Intracranial pressure waveform in patients with essential hypertension.

Background: There is a strong association between hypertension and cerebrovascular diseases, but most of the mechanistic bases to justify this correlation remains misunderstood. Objective: To evaluate intracranial pressure waveform in long-term essential hypertensive patients with a non-invasive device, brain4care (b4c). Methods: Cross-sectional study in patients with hypertension. Office blood pressure was measured with an automatic oscillometric device. Intracranial pressure evaluation was acquired through a strain sensor that could detect and monitor nanometric skull bone displacements for each cardiac cycle. Under normal physiological conditions, P1 is greater than P2, and the normal P2/P1 ratio is <1. Time to peak (TTP) is the measurement in seconds of the beginning of waveform inscription until P1 and normal values are <0.20 s. The cut-off points ≥1.2 and ≥0.25 s were used to define intracranial hypertension (ICHT). Results: 391 consecutive patients were evaluated (75% female, mean age 64.3 ± 12.0 years). Mean value of P2/P1 ratio was 1.18 ± 0.25 and TTP 0.18 ± 0.63 s The obtained P2/P1 ratios were divided in three categories according to results of previous studies of normalcy (<1.0), intracranial compliance disturbance (1.0-1.19) and ICHT (≥1.2). Normal intracranial pressure was observed in 21.7% of patients, intracranial compliance disturbance in 32.7% and intracranial hypertension in 45.6%. Females showed a higher prevalence of ICHT (50.3%). Conclusion: The prevalence of 45.6% intra-cranial hypertension in patients with long-term hypertension, particularly in women, and in those over 65 years old, emphasizes the importance of evaluate intracranial pressure behaviour in these patients and raise a question concerning the real ability of cerebral autoregulation and vascular barriers to protect the brain.

Hypertension evaluated in the public and private Brazilian health system hypertension in public and private service.

Introduction: Hypertension (HT) remains the leading cause of death worldwide. In Brazil it is estimated that 35% of the adult population has HT and that about 20% of these have blood pressure values within the targets recommended for the reduction of cardiovascular risk. There are some data that point to different control rates in patients treated by cardiologists in public and private referral center and this is an important point to be investigated and discussed. Objective: To compare sociodemographic characteristics, body mass index (BMI), antihypertensive (AH) drugs, blood pressure (BP) and control rate in public (PURC) and private (PRRC) referral centers. Methodology: A cross-sectional multicenter study that analyzed data from hypertensive patients assisted by the PURC (one in Midwest Region and other in Northeast region) and PRRC (same distribution). Variables analyzed: sex, age, BMI, classes, number of AH used and mean values of systolic and diastolic BP by office measurement and home blood pressure measurement (HBPM). Uncontrolled hypertension (HT) phenotypes and BP control rates were assessed. Descriptive statistics and χ2 tests or unpaired t-tests were performed. A significance level of p < 0.05 was considered. Results: A predominantly female (58.9%) sample of 2.956 patients and a higher prevalence of obesity in PURC (p < 0.001) and overweight in PRRC (p < 0.001). The mean AH used was 2.9 ± 1.5 for PURC and 1.4 ± 0.7 for PRRC (p < 0.001). Mean systolic and diastolic BP values were higher in PURC as were rates of uncontrolled HT of 67.8% and 47.6% (p < 0.001) by office measurement and 60.4% and 35.3% (p < 0.001) by HBPM in PURC and PRRC, respectively. Conclusion: Patients with HT had a higher prevalence of obesity in the PURC and used almost twice as many AH drugs. BP control rates are worse in the PURC, on average 15.3 mmHg and 12.1 mmHg higher than in the PRRC by office measurement.

Neuroadaptive changes and behavioral effects after a sensitization regime of MDPV.

