The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances.

RATIONALE: Toluene, a widely abused solvent with demonstrated addictive potential in humans, hasbeen reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergicneurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has beenshown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotorhyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. OBJECTIVES: The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. RESULTS: Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self-stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. CONCLUSIONS: These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure.

Neurobiological Bases of Cue- and Nicotine-induced Reinstatement of Nicotine Seeking: Implications for the Development of Smoking Cessation Medications.

A better understanding of the neurobiological factors that contribute to relapse to smoking is needed for the development of efficacious smoking cessation medications. Reinstatement procedures allow the preclinical assessment of several factors that contribute to relapse in humans, including re-exposure to nicotine via tobacco smoking and the presentation of stimuli that were previously associated with nicotine administration (i.e., conditioned stimuli). This review provides an integrated discussion of the results of animal studies that used reinstatement procedures to assess the efficacy of pharmacologically targeting various neurotransmitter systems in attenuating the cue- and nicotine-induced reinstatement of nicotine seeking. The results of these animal studies have increased our understanding of the neurobiological processes that mediate the conditioned effects of stimuli that trigger reinstatement to nicotine seeking. Thus, these findings provide important insights into the neurobiological substrates that modulate relapse to tobacco smoking in humans and the ongoing search for novel efficacious smoking cessation medications.

Null mutation of the ß2 nicotinic acetylcholine receptor subunit attenuates nicotine withdrawal-induced anhedonia in mice.

The anhedonic signs of nicotine withdrawal are predictive of smoking relapse rates in humans. Identification of the neurobiological substrates that mediate anhedonia will provide insights into the genetic variations that underlie individual responses to smoking cessation and relapse. The present study assessed the role of ß2 nicotinic acetylcholine receptor (nACh receptor) subunits in nicotine withdrawal-induced anhedonia using ß2 nACh receptor subunit knockout (ß2(-/-)) and wildtype (ß2(+/+)) mice. Anhedonia was assessed with brain reward thresholds, defined as the current intensity that supports operant behavior in the discrete-trial current-intensity intracranial self-stimulation procedure. Nicotine was delivered chronically through osmotic minipumps for 28 days (40 mg/kg/day, base), and withdrawal was induced by either administering the broad-spectrum nicotinic receptor antagonist mecamylamine (i.e., antagonist-precipitated withdrawal) in mice chronically treated with nicotine or terminating chronic nicotine administration (i.e., spontaneous withdrawal). Mecamylamine (6 mg/kg, salt) significantly elevated brain reward thresholds in nicotine-treated ß2(+/+) mice compared with saline-treated ß2(+/+) mice and nicotine-treated ß2(-/-) mice. Spontaneous nicotine withdrawal similarly resulted in significant elevations in thresholds in nicotine-withdrawing ß2(+/+) mice compared with saline-treated ß2(+/+) and nicotine-treated ß2(-/-) mice, which remained at baseline levels. These results showed that precipitated and spontaneous nicotine withdrawal-induced anhedonia was attenuated in ß2(-/-) mice. The reduced expression of anhedonic signs during nicotine withdrawal in ß2(-/-) mice may have resulted from the lack of neuroadaptations in ß2 nACh receptor subunit expression and function that may have occurred during either nicotine exposure or nicotine withdrawal in wildtype mice. In conclusion, individuals with genetic variations that result in diminished function of the ß2 nACh receptor subunit may experience less anhedonia during nicotine withdrawal, which may facilitate smoking cessation.

Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation.

Tobacco smoking continues to be a major global health hazard despite significant public awareness of its harmful consequences. Although several treatment options are currently available for smoking cessation, these medications are effective in only a small subset of smokers, and relapse rates continue to be high. Therefore, a better understanding of the neurobiological mechanisms that mediate tobacco dependence is essential for the development of effective smoking cessation medications. Nicotine is the primary psychoactive component of tobacco that drives the harmful tobacco smoking habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs) in the brain, resulting in the release of a wide range of neurotransmitters, including glutamate and γ-aminobutyric acid (GABA). This review article focuses on the role of the excitatory glutamate system and inhibitory GABA system in nicotine dependence. Accumulating evidence suggests that blockade of glutamatergic transmission or facilitation of GABAergic transmission attenuates the positive reinforcing and incentive motivational aspects of nicotine, inhibits the reward-enhancing and conditioned rewarding effects of nicotine, and blocks nicotine-seeking behavior. Chronic nicotine exposure produced long-term neuroadaptations that contribute to nicotine withdrawal, but the role of GABA and glutamate transmission in nicotine withdrawal is less understood. Overall, the findings presented in this review provide strong converging evidence for the potential effectiveness of glutamatergic and GABAergic medications in nicotine dependence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Unraveling the neurobiology of nicotine dependence using genetically engineered mice.

