Density Of Cannabinoid Receptors Research Articles

The First “Hit” to the Endocannabinoid System? Associations Between Prenatal Cannabis Exposure and Frontolimbic White Matter Pathways in Children

BackgroundCannabis is the most used federally illicit substance among pregnant people in the United States. However, emerging preclinical data show that a significant portion of cannabis constituents, such as Δ9-tetrahydrocannabinol and its bioactive metabolites, readily cross the placenta and accumulate in the fetal brain, disrupting neurodevelopment. Recent research using the Adolescent Brain Cognitive Development (ABCD) Study cohort has linked prenatal cannabis exposure (PCE) to greater neurobehavioral problems and lower total gray and white matter volume in children. Here, we examined the impact of PCE on frontolimbic white matter pathways that are critical for cognitive- and emotion-related functioning, show a high density of cannabinoid receptors, and are susceptible to cannabis exposure during other periods of rapid neurodevelopment (e.g., adolescence). MethodsThis study included 11,530 children (mean ± SD age = 118.99 ± 7.49 months; 47% female) from the ABCD Study cohort. Linear mixed-effects models were used to examine the effects of caregiver-reported PCE on fractional anisotropy of 10 frontolimbic pathways (5 per hemisphere). ResultsPCE was associated with lower fractional anisotropy of the right (β = −0.005, p < .001) and left (β = −0.003, p = .007) fornix, and these results remained significant after adjusting for a variety of covariates, multiple comparisons, fractional anisotropy of all fibers, and using a quality-control cohort only. ConclusionsIn sum, we demonstrated small, yet reliable, effects of PCE on white matter integrity during childhood, particularly in the fornix, which plays a crucial role in emotion- and memory-related processes. Future studies are needed to understand the impacts of small changes in brain structure or function on neurodevelopment and risk of neurobehavioral problems.

The Cerebellum, THC, and Cannabis Addiction: Findings from Animal and Human Studies.

Cannabis is the third most used psychoactive drug worldwide. Despite being legally scheduled as a drug with high harm potential and no therapeutic utility in countries like the USA, evidence shows otherwise and legislative changes and reinterpretations of existing ambiguous laws make this drug increasingly available by legal means. Nevertheless, this substance is able to generate clear addiction syndromes in some individuals who use it, which are accompanied by brain alterations resembling those caused by other addictive drugs. Moreover, there is no available pharmacological treatment for this disorder. This fact motivates a deep study and comprehension of the neural basis of addiction-relevant cannabinoid effects. Interestingly, the cerebellum, a hindbrain structure which involvement in functions not related to motor control and planning is being increasingly recognized in the last decades, seems to be involved in the effects of addictive drugs and addiction-related processes and also presents a high density of cannabinoid receptors. Preclinical research on the involvement of the cerebellum in cannabis' effects has focused in the drug's motor incoordinating actions, potentially underestimating its participation in addiction. Therefore, this review addresses the studies reporting cerebellar involvement in cannabis effects both in experimental animals and human subjects and the possible relevance of these changes for addiction. Additionally, future experimental approaches will be proposed and hopefully this work will stimulate research on the cerebellum in cannabis addiction and help recognizing it as an important part of the neural circuitry affected in cannabis-related disorders.

The effects of antipsychotics on the density of cannabinoid receptors in selected brain regions of male and female adolescent juvenile rats

Antipsychotic drugs have been increasingly prescribed to children and adolescents for treating various mental disorders, such as childhood-onset schizophrenia. The abnormality of endocannabinoid system is involved in the pathophysiology of these disorders in juveniles. This study investigated the effect of antipsychotics on the cannabinoid (CB) receptors in the brain of both male and female juvenile rats. The postnatal rats (PD23±1) were administered aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg) or vehicle (control) for 3 weeks. Quantitative autoradiography was used to investigate the binding densities of [3H]CP-55940 (an agonist for CB1R and CB2R) and [3H]SR141716A (a selective CB1R antagonist) in the rat brains. Risperidone significantly upregulated the [3H]CP55940 and [3H]SR141716A bindings in the prefrontal cortex (PFC), nucleus accumbens core (NAcC), nucleus accumbens shell (NAcS), cingulate cortex (Cg), and the caudate putamen (CPu) in male rats. Moreover, aripiprazole significantly elevated the [3H]SR141716A binding in the Cg and NAcS of female rats. Furthermore, there is an overall higher [3H]SR141716A binding level in the brain of female rats than male rats. Therefore, treatment with aripiprazole, olanzapine and risperidone could induce differential and gender specific effects on the binding density of cannabinoid receptors in the selected brain regions of childhood/adolescent rats.