3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with cocaine-like properties. In a previous work, we exposed adolescent mice to MDPV, finding sensitization to cocaine effects, and a higher vulnerability to cocaine abuse in adulthood. Here we sought to determine if such MDPV schedule induces additional behavioral-neuronal changes that could explain such results. After MDPV treatment (1.5 mg kg-1, twice daily, 7 days), mice were behaviorally tested. Also, we investigated protein changes in various brain regions. MDPV induced aggressiveness and anxiety, but also contributed to a faster habituation to the open field. This feature co-occurred with an induction of ΔFosB in the orbitofrontal cortex that was higher than its expression in the ventral striatum. Early after treatment, D2R:D1R ratio pointed to a preponderance of D1R but, upon withdrawal, the ratio recovered. Increased expression of Arc, CDK5 and TH, and decrease in DAT protein levels persisted longer after withdrawal, pointing to a neuroplastic lasting effect similar to that involved in cocaine addiction. The implication of the hyperdopaminergic condition in the MDPV-induced aggressiveness cannot be ruled out. We also found an initial oxidative effect of MDPV, without glial activation. Moreover, although initially the dopaminergic signal induced by MDPV resulted in increased ΔFosB, we did not observe any change in NFκB or GluA2 expression. Finally, the changes observed after MDPV treatment could not be explained according to the autoregulatory loop between ΔFosB and the epigenetic repressor G9a described for cocaine. This provides new knowledge about the neuroadaptive changes involved in the vulnerability to psychostimulant addiction.

Exposure of adolescent mice to 3,4-methylenedioxypyrovalerone increases the psychostimulant, rewarding and reinforcing effects of cocaine in adulthood.

BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with powerful psychostimulant effects. It selectively inhibits the dopamine transporter (DAT) and is 10-50-fold more potent as a DAT blocker than cocaine, suggesting a high abuse liability. The main objective of the present study was to assess the consequences of an early (adolescence) MDPV exposure on the psychostimulant, rewarding and reinforcing effects induced by cocaine in adult mice. EXPERIMENTAL APPROACH: Twenty-one days after MDPV pretreatment (1.5 mg·kg-1 , s.c., twice daily for 7 days), adult mice were tested with cocaine, using locomotor activity, conditioned place preference and self-administration (SA) paradigms. In parallel, dopamine D2 receptor density and the expression of c-Fos and ΔFosB in the striatum were determined. KEY RESULTS: MDPV treatment enhanced the psychostimulant and conditioning effects of cocaine. Acquisition of cocaine SA was unchanged in mice pretreated with MDPV, whereas the breaking point achieved under a progressive ratio programme and reinstatement after extinction were higher in this group of mice. MDPV decreased D2 receptor density but increased ΔFosB expression three-fold. As expected, acute cocaine increased c-Fos expression, but MDPV pretreatment negatively influenced its expression. ΔFosB accumulation declined during MDPV withdrawal, although it remained elevated in adult mice when tested for cocaine effects. CONCLUSION AND IMPLICATIONS: MDPV exposure during adolescence induced long-lasting adaptive changes related to enhanced responsiveness to cocaine in the adult mice that seems to lead to a higher vulnerability to cocaine abuse. This particular behaviour correlated with increased expression of ΔFosB.

Sex differences in the long-lasting consequences of adolescent ethanol exposure for the rewarding effects of cocaine in mice.

RATIONALE: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. OBJECTIVES: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. METHODS: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. RESULTS: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. CONCLUSIONS: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex.

Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review.

BACKGROUND: In recent years, growing concerns about the effects of cannabis use on mental health have renewed interest in cannabis research. In particular, there has been a marked increase in the number of neuroimaging studies of the effects of cannabinoids. We conducted a systematic review to assess the impact of acute cannabis exposure on brain function in humans and in experimental animals. METHODS: Papers published until June 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only pharmacological challenge studies involving the acute experimental administration of cannabinoids in occasional or naïve cannabis users, and naïve animals were considered. RESULTS: Two hundred and twenty-four studies were identified, of which 45 met our inclusion criteria. Twenty-four studies were in humans and 21 in animals. Most comprised studies of the acute effects of cannabinoids on brain functioning in the context of either resting state activity or activation during cognitive paradigms. In general, THC and CBD had opposite neurophysiological effects. There were also a smaller number of neurochemical imaging studies: overall, these did not support a central role for increased dopaminergic activity in THC-induced psychosis. There was a considerable degree of methodological heterogeneity in the imaging literature reviewed. CONCLUSION: Functional neuroimaging studies have provided extensive evidence for the acute modulation of brain function by cannabinoids, but further studies are needed in order to understand the neural mechanisms underlying these effects. Future studies should also consider the need for more standardised methodology and the replication of findings.

The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor.

