) receptors in the OBX rats. From these observations, we conclude that the antidepressant effects of buspirone in the OBX rat model of depression are likely mediated through the fine tuning of the regional imbalance of 5-HT(1A) receptors with even increases of about 20% in some limbic regions. The data suggest that the neurochemical effects of antidepressants should be studied in animal models of depression rather than in normal rats.     

The effects of putative 5-hydroxytryptamine receptor active agents on D-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesions

Animals in which 5,7-dihydroxytryptamine (5,7-DHT) was bilaterally injected into the median forebrain bundle (MFB) and sham lesioned animals were allowed access to an apparatus which delivered, upon lever pressing, intravenous D-amphetamine injections. MFB lesioned rats achieved stable self-injections patterns and self-administered more drug per test session than controls. A number of agents known to either directly or indirectly affect 5-hydroxytryptamine (5-HT) receptor function were administered prior to D-amphetamine access. The responses to these pretreatments in lesioned vs non-lesioned rats were markedly different. Pretreatment with L-tryptophan reduced the number of D-amphetamine self-injections in sham lesioned rats but had no effect in MFB lesioned animals. Fluoxetine pretreatment, likewise, reduced responding in non-lesioned rats and had no observable effect in lesioned animals. Quipazine markedly reduced self-injection in control rats but was not evaluated in the lesioned group. The putative 5-HT antagonists utilized, cyproheptadine and methysergide, unpredictably reduced self-injection frequency of non-lesioned animals in a dose related manner. When MFB lesioned animals were pretreated with cyproheptadine, rapid bursts of lever pressing were observed and 3 of 6 animals thus treated died as a result (presumably amphetamine overdose). In the remaining animals, methysergide produced a similar marked increase in self-injection rate. While these data may suggest that, in some instances, non-serotonergic mechanisms are involved, for the most part it would appear that 5-HT containing neurons are of major import in some aspect of D-amphetamine self-administration.     

Differential effects of para-chlorophenylalanine on amphetamine-induced locomotion and stereotypy.

Amphetamine-induced locomotion and stereotypy were concurrently evaluated in order to determine if pretreatment with para-chlorophenylalanine (PCPA) (which is reported to facilitate some of the effects of amphetamine) results in a behavioral pattern similar to the augmentation previously reported to occur with repeated amphetamine administration. In the present study the behavioral response of rats was characterized after administration of saline or various doses of D-amphetamine (0.5, 2.5 and 4.0 mg/kg) for 48 h following PCPA (300 mg/kg) or vehicle injection. The predominant effects produced by the low dose of D-amphetamine (0.5 mg/kg), i.e., enhanced crossovers and rearings, were found to be significantly elevated after PCPA administration. This effect persisted (relative to PCPA controls) when the response of non-PCPA pretreated animals returned to corresponding control levels, thus indicating that the two drugs acted synergistically. However, while the locomotor component of the amphetamine response was potentiated by PCPA pretreatment, the more focused stereotypies produced by higher doses of amphetamine (2.5 and 4.0 mg/kg) were significantly displaced by enhanced crossovers and rearings. These differential effects of PCPA on amphetamine-induced locomotion and stereotypy are in contrast to the uniform pattern of behavioral augmentation resulting from repeated amphetamine administration. The relationship between the various behavioral components of the amphetamine response and the possible neurochemical mechanisms subserving their interaction are discussed.     

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.     

Similar effects of amphetamine and methylphenidate on the performance of complex operant tasks in rats

Methylphenidate and D-amphetamine are central nervous system stimulants that have been suggested to share certain behavioral and neurochemical effects. The current study was undertaken to determine whether methylphenidate and D-amphetamine have similar effects on the performance of a battery of complex operant tasks in rats. Thus, the effects of amphetamine (0.1-6.0 mg/kg, i.p.) and methylphenidate (1.12-18.0 mg/kg, i.p) on the performance of rats in three complex food-reinforced operant tasks were examined. The tasks (and the brain functions they are intended to model) included: (1) conditioned position responding (auditory/visual/position discrimination); (2) incremental repeated acquisition (learning); and (3) temporal response differentiation (time estimation). In addition, each of these tasks was paired with a progressive ratio task to assess drug effects on the rats' motivation to lever press for the food reinforcers used. Consistent with their effects in other behavioral paradigms, methylphenidate and D-amphetamine produced very similar patterns of disruption of the four tasks. Drug-induced changes in the endpoints of the progressive ratio task generally paralleled changes in the other three tasks, suggesting a major role for appetitive motivation in the effects of these agents. Several effects of these agents seen in the current study are consistent with their effects in children with attention-deficit-hyperactivity disorder. These data further validate the use of this battery of operant tasks for the characterization of pharmacological agents, and suggest that findings using these tasks may be predictive of what is seen in humans.     

