Pharmacological and biochemical interactions between opioids and cannabinoids.

Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans. A number of studies have shown that both types of drugs share several pharmacological properties, including hypothermia, sedation, hypotension, inhibition of both intestinal motility and locomotor activity and, in particular, antinociception. Moreover, phenomena of cross-tolerance or mutual potentiation of some of these pharmacological effects have been reported. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of pharmacological interactions between opioids and cannabinoids, focusing on two aspects: antinociception and drug addiction. The potential biochemical mechanisms involved in these pharmacological interactions are also discussed together with possible therapeutic implications of opioid-cannabinoid interactions.     

AMPA receptor stimulation within the central nucleus of the amygdala elicits a differential activation of central dopaminergic systems.

Appetitive and aversive arousing stimuli increase rates of dopamine (DA) release, particularly within the prefrontal cortex (PFC). Evidence suggests an activating influence of both the central (CeA) and basolateral (BlA) nuclei of the amygdala on DA neurotransmission. For example, lesions of CeA block stressor-induced increases in DA release. Additionally, electrical stimulation of BlA increases DA release in select terminal fields. Previous studies indicate that glutamatergic AMPA receptors modulate CeA and BlA output. However, the extent to which AMPA receptors participate in amygdala-dependent activation of DA neurotransmission is unknown. The current studies examined the effects of bilateral AMPA infusions within CeA or BlA on post-mortem and in vivo microdialysis indices of DA release. Additionally, stress is associated with moderate increases in serotonin (5-HT) neurotransmission that are also blocked by CeA lesions. Thus, the current studies also examined the impact of AMPA infusions on post-mortem indices of 5-HT utilization. AMPA infusion into CeA, but not BlA, increased post-mortem indices of DA and 5-HT release in a pattern comparable to that observed under appetitive/aversive conditions. In vivo microdialysis studies confirmed that AMPA infusions into CeA, but not BlA, increase extracellular PFC DA levels. When infused into sleeping animals, CeA-AMPA infusion also elicited a rapid-onset transition into waking. Thus, CeA-AMPA receptors exert an excitatory influence on DA and 5-HT neurotransmission and on behavioral state. Combined, these results suggest that CeA-AMPA receptors may participate in the coordination of neural systems involved in the regulation of behavioral state under high-arousal conditions.     

Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala

Brain norepinephrine (NE) modulates many aspects of the stress response. The interaction between NE and neuropeptides such as galanin, with which it is closely associated and which may be released from noradrenergic terminals under conditions of high activity, has not been well studied. We therefore investigated the modulatory effects of galanin in the central nucleus of the amygdala (CeA) on behavioral responsivity to stress when activation of the noradrenergic system was amplified using the adrenergic autoreceptor antagonist yohimbine (2.5 mg/kg ip). Either immobilization stress or yohimbine alone had anxiogenic effects on rat behavior in the elevated plus maze. However, yohimbine pretreatment before stress produced a paradoxical anxiolytic response, which we hypothesized was attributable to galanin release in CeA. Microdialysis verified that yohimbine amplified NE release in CeA during immobilization stress, and also showed that whereas there was no detectable change in galanin release in CeA during stress alone, there was an increase during immobilization stress after yohimbine pretreatment. Bilateral administration of the galanin antagonist M40 into CeA before stress blocked the anxiolytic influence of yohimbine pretreatment. Exogenous galanin mimicked the anxiolytic effect of yohimbine pretreatment, and this too was blocked by M40. These results suggest that amplifying the noradrenergic response to stress can recruit galanin release in CeA, which buffers the anxiety-like behavioral response to acute stress. The balance between noradrenergic and peptidergic neurotransmission may be modified by prior stress, drug treatment or genetic variability, and may represent a novel target for treatment of stress-related neuropsychiatric disorders.     