Tetrabenazine (TBZ) is a reversible inhibitor of vesicular monoamine storage that is used to treat Huntington's disease. TBZ preferentially depletes striatal dopamine (DA), and patients being treated with TBZ often experience parkinsonian side effects. The present studies were conducted to investigate the ability of TBZ to induce tremulous jaw movements (TJMs), which are a rodent model of parkinsonian tremor, and to determine if interference with adenosine A2A receptor transmission can attenuate TJMs and other motor effects of TBZ. In rats, TBZ (0.25-2.0mg/kg) significantly induced TJMs, which primarily occurred in the 3.0-7.5-Hz frequency range. The adenosine A2A antagonist MSX-3 (1.25-10.0mg/kg) significantly attenuated the TJMs induced by 2.0mg/kg TBZ in rats, and also significantly reduced the display of catalepsy and locomotor suppression induced by TBZ. In mice, TBZ (2.5-10.0mg/kg) dose dependently induced TJMs, and adenosine A2A receptor knockout mice showed significantly fewer TJMs compared to wild-type controls. MSX-3 (2.5-10.0mg/kg) also significantly reduced TBZ-induced TJMs in CD1 mice. To provide a cellular marker of these pharmacological conditions, we examined c-Fos expression in the ventrolateral neostriatum (VLS). TBZ (2.0mg/kg) significantly increased the number of c-Fos-positive cells in the VLS, which is indicative of reduced DA D2 receptor transmission, and 10.0mg/kg MSX-3 significantly attenuated the TBZ-induced c-Fos expression. These results indicate that TBZ induces tremor as measured by the TJM model, and that pharmacological antagonism and genetic deletion of adenosine A2A receptors are capable of attenuating this oral tremor.

Effect of subtype-selective adenosine receptor antagonists on basal or haloperidol-regulated striatal function: studies of exploratory locomotion and c-Fos immunoreactivity in outbred and A(2A)R KO mice.

Behavioral activation is regulated by dopamine (DA) in striatal areas. At low doses, while typical antipsychotic drugs produce psychomotor slowing, psychostimulants promote exploration. Minor stimulants such as caffeine, which act as adenosine receptor antagonists, can also potentiate behavioral activation. Striatal areas are rich in adenosine and DA receptors, and adenosine A2A receptors are mainly expressed in the striatum where they are co-localized with DA D2 receptors. Adenosine antagonists with different receptor-selectivity profiles were used to study spontaneous or haloperidol-impaired exploration and c-Fos expression in different striatal areas. Because A2A antagonists were expected to be more selective for reversing the effects of the D2 antagonist haloperidol, A2A receptor knockout (A2ARKO) mice were also assessed. CD1 and A2ARKO male mice were tested in an open field and in a running wheel. Only the A1/A2A receptor antagonist theophylline (5.0-15.0 mg/kg) and the A2A antagonist MSX-3 (2.0 mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0-15.0 mg/kg), and MSX-3 (1.0-3.0 mg/kg) reversed haloperidol-induced suppression of locomotion. The A1 antagonist CPT was only marginally effective in reversing the effects of haloperidol. Although adenosine antagonists did not affect c-Fos expression on their own, theophylline and MSX-3, but not CPT, attenuated haloperidol induction of c-Fos expression. A2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1 mg/kg) in the open field and in the running wheel. A2A receptors are important for regulating behavioral activation, and interact with D2 receptors in striatal areas to regulate neural processes involved in exploratory activity.

Paclitaxel-induced neuropathic pain is age dependent and devolves on glial response.

BACKGROUND: Paclitaxel is an antimitotic antitumour drug highly effective against a broad range of cancers considered refractory to conventional chemotherapy. One of the main serious side effects of paclitaxel treatment is the induction of peripheral neuropathic pain that often diminishes the patient's quality of life. In this study, we evaluated the severity of the neuropathy induced by paclitaxel and the inflammatory reaction in the dorsal horn of the spinal cord in young, adult and aged male CD1 mice. METHOD: Hyperalgesia to noxious thermal stimulus and allodynia to non-noxious mechanical stimulus were evaluated using the plantar test and the von Frey filament model, respectively. Spinal cord microglia and astrocytes expression was assessed using Iba1 and glial fibrillary acidic protein immunofluorescence staining, respectively. RESULTS: All groups of mice showed a higher nociceptive reaction to thermal noxious (hyperalgesia) and mechanical non-noxious (allodynia) stimuli after paclitaxel treatment. However, these signs of neuropathy were enhanced in young mice followed by aged animals. Additionally, paclitaxel evoked a marked microglial and astrocytic response in the spinal cord of young and aged mice, whereas this enhanced reactivity was less important in adult mice. Indeed, the most severe glial activation observed in juvenile animals correlated well with major signs of neuropathy in this group of age. CONCLUSION: Our results demonstrate that paclitaxel-induced neuropathy in mice is an age-dependent phenomenon whose severity devolves on glial response.