Herpes virus-mediated preproenkephalin gene transfer in the ventral striatum mimics behavioral changes produced by olfactory bulbectomy in rats

The syndrome of behavioral, physiological, and neurochemical changes caused by ablation of the olfactory bulbs (OBX) in rats serves as a reliable and well-validated model of depression. Previous experiments have demonstrated that OBX leads to increased expression of the preproenkephalin (ENK) gene in the olfactory tubercle (OT) portion of the ventral striatum in rats. The aim of the present experiments was to investigate the role of OBX-induced ENK overexpression in the OT in the behavioral abnormalities exhibited by bulbectomized rats. A recombinant herpes virus carrying human preproENK cDNA was used to manipulate ENK gene expression in the OT of bulbectomized and sham-operated rats. Motivational deficits were assessed by the sucrose preference test, and 'agitation-like' behaviors were measured with the novel open field and footshock-induced freezing tests. ENK gene transfer in sham-operated rats mimicked some of the effects of OBX; it decreased freezing behavior in response to mild footshock and produced behavioral activation in the open field. In another experiment, virally mediated ENK gene transfer into the OT of intact rats decreased footshock-induced freezing, and this effect was reversed by naltrexone administration. PreproENK gene transfer into the OT did not produce analgesic effects in the tail-flick test. No effects on freezing behavior were observed following preproENK gene transfer into the frontal cortex. An additional experiment revealed that naltrexone administration attenuated the OBX-induced abnormality in freezing behavior. The results indicate that overexpression of the preproENK gene in the ventral striatum may mediate the 'agitation-like' behavior exhibited by bulbectomized rats.     

Comparative effects of amphetamine-like psychostimulants on rat hippocampal cell genesis at different developmental ages

The aim of this study was to compare the effects of amphetamine-like psychostimulant drugs (i.e., MDMA, methamphetamine, D-amphetamine) on rat hippocampal cell genesis at different developmental ages (i.e., early adolescence vs. young adulthood) to determine if there were periods of vulnerability to drug-induced brain changes. Although adolescence is a period of great vulnerability to the neurochemical effects of specific drugs of abuse, several reports suggest that adult rats are more susceptible than adolescents to the negative effects of these drugs. The main results suggest that the effects of these amphetamine drugs on cell genesis depend on the rat⿿s developmental age, with the young adult period being more sensitive than the early adolescent one. In particular, MDMA and methamphetamine, but not D-amphetamine impaired hippocampal cell genesis (i.e., cell proliferation and cell survival) in young adult rats. These effects were dependent on the accumulative dose administered, as they were only observed with the highest dose tested (12 pulses of 5 mg/kg over 4 days: 60 mg/kg total). The present results extend previous reports on adolescent insensitivity (i.e., better adaptation) to amphetamine-drugs and suggest for young adult rats certain degree of hippocampal damage that may mediate some of the addiction-like behaviors that depend on this brain region. Moreover, the present results, in line with previous data, suggest a possible role for the neuroplasticity marker BDNF and serotonin in regulating cell survival, as mBDNF protein regulation paralleled hippocampal cell survival and 5-HT_2C-receptor content in young adult rats treated with these psychostimulant drugs.     

Sub-chronic nandrolone treatment modifies neurochemical and behavioral effects of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in rats

Misuse of anabolic-androgenic steroids (AASs) is increasing, and appears to have much in common with the use of substances known to induce drug dependence. Moreover, persons who abuse AASs also tend to abuse other psychotropic drugs such as amphetamine or 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The aim of this study was to investigate whether nandrolone (5 x 5 or 5 x 20 mg/kg) pre-exposure modulates the acute neurochemical and behavioral effects of amphetamine (1mg/kg) and MDMA (5 mg/kg) in rats. Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from samples collected from the nucleus accumbens (NAc) by in vivo microdialysis. The behavior of the animals was recorded on videotapes, from which it was later rated. Our results demonstrate that sub-chronic treatments with supraphysiological doses of nandrolone attenuate dose-dependently the increase in extracellular DA concentration evoked by amphetamine or MDMA. The lower dose of nandrolone attenuated MDMA-induced increase in 5-HT-levels, while the higher dose potentiated it. Analysis of the behavioral data suggests that effects of the amphetamine and MDMA are dose-dependently attenuated by AAS-treatment, paralleling DA results. In conclusion, the results of this study show that AAS-pre-treatment is able to modulate the reward-related neurochemical and behavioral effects of amphetamine and MDMA.     