This review article provides an overview of recent studies of nicotine dependence and withdrawal that used genetically engineered mice. Major progress has been made in recent years with mutant mice that have knockout and gain-of-function of specific neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. Nicotine exerts its actions by binding to neuronal nAChRs that consist of five subunits. The different nAChR subunits that combine to compose a receptor determine the distinct pharmacological and kinetic properties of the specific nAChR. Recent findings in genetically engineered mice have indicated that while α4-containing and ß2-containing nAChRs are involved in the acquisition of nicotine self-administration and initial stages of nicotine dependence, α7 homomeric nAChRs appear to be involved in the later stages of nicotine dependence. In the medial habenula, α5-containing, α3-containing, and ß4-containing nAChRs were shown to be crucially important in the regulation of the aversive aspects of nicotine. Studies of the involvement of α6 nAChR subunits in nicotine dependence have only recently emerged. The use of genetically engineered mice continues to vastly improve our understanding of the neurobiology of nicotine dependence and withdrawal.

Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice.

Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances, including motor incoordination and cognitive impairment. Toluene alters the function of a large number of receptors and ion channels. Blockade of N-methyl-d-aspartate (NMDA) receptors has been suggested to play a critical role in toluene-induced behavioral manifestations. The present study determined the effects of various toluene doses on motor coordination, recognition memory, body temperature, and intracranial self-stimulation (ICSS) thresholds in mice. Additionally, the effects of sarcosine on the behavioral and physiological effects induced by toluene were evaluated. Sarcosine may reverse toluene-induced behavioral manifestations by acting as an NMDA receptor co-agonist and by inhibiting the effects of the type I glycine transporter (GlyT1). Mice were treated with toluene alone or combined with sarcosine pretreatment and assessed for rotarod performance, object recognition memory, rectal temperature, and ICSS thresholds. Toluene dose-dependently induced motor incoordination, recognition memory impairment, and hypothermia and lowered ICSS thresholds. Sarcosine pretreatment reversed toluene-induced changes in rotarod performance, novel object recognition, and rectal temperature but not ICSS thresholds. These findings suggest that the sarcosine-induced potentiation of NMDA receptors may reverse motor incoordination, memory impairment, and hypothermia but not the enhancement of brain stimulation reward function associated with toluene exposure. Sarcosine may be a promising compound to prevent acute toluene intoxications by occupational or intentional exposure.

Role of α7- and ß4-containing nicotinic acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies in knockout mice.

To assess which nicotinic acetylcholine receptors (nAChRs) are involved in the aversive aspects of nicotine withdrawal, brain reward function and the somatic signs of nicotine withdrawal were assessed in mice that lack α7 and ß4 nAChR subunits. Brain reward function was assessed with the intracranial self-stimulation (ICSS) procedure, in which elevations in ICSS thresholds reflect an anhedonic mood state. At 3-6 h of spontaneous nicotine/saline withdrawal, thresholds were elevated in nicotine-withdrawing α7(+/+) and ß4(+/+), but not α7(-/-) or ß4(-/-), mice compared with saline-withdrawing mice, indicating a delay in the onset of withdrawal in the knockout mice. From 8 to 100 h of withdrawal, thresholds in α7(+/+) and α7(-/-) mice were equally elevated, whereas thresholds in ß4(+/+) and ß4(-/-) mice returned to baseline levels. Somatic signs were attenuated in nicotine-withdrawing ß4(-/-), but not α7(-/-), mice. Administration of a low dose of the nAChR antagonist mecamylamine induced threshold elevations in α7(-/-), but not α7(+/+), mice, whereas the highest dose tested only elevated thresholds in α7(+/+) mice. Mecamylamine-induced threshold elevations were similar in ß4(-/-) and ß4(+/+) mice. In conclusion, null mutation of the α7 and ß4 nAChR subunits resulted in a delayed onset of the anhedonic aspects of the spontaneous nicotine withdrawal syndrome. Previous findings of attenuated somatic signs of nicotine withdrawal in ß4(-/-), but not α7(-/-), mice were confirmed in the present study, indicating an important role for ß4-containing nAChRs in the somatic signs of nicotine withdrawal. The mecamylamine-precipitated withdrawal data suggest that compensatory adaptations may occur in constitutive α7(-/-) mice or that mecamylamine may interact with other receptors besides nAChRs in these mice. In summary, the present results indicate an important role for α7 and ß4-containing nAChRs in the anhedonic or somatic signs of nicotine withdrawal.

Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal.

RATIONALE: The involvement of metabotropic glutamate 5 (mGlu5) receptors has been suggested in the reinforcing effects of psychostimulants. However, little is known about the role of these receptors in psychostimulant withdrawal. OBJECTIVES: The role of mGlu5 receptors was assessed in the anhedonic and somatic aspects of psychostimulant withdrawal. METHODS: Anhedonia was assessed with the discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure after the termination of cocaine (180 mg kg(-1) day(-1), salt, 3 days, i.p.) or nicotine (40 mg kg(-1) day(-1), base, 28 days, s.c.) administration via osmotic minipumps in mGlu5 receptor knockout (mGluR5(-/-)) and wild-type (mGluR5(+/+)) mice. Somatic signs were assessed during nicotine withdrawal. The effects of the nicotinic acetylcholine receptor antagonist mecamylamine on ICSS thresholds were assessed during chronic nicotine administration. RESULTS: Nicotine-treated mGluR5(+/+) and mGluR5(-/-) mice demonstrated similar threshold elevations during mecamylamine-precipitated withdrawal compared with their saline-treated counterparts. During spontaneous nicotine and cocaine withdrawal, thresholds in drug-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice were elevated up to 72 h of nicotine/cocaine withdrawal and then returned to baseline, indicating attenuation of withdrawal-induced anhedonia in mGluR5(-/-) mice. Nicotine-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice showed increases in somatic signs compared with saline-treated counterparts. CONCLUSIONS: mGlu5 receptor null mutation attenuates the anhedonic and somatic effects of psychostimulant withdrawal. This attenuated withdrawal in mGluR5(-/-) mice may result from the lack of drug-induced adaptations in mGlu5 receptor function that may occur in mGluR5(+/+) mice with chronic drug administration. Thus, these results suggest the involvement of mGlu5 receptors in psychostimulant dependence and the mediation of the anhedonic and somatic signs of psychostimulant withdrawal.

Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice.

Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3-100 h post-pump removal. Anxiety-like behavior was assessed in the light-dark box 24h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light-dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure.

Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice.

The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.

Effects of genetic background and environmental novelty on wheel running as a rewarding behaviour in mice.

Recent studies suggest running wheel activity to be naturally rewarding and reinforcing; considering the shared neuro-behavioural characteristics with drug-induced reward situations, wheel running behaviour gains interest as a tool to study mechanisms underlying reward-sensitivity. Previously, we showed that wheel running has the potential to disrupt the daily organization of home cage behaviour in female C57BL/6 [de Visser L, van den Bos R, Spruijt BM. Automated home cage observations as a tool to measure the effects of wheel running on cage floor locomotion. Behav Brain Res 2005;160:382-8]. In the present study, we investigated the effects of novelty-induced stress on wheel running and its impact on home cage behaviour in male C57BL/6 and DBA/2 mice. Our aim was to determine whether wheel running may be used as a tool to study both genetic and environmentally induced differences in sensitivity to rewarding behaviour in mice. One group of male mice was placed in an automated home cage observation system for 2 weeks with a wheel integrated in the cage. A second group of mice was allowed to habituate to this cage for 1 week before a running wheel was introduced. Results showed a pronounced sensitising effect of novelty on the level of wheel running in C57Bl/6 mice but not in DBA mice. Overall levels of wheel running were higher in DBA/2 mice. Furthermore, wheel running affected circadian rhythmicity in DBA/2 mice but not in C57BL/6 mice. From these findings we tentatively suggest that wheel running behaviour could serve as a tool to study the interaction between genetic and environmental factors in sensitivity to rewarding behaviour in mice. As it is displayed spontaneously and easy to monitor, wheel running may be well suitable to be included in high-throughput phenotyping assays.