Synergistic interactions between PBDEs and PCBs in human neuroblastoma cells

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants. Exposure to these chemicals has been associated with developmental neurotoxicity, endocrine dysfunction, and reproductive disorders. Humans and wildlife are generally exposed to a mixture of these environmental pollutants, highlighting the need to evaluate the potential effects of combined exposures. In this study, we investigated the cytotoxic effects of the combined exposure to two PBDEs and two PCBs in a human neuronal cell line. 2,2′,4,4′‐Tetrabromodiphenyl ether, 2,2′,4,4′,5‐pentabromodiphenyl ether, PCB‐126 (3,3′,4,4′,5‐pentachlorobiphenyl; a dioxin‐like PCB), and PCB‐153 (2,2′,4,4′,5,5′‐hexachlorobiphenyl; a non‐dioxin‐like PCB) were chosen, because their concentrations are among the highest in human tissues and the environment. The results suggest that the nature of interactions is related to the PCB structure. Mixtures of PCB‐153 and both PBDEs had a prevalently synergistic effect. In contrast, mixtures of each PBDE congener with PCB‐126 showed additive effects at threshold concentrations, and synergistic effects at higher concentrations. These results emphasize the concept that the toxicity of xenobiotics may be affected by possible interactions, which may be of significance given the common coexposures to multiple contaminants. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 418–427, 2014.     

Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine,serotonin, and glutamate systems

Abstract

An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.     

Synergistic interactions between commonly used food additives in a developmental neurotoxicity test.

Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioral disorders such as attention deficit hyperactivity disorder (ADHD). Although the use of single food additives at their regulated concentrations is believed to be relatively safe in terms of neuronal development, their combined effects remain unclear. We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. Mouse NB2a neuroblastoma cells were induced to differentiate and grow neurites in the presence of additives. After 24 h, cells were fixed and stained and neurite length measured by light microscopy with computerized image analysis. Neurotoxicity was measured as an inhibition of neurite outgrowth. Two independent models were used to analyze combination effects: effect additivity and dose additivity. Significant synergy was observed between combinations of Brilliant Blue with L-glutamic acid, and Quinoline Yellow with aspartame, in both models. Involvement of N-methyl-D-aspartate (NMDA) receptors in food additive-induced neurite inhibition was assessed with a NMDA antagonist, CNS-1102. L-glutamic acid- and aspartame-induced neurotoxicity was reduced in the presence of CNS-1102; however, the antagonist did not prevent food color-induced neurotoxicity. Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. In addition, Trypan Blue dye exclusion was used to evaluate the cellular toxicity of food additives on cell viability of NB2a cells; both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the cellular effects of common chemical entities ingested individually and in combination.     

Prefrontal cortex interactions with the amygdala in primates

This review addresses functional interactions between the primate prefrontal cortex (PFC) and the amygdala, with emphasis on their contributions to behavior and cognition. The interplay between these two telencephalic structures contributes to adaptive behavior and to the evolutionary success of all primate species. In our species, dysfunction in this circuitry creates vulnerabilities to psychopathologies. Here, we describe amygdala–PFC contributions to behaviors that have direct relevance to Darwinian fitness: learned approach and avoidance, foraging, predator defense, and social signaling, which have in common the need for flexibility and sensitivity to specific and rapidly changing contexts. Examples include the prediction of positive outcomes, such as food availability, food desirability, and various social rewards, or of negative outcomes, such as threats of harm from predators or conspecifics. To promote fitness optimally, these stimulus–outcome associations need to be rapidly updated when an associative contingency changes or when the value of a predicted outcome changes. We review evidence from nonhuman primates implicating the PFC, the amygdala, and their functional interactions in these processes, with links to experimental work and clinical findings in humans where possible.Subject terms: Neuroscience, Anatomy     

Molecular mechanisms regulating the interactions between the benzodazepines and GABA receptors in the central nervous system.

Using radioreceptor assay techniques to measure the kinetics of GABA and diazepam receptors, a relationship between GABA and benzodiazepine receptors has been firmly established in membranes of brain and neuroblastoma NB2a clonal cell lines. Occupancy of benzodiazepine receptors uncovers a new population of GABA receptors (GABA2 receptors) endowed with high affinity for GABA. Moreover, stimulation of GABA receptors increases the affinity of 1,4-benzodiazepine receptors for 1,4-benzodiazepines. This reciprocal interaction appears to be mediated by an endogenous regulatory protein (for details on this protein see [14 and 29]) which allosterically regulates GABA2 receptors while it competitively interacts with benzodiazepines for their specific binding sites. The rank order of potency of the various 1,4-benzodiazepines to block the action of this protein inhibitor on GABA receptors is related to their capacity to displace 3H-diazepam binding. These data suggest that the interaction between the 1,4-benzodiazepine receptors and the endogenous protein modulator of GABA2 receptors might play a role in the pharmacological action of the 1,4-benzodiazepines.     