Cannabinoid modulation of memory consolidation within the cerebellum

Cannabinoid receptors contribute to learning and synaptic plasticity mechanisms. The cerebellum contains a high density of cannabinoid receptors and manipulations of cannabinoid receptors affect synaptic plasticity within the cerebellar cortex. In vivo studies have found that cannabinoid agonists impair learning of cerebellum-dependent eyeblink conditioning in rodents and humans. However, the role of cannabinoid receptors or endocannabinoids in memory consolidation within the cerebellum has not been examined. In the current study, we examined the role of cannabinoid receptors and endocannabinoids during learning and consolidation of eyeblink conditioning in rats. Administration of the cannabinoid receptor agonist WIN55,212-2 or drugs that increase/decrease endocannabinoid levels directly into the cerebellar cortex before each training session resulted in marked learning impairments. When administered 1 h after each training session, during memory consolidation, the cannabinoid inverse agonist SR141716A or the endocannabinoid suppressor THL impaired memory. In contrast, increasing endocannabinoid levels with JZL-184 or infusion of WIN55,212-2 within the cerebellar cortex facilitated memory consolidation 1h post-training. Intracerebellar manipulations of cannabinoid receptors or endocannabinoid levels had no effect on memory consolidation when administered 3 or 6h after each training session. The results demonstrate that cannabinoids impair cerebellar learning, but facilitate memory consolidation mechanisms within the cerebellar cortex 1–3h after training.

Sexually-dimorphic alterations in cannabinoid receptor density depend upon prenatal/early postnatal history

Recent research has demonstrated that the endogenous cannabinoid system is central to the brain's response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48–50 within 2hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system.

Attenuated frontal and sensory inputs to the basal ganglia in cannabis users.

Heavy cannabis use is associated with reduced motivation. The basal ganglia, central in the motivation system, have the brain's highest cannabinoid receptor density. The frontal lobe is functionally coupled to the basal ganglia via segregated frontal-subcortical circuits conveying information from internal, self-generated activity. The basal ganglia, however, receive additional influence from the sensory system to further modulate purposeful behaviors according to the context. We postulated that cannabis use would impact functional connectivity between the basal ganglia and both internal (frontal cortex) and external (sensory cortices) sources of influence. Resting-state functional connectivity was measured in 28 chronic cannabis users and 29 controls. Selected behavioral tests included reaction time, verbal fluency and exposition to affective pictures. Assessments were repeated after one month of abstinence. Cannabis exposure was associated with (1) attenuation of the positive correlation between the striatum and areas pertaining to the 'limbic' frontal-basal ganglia circuit, and (2) attenuation of the negative correlation between the striatum and the fusiform gyrus, which is critical in recognizing significant visual features. Connectivity alterations were associated with lower arousal in response to affective pictures. Functional connectivity changes had a tendency to normalize after abstinence. The results overall indicate that frontal and sensory inputs to the basal ganglia are attenuated after chronic exposure to cannabis. This effect is consistent with the common behavioral consequences of chronic cannabis use concerning diminished responsiveness to both internal and external motivation signals. Such an impairment of the fine-tuning in the motivation system notably reverts after abstinence.

Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n=70) of 14-year olds with a history of cannabis use to a group (n=70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.

Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes

The use of recreational marijuana is widespread and frequently begins and persists through adolescence. Some research has shown negative consequences of adolescent marijuana use, but this is not seen across studies, and certain factors, like genetic background and sex, may influence the results. It is critical to identify which characteristics predispose an individual to be susceptible to the negative consequences of chronic exposure to marijuana in adolescence on brain health and behavior. To this end, using males and females of two strains of rats, Long–Evans hooded (LER) and Wistar (WR) rats, we explored whether these anatomically and behaviorally dimorphic strains demonstrated differences in puberty onset and strain-specific effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. Daily 5mg/kg treatment began on the day of puberty onset and continued for 14days. Of particular interest were metrics of growth and volumetric estimates of brain areas involved in cognition that contain high densities of cannabinoid receptors, including the hippocampus and its subregions, the amygdala, and the frontal cortex. Brain volumetrics were analyzed immediately following the treatment period. LER and WR females started puberty at different ages, but no strain differences were observed in brain volumes. THC decreased weight gain throughout the treatment period for all groups. Only the hippocampus and some of its subregions were affected by THC, and increased volumes with THC administration was observed exclusively in females, regardless of strain. Long-term treatment of THC did not affect all individuals equally, and females displayed evidence of increased sensitivity to the effects of THC, and by extension, marijuana. Identifying differences in adolescent physiology of WR and LER rats could help determine the cause for strain and sex differences in brain and behavior of adults and help to refine the use of animal models in marijuana research.

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia. In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases. In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor.

Endocannabinoid signaling mechanisms in the substantia nigra pars reticulata modulate GABAergic nigrotectal pathways in mice threatened by urutu-cruzeiro venomous pit viper

The substantia nigra pars reticulata (SNpr) is rich in γ-aminobutyric acid (GABA)-ergic neurons and connected to the mesencephalic tectum (MT) structures, such as the superior colliculus and dorsal periaqueductal gray matter. The SNpr presents a high density of cannabinoid receptors (CBRs), suggesting a possible regulatory role that is played by endocannabinoids (eCBs) in the ventral mesencephalon. The present study investigated the involvement of SNpr eCB mechanisms in nigrotectal pathways in the expression of defensive behavior associated with instinctive fear and panic reactions in mice that are confronted with the venomous Viperidae snake Bothrops alternatus. The localization of CB1 receptors (CB1RS) and synaptophysin glycoprotein in the SNpr was also evaluated. Administration of the GABAA receptor antagonist bicuculline in the MT increased defensive responses to the snake that are related to panic, such as freezing and non-oriented escape reactions, sometimes toward the snake itself. Mice that were pretreated with anandamide (5 or 50pmol) in the SNpr, followed by an injection of physiological saline or bicuculline in the MT, exhibited significant decreases in the expression of alertness, freezing, and escape responses. Immunofluorescence showed the presence of fibers that were rich in CB1RS and synaptophysin in the SNpr, indicating that these receptors appear to be located mainly in presynaptic terminals in the striatonigral pathway. These findings suggest that eCB mechanisms in the SNpr facilitate the activity of nigrotectal GABAergic pathways, modulating the activity of striatonigral links during the elaboration and organization of innate fear and panic-like responses in threatening situations.

Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.

Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). We therefore determined CBR densities and expression of the translocator protein 18 kDA (TSPO) in newborn piglets after experimental TBI. Newborn female piglets were subjected to sham operation (n=6) or fluid-percussion (FP) injury (n=7) under controlled physiological conditions. After six hours, brains were frozen, sagittally cut and incubated with radioligands for CBR ([3HCP-55,940, [3H]SR141716A) and TSPO ([3H]PK11195), an indicator of gliosis/brain injury. Early after injury, FP-TBI elicited a significant ICP increase at a temporary reduced cerebral perfusion pressure; however, CBF and CMRO2 remained within physiological range. At 6 hours post injury, we found a statistically significant increase in binding of the non-selective agonist [3H]CP-55,940 in 15 of the 24 investigated brain regions of injured animals. By contrast, no significant changes in binding of the CB1R-selective antagonist [3H]SR141716A were observed. A non-significant trend towards increased binding of [3H]PK11195 was observed, suggesting an incipient microglial activation. We therefore conclude that in this model and time span after injury, the increase in [3H]CP-55,940 binding reflects changes in CB2R density, while CB1R density is not affected. The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.