Brain output dysregulation induced by olfactory bulbectomy: an approximation in the rat of major depressive disorder in humans?

Mounting evidence indicates that the emotional, cognitive, neurovegetative and behavioral symptoms of patients with major depressive disorder are due to abnormal neurochemical substrates in the brain. Although the specific neurochemical abnormalities responsible have not been identified, the presenting symptoms of major depression are consistent with a disruption of normal neural communications between the limbic system and hypothalamus. Following removal of the olfactory bulbs, rats display a syndrome of behavioral deficits that also reflect a disruption of the limbic-hypothalamic axis. Moreover, the bulbectomy induced deficits are selectively reduced by the chronic administration of the same drugs that alleviate the symptoms of depression when given chronically to the patients. In addition to this pharmacological similarity, there are also numerous behavioral parallels between bulbectomized rats and major depression patients. The bulbectomized rat provides a good model in which to study antidepressant drugs and also may provide neurochemical and neuroanatomical data that are relevant to understanding the biological substrates of emotion and the causes of depression in humans.     

Experimental approach to individual vulnerability to psychostimulant addiction

Vulnerability to the development of drug-intake has been studied by using the acquisition of intravenous amphetamine self-administration in the rat. In a series of neurobiological experiments we provoked imbalances in the functioning of the dopaminergic (DA) network by performing lesions of the DA cell bodies in the ventral tegmental area, DA terminals in the amygdala or median raphe nucleus. These imbalances which resulted in enhanced DA transmission ratio between the nucleus accumbens and the prefrontal cortex led to an increase in the rapidity of self-administration acquisition. With a psychobiological approach, we showed that individual differences in vulnerability to develop self-administration in rats of the same strain were correlated with locomotor responses to stress and to an acute injection of amphetamine. Moreover, activation of DA transmission by repeated amphetamine injections changed animals resistant to drug-intake into vulnerable ones. It is suggested that some inherited or acquired factors, at least in part by affecting the activity of DA network, can predispose individuals to drug abuse.     

Rat strain differences in nicotine self-administration using an unlimited access paradigm

An effective animal model for elucidating the neurobiological basis of human smoking should simulate important aspects of this behavior. Therefore, a 23 h unlimited access nicotine self-administration model was used to compare inbred Lewis rats, which have a propensity to self-administer drugs of abuse, to inbred Fisher 344 rats and to the outbred Holtzman strain. Using this unlimited access model, 88.8% of Lewis vs. 57.1% of Holtzman rats achieved maintenance self-administration at a fixed ratio 1 (FR 1) at 0.03 mg/kg IV nicotine (P<0.05). In contrast, Fisher rats did not acquire self-administration under these conditions. Of the Lewis and Holtzman rats that achieved maintenance self-administration on an FR 1 schedule, a greater percentage of Lewis rats acquired nicotine self-administration at FR 2 (P<0.05) and progressed to FR 4 (P<0.05). Using naïve cohorts in a progressive dose reduction study, 83.3% of Lewis rats achieved maintenance at 0.0075 mg/kg nicotine as compared to 31.8% of Holtzman rats (P<0.05). Furthermore, only Lewis rats showed differences in active vs. inactive bar presses during maintenance at sequential dose reductions (P<0.001). Thus, in this unlimited access model, inbred Lewis rats will more reliably acquire nicotine self-administration than outbred Holtzman rats. Moreover, Lewis rats showed a significantly higher likelihood of continuing to self-administer nicotine in face of both increasing work requirements and decreasing drug reinforcement. Therefore, it is likely that Lewis rats would be genetically susceptible to nicotine addiction.     