中枢抑制药物与P-糖蛋白相互作用的研究进展

药物效应是由药物代谢酶、药物转运体、药物作用靶点等影响其药代动力学和药效学的基因产物所决定的。P-糖蛋白(P-gp)是目前研究较多的一类ATP结合盒转运体,P-gp的结构、特点及组织分布决定了其在药物体内过程的重要作用。很多中枢抑制药物都是P-gp的底物或调节子,P-gp在其体内的药代动力学行为中扮演着重要角色,可能决定着药物的有效性和安全性。为此本文就P-gp与各类中枢抑制药物相互作用的研究进展进行阐述。     

Evidence for interactions between central noradrenergic neurons and adrenal hormones in learning and memory.

The role of ascending noradrenergic projections in the acquisition and retention of a passive avoidance step-down response was evaluated by means of bilateral stereotaxic 6-hydroxydopamine-induced lesions of these systems. Lesions of the dorsal NA bundle alone, or in combination with lesions of the ventral NA bundle, failed to influence either the acquisition or retention of the passive avoidance response. In contrast, animals subjected to dorsal and ventral NA bundle lesions and adrenalectomy exhibited severe deficits in both the acquisition and retention of this response, and this effect was of the same magnitude as was observed after posttrial injections of diethyldithiocarbamate (DDC, 300 mg/kg). Adrenalectomy by itself had a small but significant effect on retention but did not influence acquisition of the response. The results are discussed with reference to the possibility that interactions between adrenal hormones and central NA mechanisms may serve important roles in learning and memory. However, the data provide no support for the hypothesis that central NA neurons are, by themselves, critically involved in these phenomena.     

Psychophysiological interactions between smoking and stress coping?

Earlier studies with different types of stressors suggested that cigarette smoking might selectively dampen physiological stress reactions in passive rather than in active coping situations. This hypothesis was tested in the present study using the same task for both types of coping, but with two different instructions. Twenty-four female regular smokers were assigned either to a group requiring active coping or to a group requiring passive coping with ongoing electric shocks, and tested in two sessions where they performed a pre- and a postsmoking/non-smoking trial of the rapid information processing task (RIP). Smoking increased RIP task performance, cardiovascular and electrocortical arousal, and reduced anxiety throughout the session. Active coping, as compared to passive coping, produced greater increases in heart rate and blood pressure, a greater pre- to post-treatment decrease in reaction time and higher pain ratings of the electrical shocks. However, interactions between the effects of smoking and the type of coping were few and did not suggest a plausible concept. Thus, it was concluded that, although the typical effects of smoking as well as the differentiation between active and passive coping seen earlier with the same paradigm were confirmed, cigarette smoking did not affect the effects of the two coping conditions in a differential way.     

Synergistic interactions between piracetam and dihydroergocristine in some animal models of cerebral hypoxia and ischaemia

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.     

Functional interactions between cannabinoid and metabotropic glutamate receptors in the central nervous system

The recent appreciation that two G-protein-coupled receptors, metabotropic glutamate and cannabinoid, are trans-synaptically linked by a small lipid messenger has profound implications, both for control of synaptic transmission and for novel therapeutic strategies. There is much evidence for this assertion and on the significance of this dual receptor cooperation for modulation of synaptic transmission in the central nervous system.     

Chronic ethanol exposure and protracted abstinence alter NMDA receptors in central amygdala.