Adenosine A2A receptor antagonism and genetic deletion attenuate the effects of dopamine D2 antagonism on effort-based decision making in mice.

Brain dopamine (DA) and adenosine interact in the regulation of behavioral activation and effort-related processes. In the present studies, a T-maze task was developed in mice for the assessment of effort-related decision making. With this task, the two arms of the maze have different reinforcement densities, and a vertical barrier is positioned in the arm with the higher density (HD), presenting the animal with an effort-related challenge. Under control conditions mice prefer the HD arm, and climb the barrier to obtain the larger amount of food. The DA D(2) receptor antagonist haloperidol decreased selection of the HD arm and increased selection of the arm with the low density of reinforcement. However, the HD arm was still the preferred choice in haloperidol-treated mice trained with barriers in both arms. Pre-feeding the mice to reduce food motivation dramatically increased omissions, an effect that was distinct from the actions of haloperidol. Co-administration of theophylline, a nonselective adenosine receptor antagonist, partially reversed the effects of haloperidol. This effect seems to be mediated by the A(2A) receptor but not the A(1) receptor, since the A(2A) antagonist MSX-3, but not the A(1) antagonist CPT, dose dependently reversed the effects of haloperidol on effort-related choice and on c-Fos expression in the dorsal striatum and nucleus accumbens. In addition, adenosine A(2A) receptor knockout mice were resistant to the effects of haloperidol on effort-related choice in the maze. These results indicate that DA D(2) and adenosine A(2A) receptors interact to regulate effort-related decision making and effort expenditure in mice.

CB1 receptor-deficient mice as a model for depression.

In the last 10 years, numerous experimental studies have revealed the participation of the endocannabinoid system in the control of emotional behavior and mood through the activation of the CB1 cannabinoid receptors. Endocannabinoids are able to exert a regulative control of different physiological mechanisms that are impaired during mood disorders, including monoaminergic system, the activity of pituitary-adrenal axis, the release and activation of neurotrophic factors that promotes neuroplasticity and adapted behavior, and probably neuroinflammatory cytokines release during the depressive disorders. Considering the body of elements that acts under the control of the endocannabinoid system and the key role played by the activation of the CB1 cannabinoid receptors in the control of emotion and mood, we had proposed that genetically modified mice lacking the CB1 cannabinoid receptors could represent a genetic model for depression. These animals generated by three distinct laboratories behave normally under basal conditions, but they could display an altered behavior under adverse environmental conditions. In this review, we have integrated most of the study that have been developed using mice lacking CB1 cannabinoid receptor for the studies of emotional responses. We have focused our attention not only in the data obtained using different behavioral paradigms, but also in different biomarkers that have been classically or recently associated to mood disorders, such as the deregulation of the serotonergic system, the reported impairment in neurotrophic factors and plasticity function described for depression, the alterations in the pituitary-adrenal axis function, and the lately reported role for inflammatory factors in the mood regulation. Finally, clinical studies support and confirm the obtained findings in animal models and lead us to propose that mice lacking CB1 cannabinoid receptor could represent a validate and appropriate model to evaluate depressive-like disorders in animals.

Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference.

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5mg/kg) or the CB1 cannabinoid antagonist SR 141716A (0.3mg/kg), was administered on alternate days. The CB1 receptor antagonist, alone or with any of the priming doses of MDMA, induced reinstatement of the preference. In contrast, WIN 55,212-2 had no effect on reinstatement of the MDMA-induced CPP when administered alone, but potentiated the effects of subthreshold priming doses of MDMA. These results highlight the important role of the CB1 receptor in vulnerability to reinstatement of drug-seeking behavior and point to the importance of the endocannabinoid system in the addictive potential of MDMA.

Regulation of Fas receptor/Fas-associated protein with death domain apoptotic complex and associated signalling systems by cannabinoid receptors in the mouse brain.