Activation of group II mGlu receptors blocks the enhanced drug taking induced by previous exposure to amphetamine

Repeated exposure to amphetamine (AMPH) leads to the development of behavioural sensitization that can be demonstrated in rats as enhanced locomotor responding to and self-administration of the drug. Glutamate systems are known to participate in the induction and expression of sensitization by psychostimulants. Group II metabotropic glutamate receptors (mGluRs), because they negatively regulate both vesicular and nonvesicular glutamate release, are thus well positioned to gate its expression. Here we report that the expression of locomotor sensitization by AMPH is completely prevented by a systemic injection of the selective group II mGluR agonist LY379268 at a dose that produced no effects when administered alone. The activation of group II mGluRs in AMPH-sensitized rats also reduced the enhanced overflow of both dopamine and glutamate normally observed in the nucleus accumbens, a brain region critical for the generation of locomotor and drug self-administration behaviours. To directly determine the effect of group II mGluR activation on enhanced drug self-administration, AMPH-sensitized rats were allowed to self-administer a mixture of LY379268 and AMPH. These rats continued to self-administer but did not exhibit the enhanced work output and drug intake observed in AMPH-sensitized rats self-administering AMPH alone. Thus, activating group II mGluRs prevents the expression of different manifestations of AMPH sensitization including enhanced self-administration of the drug. These receptors may represent a potentially important target for therapeutic intervention directed at drugs of abuse.     

Previous Exposure to Nicotine Enhances the Incentive Motivational Effects of Amphetamine via Nicotine-Associated Contextual Stimuli

The effect of nicotine exposure on the subsequent self-administration of amphetamine, extinction of this behavior, and amphetamine-induced reinstatement of drug seeking was assessed with particular attention to the contribution of contextual stimuli paired or unpaired with nicotine during exposure. Rats were exposed to five injections, one injection every third day, of either saline or nicotine (0.4?mg/kg, IP, base) in three experiments. In one, exposure injections were administered in the home cage. In another, they were administered in the self-administration chambers with the levers retracted. In a third, nicotine was administered either explicitly paired or unpaired with the self-administration chambers using a discrimination learning procedure. Starting 13-15 days later, rats were trained to self-administer amphetamine (100?μg/kg/infusion, IV), tested under a progressive ratio (PR) schedule for 6 days, subjected to up to 20 days of extinction training, and were then tested for reinstatement by non-contingent injections of amphetamine (0, 0.2, 0.4, and 0.75?mg/kg, IP). Nicotine enhanced the self-administration of amphetamine under the PR schedule and amphetamine-induced reinstatement but only when rats were tested in the chamber in which they were previously exposed to nicotine. These effects were not observed in rats exposed to nicotine in the home cage or in rats exposed to nicotine explicitly unpaired with the self-administration chambers. Exposure to nicotine also rendered rats resistant to extinction when amphetamine was withheld but this effect was observed regardless of nicotine exposure context, suggesting a separate consequence of drug exposure. Together, these results show that previous exposure to nicotine can enhance the incentive motivational effects of other psychostimulants like amphetamine and indicate a critical role for nicotine-associated contextual stimuli in the mediation of this effect. These findings have important implications for the treatment of addictions in humans.     

Correlation of dose-dependent effects of acute amphetamine administration on behavior and local cerebral metabolism in rats

Rates of local cerebral glucose utilization were measured by means of the quantitative autoradiographic 2-[14C]deoxyglucose technique in conscious rats following the acute administration of D-amphetamine (0.2-5.0 mg/kg, i.v.). Changes in locomotor and stereotypic behavior in similarly treated rats were examined as well. Administration of low doses (0.2 and 0.5 mg/kg) of amphetamine resulted in increased locomotor activity, accompanied by elevations in glucose utilization limited mainly to the nucleus accumbens. A moderate dose of D-amphetamine (1.0 mg/kg) produced locomotion and stereotypic sniffing. Metabolic activity at this dose was increased in the nucleus accumbens, throughout neocortical areas, and in components of the extrapyramidal system. A high dose of amphetamine (5.0 mg/kg) produced stereotypic gnawing and licking and was associated with significant increases in glucose utilization in the extrapyramidal system, most prominently in the subthalamic nucleus. These data demonstrate that the acute administration of D-amphetamine produces effects on local cerebral glucose utilization and on behavior that differ with dose. The results also show a strong coupling between locomotion and the level of metabolic activity in the nucleus accumbens and demonstrate that the different forms of stereotypic behavior elicited by high and moderate doses of amphetamine are correlated with distinct patterns of distribution of local cerebral glucose utilization, indicating mediation by different neuronal circuits.