We recently reported that chronic ethanol treatment (CET) and early withdrawal (2-8 h) altered glutamatergic transmission at both pre- and postsynaptic sites in central nucleus of the amygdala (CeA). Acute ethanol (44 mM) inhibited the NMDA receptor (NMDAR)-mediated EPSCs (NMDA-EPSCs) more in CeA neurons from CET rats than from na?ve rats and also decreased paired-pulse facilitation (PPF) of NMDA-EPSCs only in CET rats. To determine whether these CET effects persisted after prolonged withdrawal, we recorded intracellularly in rat CeA slices and measured mRNA and protein expression of CeA NMDAR subunits from CET rats and those withdrawn from ethanol for 1 or 2 weeks. At 1 week withdrawal, acute ethanol decreased evoked NMDA-EPSC amplitudes and NMDA currents induced by exogenous NMDA ( approximately 20%) equally to that in na?ve rats, indicating that CET effects on postsynaptic mechanisms reversed 1 week after CET cessation. However, acute ethanol still decreased PPF of NMDA-EPSCs, indicating that the acute ethanol-induced increase in glutamate release in CeA seen in CET rats was still present at this time. CET also significantly increased mRNA levels of NR1 and NR2B NMDAR subunits compared to control rats. At 1 week withdrawal, mRNA levels for NR1 and NR2B subunits were significantly decreased. These changes reversed at 2 weeks withdrawal. In Western blots, a significant increase in protein for all three subunits occurred in CeA from CET rats, but not after 1 and 2 weeks of withdrawal. These data indicate that CET induces reversible neuroadaptations in synaptic function, gene expression, and protein composition of NMDAR at CeA synapses.     

Individual differences in amphetamine self-administration: the role of the central nucleus of the amygdala.

Rats categorized as high responder (HR), based on their activity in an inescapable novel environment, self-administer more amphetamine than low responder (LR) rats. The current study examined if the central nucleus of the amygdala (ACe) contributes to the elevated response for amphetamine in HR rats. Male Sprague-Dawley rats were classified as HR and LR rats based on their activity in inescapable novelty and novelty place preference, and then were trained to self-administer amphetamine (0.1 mg/kg/infusion). Once stable responding was achieved, rats received microinfusions of the GABA(A) agonist muscimol (0.5 microg/0.5 microl) or phosphate-buffered saline into the ACe immediately before self-administration of amphetamine (0.1, 0.03, 0.01, or 0.001 mg/kg/infusion) or saline. An additional group of rats was trained to lever press for sucrose rather than amphetamine. Based on the inescapable novelty test, HR rats self-administered more amphetamine than LR rats at the 0.03 and 0.01 mg/kg/infusion unit doses; there were no significant individual differences in amphetamine self-administration based on the novelty place preference test. Inactivation of the ACe with muscimol decreased self-administration at the 0.03 and 0.01 mg/kg/infusion unit doses in HR rats, but had no effect on LR rats. ACe inactivation had no reliable effect on inactive lever responding and appeared to be region specific based on anatomical controls. In addition, while inactivation of the ACe decreased responding for sucrose, inactivation did not differentially affect HR and LR rats. These results suggest that the ACe contributes to the elevated rate of amphetamine self-administration in HR rats.     

Endogenous cannabinoids induce fever through the activation of CB1 receptors

Background and purpose:

The effects of centrally administered cannabinoids on body core temperature (Tc) and the contribution of endogenous cannabinoids to thermoregulation and fever induced by lipopolysaccharide (LPS) (Sigma Chem. Co., St. Louis, MO, USA) were investigated.

Experimental approach:

Drug-induced changes in Tc of male Wistar rats were recorded over 6 h using a thermistor probe (Yellow Springs Instruments 402, Dayton, OH, USA) inserted into the rectum.

Key results:

Injection of anandamide [(arachidonoylethanolamide (AEA); Tocris, Ellisville, MO, USA], 0.01–1 µg i.c.v. or 0.1–100 ng intra-hypothalamic (i.h.), induced graded increases in Tc (peaks 1.5 and 1.6°C at 4 h after 1 µg i.c.v. or 10 ng i.h.). The effect of AEA (1 µg, i.c.v.) was preceded by decreases in tail skin temperature and heat loss index (values at 1.5 h: vehicle 0.62, AEA 0.48). Bell-shaped curves were obtained for the increase in Tc induced by the fatty acid amide hydrolase inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (Cayman Chemical Co., Ann Arbor, MI, USA) (0.001–1 ng i.c.v.; peak 1.9°C at 5 h after 0.1 ng) and arachidonyl-2-chloroethylamide (ACEA; Tocris) (selective CB₁ agonist; 0.001–1 µg i.c.v.; peak 1.4°C 5 h after 0.01 µg), but (R,S)-(+)-(2-Iodo-5-nitrobenzoyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indole-3-yl] methanone (Tocris) (selective CB₂ agonist) had no effect on Tc. AEA-induced fever was unaffected by i.c.v. pretreatment with 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl) methanone (Tocris) (selective CB₂ antagonist), but reduced by i.c.v. pretreatment with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; Tocris) (selective CB₁ antagonist). AM251 also reduced the fever induced by ACEA or LPS.

Conclusions and implications:

The endogenous cannabinoid AEA induces an integrated febrile response through activation of CB₁ receptors. Endocannabinoids participate in the development of the febrile response to LPS constituting a target for antipyretic therapy.     

Synergistic interactions between forskolin, isoprenaline and substance P as secretagogues in rat parotid glands

Substance P, forskolin and isoprenaline stimulated rat parotid alpha-amylase secretion in vitro. Synergistic responses were observed with combinations of any two of the three secretagogues such that subthreshold doses of one caused a pronounced shift in the dose-response curve to the second. This potentiation of secretion could neither be explained by an interaction at the receptor recognition binding site, as identified by ligand binding, nor wholly by interactions in second messenger systems. Thus forskolin and isoprenaline were unable to alter substance P-induced changes in phosphatidylinositol metabolism. Similarly substance P was without effect on forskolin or isoprenaline-stimulated cAMP production. In contrast the potentiation of isoprenaline-induced amylase secretion by forskolin was preceded by a marked enhancement of cAMP production suggesting that the activation of the adenylate cyclase complex is reflected in the cellular response.     

beta-Adrenergic manipulation in amygdala central n. alters rabbit heart rate conditioning

The present study was conducted to assess the effects of beta-adrenergic manipulation within the central nucleus of the amygdala on Pavlovian heart rate conditioning in the rabbit. Administration of the beta-adrenergic antagonist dl-propranolol into the central nucleus impaired the acquisition of conditioned heart rate responding compared to a vehicle injected control group. No significant effects of dl-propranolol on either baseline heart rate or on the heart rate orienting response were observed. The effect of dl-propranolol on conditioning exhibited stereospecificity, and animals receiving combined intracerebral injections of dl-propranolol and the beta-adrenergic agonist 1-isoproterenol did not exhibit comparable conditioning impairments. In addition, dl-propranolol administration dorsal to the central nucleus or into amygdala sites anterior or posterior to the central nucleus was less effective. These results support the interpretation that beta-adrenergic activity within the central nucleus region of the amygdala complex contributes to the acquisition of classically conditioned heart rate responding.     

Effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat.

The effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat were determined using two animal models, the conditioned suppression of drinking (CSD) and defensive burying paradigms. For CSD conflict testing, water-restricted rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. CSD test sessions were 10 min in duration and were conducted 4 days per week. After at least 3 weeks of conflict testing, both punished (30-40 shocks per session) and unpunished (10-12 ml water per session) responding had stabilized. Subjects then received bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a 1-week recovery period, CSD conflict testing was reinstated and continued for 20 weeks. Amygdaloid-lesioned subjects accepted significantly more shocks than did sham controls. In addition, acute challenges with the benzodiazepine chlordiazepoxide (2.5-10 mg/kg, IP, 30-min pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-min pretreatment), and carbamazepine (10 mg/kg, IP, 10-min pretreatment) produced an increase in punished responding in both amygdaloid-lesioned and sham-treated subjects. Analysis of covariance (ANCOVA)-based adjusted means for the change in shocks received were not significantly different between the two groups. Following completion of the CSD studies, subjects were tested in the defensive burying paradigm. Although there was no significant difference between lesioned and sham-treated subjects on the percent of animals that exhibited burying, subjects with lesions of the central nucleus of the amygdala exhibited a significantly greater latency to initiate defensive burying.(ABSTRACT TRUNCATED AT 250 WORDS)