BACKGROUND AND PURPOSE: Natural and synthetic cannabinoids (CBs) induce deleterious or beneficial actions on neuronal survival. The Fas-associated protein with death domain (FADD) promotes apoptosis, and its phosphorylated form (p-FADD) mediates non-apoptotic actions. The regulation of Fas/FADD, mitochondrial apoptotic proteins and other pathways by CB receptors was investigated in the mouse brain. EXPERIMENTAL APPROACH: Wild-type, CB(1) and CB(2) receptor knock-out (KO) mice were used to assess differences in receptor genotypes. CD1 mice were used to evaluate the effects of CB drugs on canonical apoptotic pathways and associated signalling systems. Target proteins were quantified by Western blot analysis. KEY RESULTS: In brain regions of CB(1) receptor KO mice, Fas/FADD was reduced, but p-Ser191 FADD and the p-FADD/FADD ratio were increased. In CB(2) receptor KO mice, Fas/FADD was increased, but the p-FADD/FADD ratio was not modified. In mutant mice, cleavage of poly(ADP-ribose)-polymerase (PARP) did not indicate alterations in brain cell death. In CD1 mice, acute WIN55212-2 (CB(1) receptor agonist), but not JWH133 (CB(2) receptor agonist), inversely modulated brain FADD and p-FADD. Chronic WIN55212-2 induced FADD down-regulation and p-FADD up-regulation. Acute and chronic WIN55212-2 did not alter mitochondrial proteins or PARP cleavage. Acute, but not chronic, WIN55212-2 stimulated activation of anti-apoptotic (ERK, Akt) and pro-apoptotic (JNK, p38 kinase) pathways. CONCLUSIONS AND IMPLICATIONS: CB(1) receptors appear to exert a modest tonic activation of Fas/FADD complexes in brain. However, chronic CB(1) receptor stimulation decreased pro-apoptotic FADD and increased non-apoptotic p-FADD. The multifunctional protein FADD could participate in the mechanisms of neuroprotection induced by CBs.

Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A(2A) receptor knockout mice.

BACKGROUND AND PURPOSE: The purinergic system through the A(2A) adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A(2A) adenosine receptors (A(2A)Rs) in the behavioural and neurochemical responses to morphine associated with its motivational properties. EXPERIMENTAL APPROACH: Mice lacking A(2A)Rs (A(2A) knockout (KO) mice) and wild-type littermates were used to evaluate behavioural responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place-conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A(2A) KO mice after morphine administration. KEY RESULTS: The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A(2A) KO mice. Also, naloxone did not induce place aversion in animals lacking the A(2A)Rs. CONCLUSIONS AND IMPLICATIONS: Our findings demonstrate that the rewarding and aversive effects associated with morphine abstinence were abolished in A(2A) KO mice, supporting a differential role of the A(2A) adenosine receptor in the somatic and motivational effects of morphine addiction. This study provides evidence for the role of A(2A)Rs as general modulators of the motivational properties of drugs of abuse. Pharmacological manipulation of these receptors may represent a new target in the management of drug addiction.

Chronic cocaine treatment alters dendritic arborization in the adult motor cortex through a CB1 cannabinoid receptor-dependent mechanism.

The CB1 cannabinoid receptors modulate the addictive processes associated with different drugs of abuse, including psychostimulants. Mice lacking CB1 receptors exhibit an important attenuation of the reinforcing responses produced by cocaine in an operant self-administration paradigm. We have investigated the effect of chronic cocaine treatment on dendrite structure and spine density of the principal cortical neuron, the pyramidal neuron, in CB1 knockout mice and wild type littermates. Layer III pyramidal cells of the motor cortex were injected intracellularly in fixed cortical slices and their morphometric parameters analyzed. Under basal conditions, the field area of the dendritic arbors was more extensive and dendritic spine density was higher in wild type mice than in CB1 knockout mice. Chronic treatment of cocaine diminished the size and length of the basal dendrites and spine density on pyramidal cells from wild type mice. However, the total number of spines in the pyramidal cells of CB1 knockout mice augmented slightly following chronic cocaine treatment, although no changes in the morphology of the dendritic arbor were observed. Our data demonstrate that microanatomy and synaptic connectivity are affected by cocaine, the magnitude and nature of these changes depend on the presence of CB1 receptors.

Genetic and pharmacological approaches to evaluate the interaction between the cannabinoid and cholinergic systems in cognitive processes.