A Preliminary Study of Functional Brain Activation among Marijuana Users during Performance of a Virtual Water Maze Task

Numerous studies have reported neurocognitive impairments associated with chronic marijuana use. Given that the hippocampus contains a high density of cannabinoid receptors, hippocampal-mediated cognitive functions, including visuospatial memory, may have increased vulnerability to chronic marijuana use. Thus, the current study examined brain activation during the performance of a virtual analogue of the classic Morris water maze task in 10 chronic marijuana (MJ) users compared to 18 nonusing (NU) comparison subjects. Imaging data were acquired using blood oxygen level-dependent (BOLD) functional MRI at 3.0 Tesla during retrieval (hidden platform) and motor control (visible platform) conditions. While task performance on learning trials was similar between groups, MJ users demonstrated a deficit in memory retrieval. For BOLD fMRI data, NU subjects exhibited greater activation in the right parahippocampal gyrus and cingulate gyrus compared to the MJ group for the Retrieval-Motor Control contrast (NU > MJ). These findings suggest that hypoactivation in MJ users may be due to differences in the efficient utilization of neuronal resources during the retrieval of memory. Given the paucity of data on visuospatial memory function in MJ users, these findings may help elucidate the neurobiological effects of marijuana on brain activation during memory retrieval.

125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer’s disease

The cannabinoid type-1 receptor (CB1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB1Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB1R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB1R radioligand to investigate regional variations in CB1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer’s disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB1Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB1R autoradiography with [125I]SD-7015 as radioligand. Regional concentration of [125I]SD-7015, corresponding to, and thereby representing, regional CB1R densities, were expressed in fM/g_tissue. The results show that CB1R density inversely correlates with Braak tau pathology with the following tendency: controls <AD Braak stage V–VI <AD Braak stage III–IV <AD Braak stage I–II. Differences were significant between control and AD Braak stage I–II groups, as well as between controls and the AD group comprising all Braak stages. These findings indicate an up-regulation of the tissue binding of the selective CB1R radioligand [125I]SD7015 in human brains, allowing the detection of fine modalities of receptor expression and radioligand binding during the progression of AD.

Striatal direct pathway modulates response time in execution of conditional discrimination

The substantia nigra pars reticulata (SNpr) is rich in γ-aminobutyric acid (GABA)-ergic neurons and connected to the mesencephalic tectum (MT) structures, such as the superior colliculus and dorsal periaqueductal gray matter. The SNpr presents a high density of cannabinoid receptors (CBRs), suggesting a possible regulatory role that is played by endocannabinoids (eCBs) in the ventral mesencephalon. The present study investigated the involvement of SNpr eCB mechanisms in nigrotectal pathways in the expression of defensive behavior associated with instinctive fear and panic reactions in mice that are confronted with the venomous Viperidae snake Bothrops alternatus. The localization of CB1 receptors (CB1RS) and synaptophysin glycoprotein in the SNpr was also evaluated. Administration of the GABAA receptor antagonist bicuculline in the MT increased defensive responses to the snake that are related to panic, such as freezing and non-oriented escape reactions, sometimes toward the snake itself. Mice that were pretreated with anandamide (5 or 50 pmol) in the SNpr, followed by an injection of physiological saline or bicuculline in the MT, exhibited significant decreases in the expression of alertness, freezing, and escape responses. Immunofluorescence showed the presence of fibers that were rich in CB1RS and synaptophysin in the SNpr, indicating that these receptors appear to be located mainly in presynaptic terminals in the striatonigral pathway. These findings suggest that eCB mechanisms in the SNpr facilitate the activity of nigrotectal GABAergic pathways, modulating the activity of striatonigral links during the elaboration and organization of innate fear and panic-like responses in threatening situations.

Central cannabinoid receptors modulate acquisition of eyeblink conditioning

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning.

P.1.e.005 Delta9-tetrahydrocannabinol (THC) impairs working memory system capacity: a pharmacological MRI study

We investigated the effects of acute i.v. administration of 2 mg of Δ9-tetrahydrocannabinol (THC) on regional brain glucose metabolism using 18F-2-fluoro-2-deoxyglucose and positron emission tomography (PET) in eight normal subjects. Subjects were tested twice: during baseline conditions and 30–40 min after THC administration. Changes in global cerebral glucose metabolism in response to THC were variable: three subjects showed an increase, three showed a decrease, and two showed no change. In contrast, all subjects showed an increase in normalized metabolism in the cerebellum following THC administration. Cerebellar changes were the only significant regional metabolic changes due to THC administration. The increase in metabolic activity in the cerebellum was correlated with the subjective sense of THC intoxication and with plasma THC concentration. Cerebellar localization of metabolic effects due to THC administration corresponds well with the high density of cannabinoid receptors known to be in this area.

Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice

The present studies examined the effect of chronic neuropathic pain on cannabinoid receptor density and receptor-mediated G-protein activity within supraspinal brain areas involved in pain processing and modulation in mice. Chronic constriction injury (CCI) produced a significant decrease in WIN 55,212-2-stimulated [ 35S]GTPγS binding in membranes prepared from the rostral anterior cingulate cortex (rACC) of CCI mice when compared to sham-operated controls. Saturation binding with [ 3H]SR 141716A in membranes of the rACC showed no significant differences in binding between CCI and sham mice. Analysis of levels of the endocannabinoids anandamide (AEA) or 2-arachidonoylglycerol (2-AG) in the rACC following CCI showed no significant differences between CCI and sham mice. These data suggest that CCI produced desensitization of the cannabinoid 1 receptor in the rACC in the absence of an overall decrease in cannabinoid 1 receptor density or change in levels of AEA or 2-AG. These data are the first to show alterations in cannabinoid receptor function in the rostral anterior cingulate cortex in response to a model of neuropathic pain.

Endocannabinoids: Stress, Anxiety, and Fear

Endocannabinoids: Stress, Anxiety, and Fear

Chronic nicotine alters cannabinoid-mediated locomotor activity and receptor density in periadolescent but not adult male rats

A significant number of youths use cigarettes, and more than half of the youths who smoke daily also use illicit drugs. The focus of these studies is on how exposure to nicotine affects subsequent responses to both nicotine and cannabinoids in adolescents compared with adults. We have shown previously that chronic treatment with nicotine produces sensitization to its locomotor-activating effects in female and adult rats but not male adolescent rats. To better understand the effects of nicotine on adolescent and adult rats, rats were injected with nicotine or saline for 7 days and, on day 8, either challenged with delta-9-tetrahydrocannabinol (Δ9-THC) or the cannabinoid agonist CP 55,940 and tested for locomotor activity, or the brains were removed for quantitative autoradiography studies of the cannabinoid1 receptor. A separate group of rats was treated with nicotine plus the cannabinoid antagonist AM 251 and then challenged with CP 55,940. In adolescent male rats, nicotine administration led to sensitization to the locomotor-decreasing effects of both Δ9-THC and CP 55,940, but in adult male rats, the response to either drug was unchanged compared to controls. The effect of nicotine on CP 55,940-mediated locomotor activity was blocked by co-administration of AM 251 with the nicotine. Further, cannabinoid receptor density was increased in the prelimbic prefrontal cortex, ventral tegmental area, and select regions of the hippocampus in adolescent male rats pretreated with nicotine compared to vehicle-treated controls. There were no significant changes in cannabinoid receptor binding, however, in any of the brain regions examined in adult males pretreated with nicotine. The prelimbic prefrontal cortex and the hippocampus have been shown previously to be involved in stimulant reinforcement; thus it is possible that these changes contribute to the unique behavioral effects of chronic nicotine and subsequent drug administration in adolescents compared with adults.

The effects of antipsychotics on the density of cannabinoid receptors in the dorsal vagal complex of rats: implications for olanzapine-induced weight gain

Some atypical antipsychotics clinically used to treat schizophrenia induce weight gain by unknown mechanisms. The dorsal vagal complex (DVC) of the brainstem and the endogenous cannabinoid system are implicated in the regulation of appetite signalling and food intake. We investigated whether antipsychotic drugs alter cannabinoid receptor-binding density in the DVC. Female Spraguewk (short-term) or 120.83, p=0.01). In addition, only chronic olanzapine treatment increased food intake. These results show that olanzapine, an antipsychotic with a high risk of weight gain as a side-effect, significantly decreased cannabinoid receptor binding in the DVC, whilst aripiprazole and haloperidol, antipsychotics with a low risk of weight gain had little or no effect on binding. These results suggest that a mechanism for antipsychotic-induced weight gain may be through the modulation of cannabinoid receptors in the DVC.