BACKGROUND AND PURPOSE: The objective of this study was to investigate the possible interactions between the cannabinoid and cholinergic systems in memory and learning processes by using genetic and pharmacological approaches in two different behavioural models, the active avoidance and the object recognition test. EXPERIMENTAL APPROACH: The effects induced by nicotine, physostigmine and scopolamine were studied in CB(1) receptor knockout and wild-type mice in the active avoidance paradigm. In addition, the effects of pretreatment with the CB(1) receptor antagonist rimonabant were evaluated on the responses induced by nicotine in the active avoidance and the object recognition tasks in wild-type mice. KEY RESULTS: Nicotine (0.5 mg kg(-1) s.c.) did not modify the performance of CB(1) knockout and wild-type mice in this model, whereas scopolamine (0.5 mgkg(-1) i.p.) impaired the performance in both genotypes. Physostigmine (0.1 mg kg(-1) i.p.) increased the active avoidance performance in wild-type but not in CB(1) knockout mice. Rimonabant (0.3, 1, 3, and 10 mg kg(-1)) did not modify the performance in the active avoidance test, given alone or co-administered with nicotine. In contrast, nicotine enhanced the performance in the object recognition task but this response was attenuated by rimonabant co-administration. CONCLUSIONS AND IMPLICATIONS: The present findings revealed that the cognitive effects of nicotine and physostigmine were attenuated in the absence of CB(1) receptor activity. Scopolamine effects were independent from CB(1) receptors.

Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors.

The molecular mechanisms contributing to the normal age-related decline of cognitive functions or to pathological learning and memory impairment are largely unknown. We demonstrate here that young mice (6-7 weeks) with a genetic deletion of the cannabinoid CB1 receptor performed as well as WT mice, or often better, in a number of learning and memory paradigms, including animal models of skill-learning, partner recognition, and operant conditioning. In contrast, the performance of mature mice (3-5 months) lacking CB1 receptors was much worse than that of age-matched WT animals. In most tests, these mice performed at the same level as old animals (14-17 months), suggesting that the decline in cognitive functions is accelerated in the absence of CB1 receptors. This rapid decline in CB1-deficient animals is accompanied by a loss of neurons in the CA1 and CA3 regions of the hippocampus.

Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice.

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. To date, three lines of CB1 knockout mice have been established independently in different laboratories. This chapter reviews the main results obtained with these lines of CB1 knockout mice in several physiological responses that have been previously related to the activity of the endocannabinoid system. Studies using CB1 knockout mice have demonstrated that this receptor participates in the control of several behavioural responses including locomotion, anxiety- and depressive-like states, cognitive functions such as memory and learning processes, cardiovascular responses and feeding. Furthermore, the CB1 cannabinoid receptor is involved in the control of pain by acting at peripheral, spinal and supraspinal levels. The involvement of the CB1 cannabinoid receptor in the behavioural and biochemical processes underlying drug addiction has also been investigated. These CB1 knockouts have provided new findings to clarify the interactions between cannabinoids and the other drugs of abuse such as opioids, psychostimulants, nicotine and ethanol. Recent studies have demonstrated that endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitters, including opioids, gamma-aminobutyric acid (GABA), and cholecystokinin (CCK), which could explain some of the responses observed after the stimulation of the CB1 cannabinoid receptor. This review provides an update of the apparently controversial data reported in the literature using the three different lines of CB1 knockout mice, which seem to be mainly due to the use of different experimental procedures rather than any constitutive alteration in these lines of knockouts.

Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence.

Cannabis is the most widely consumed illicit drug and its consumption is currently associated with tobacco, which contains another psychoactive compound, namely nicotine. Interactions between cannabinoids and other drugs of abuse, such as opioids, have been previously reported. The aim of the present study was to evaluate the possible role of CB1 cannabinoid receptor in responses induced by acute and repeated nicotine administration by using knockout mice lacking the CB1 cannabinoid receptor and their wild-type littermates. Acute nicotine (0.5, 1, 3 and 6 mg/kg, sc) administration decreased locomotor activity and induced antinociceptive responses in the tail-immersion and the hot-plate test, in wild-type animals. The antinociceptive effects in the tail-immersion test were significantly enhanced in CB1 knockout mice. In wild-type mice nicotine (0.5 mg/kg, sc) produced a significant rewarding effect, as measured by a conditioned place preference paradigm. This response was absent in CB1 knockout mice. Finally, a model of mecamylamine-induced abstinence in chronic nicotine-treated mice (10 mg/kg/day, sc) was developed. Mecamylamine (1 and 2 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type dependent mice. However, no difference in the severity of nicotine withdrawal was observed in CB1 knockout mice. These results demonstrate that some acute effects and motivational responses elicited by nicotine can be modulated by the endogenous cannabinoid system and support the existence of a physiological interaction between these two systems.

Absence of delta -9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice.

The involvement of dynorphin on Delta-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin (Pdyn) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.