CB and cortex

Functional CB1 receptors are broadly expressed in neocortical GABAergic and glutamatergic neurons.

Related Articles

Functional CB1 receptors are broadly expressed in neocortical GABAergic and glutamatergic neurons.

J Neurophysiol. 2007 Apr;97(4):2580-9

Authors: Hill EL, Gallopin T, Férézou I, Cauli B, Rossier J, Schweitzer P, Lambolez B

The cannabinoid receptor CB1 is found in abundance in brain neurons, whereas CB2 is essentially expressed outside the brain. In the neocortex, CB1 is observed predominantly on large cholecystokinin (CCK)-expressing interneurons. However, physiological evidence suggests that functional CB1 are present on other neocortical neuronal types. We investigated the expression of CB1 and CB2 in identified neurons of rat neocortical slices using single-cell RT-PCR. We found that 63% of somatostatin (SST)-expressing and 69% of vasoactive intestinal polypeptide (VIP)-expressing interneurons co-expressed CB1. As much as 49% of pyramidal neurons expressed CB1. In contrast, CB2 was observed in a small proportion of neocortical neurons. We performed whole cell recordings of pyramidal neurons to corroborate our molecular findings. Inhibitory postsynaptic currents (IPSCs) induced by a mixed muscarinic/nicotinic cholinergic agonist showed depolarization-induced suppression of inhibition and were decreased by the CB1 agonist WIN-55212-2 (WIN-2), suggesting that interneurons excited by cholinergic agonists (mainly SST and VIP neurons) possess CB1. IPSCs elicited by a nicotinic receptor agonist were also reduced in the presence of WIN-2, suggesting that neurons excited by nicotinic agonists (mainly VIP neurons) indeed possess CB1. WIN-2 largely decreased excitatory postsynaptic currents evoked by intracortical electrical stimulation, pointing at the presence of CB1 on glutamatergic pyramidal neurons. All WIN-2 effects were strongly reduced by the CB1 antagonist AM 251. We conclude that CB1 is expressed in various neocortical neuronal populations, including glutamatergic neurons. Our combined molecular and physiological data suggest that CB1 widely mediates endocannabinoid effects on glutamatergic and GABAergic transmission to modulate cortical networks.

PMID: 17267760 [PubMed - indexed for MEDLINE]

CB and Nuc. Acc.

Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

Related Articles

Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

Ideggyogy Sz. 2007 Mar 30;60(3-4):187-91

Authors: Mátyás F, Watanabe M, Mackie K, Katona I, Freund TF

Several abused drugs are known to alter glutamatergic signaling in reward pathways of the brain, and these plastic changes may contribute to the establishment of addiction-related behaviour. Glutamatergic synapses of the prefrontal cortical projections to the nucleus accumbens (nAcb)--which are suggested to be under endocannabinoid (eCB) control - play a central role in the addiction process. The most abundant eCB in the brain is 2-arachi-donoyl-glycerol (2-AG). It is synthesized by diacylglycerol lipase alpha (DGL-alpha), and exerts its action via type 1 cannabinoid receptors (CB1). However, the precise localization of DGL-alpha and CB1 - i.e. the sites of synthesis and action of 2AG - is still unknown. At the light microscopic level, immunocytochemistry revealed a granular pattern of DGL-alpha distribution in the core of the nAcb. Electron microscopic analysis confirmed that these granules corresponded to the heads of dendritic spines. On the other hand, presynaptic axon terminals forming excitatory synapses on these spineheads were found to express CB1 receptors. Our results demonstrate that the molecular constituents for a retrograde endocannabinoid control of glutamatergic transmission are available in the core of the nAcb, and their relative subcellular location is consistent with a role of 2-AG in addiction-related plasticity of cortical excitatory synapses in this reward area.

PMID: 17451066 [PubMed - indexed for MEDLINE]

Glial Kir and epilepsy in hippocampus

Inwardly rectifying K(+) (Kir) channels antagonize ictal-like epileptiform activity in area CA1 of the rat hippocampus.

Related Articles

Inwardly rectifying K(+) (Kir) channels antagonize ictal-like epileptiform activity in area CA1 of the rat hippocampus.

Hippocampus. 2007 Jun 29;

Authors: Andreasen M, Skov J, Nedergaard S

Reactive glial cells, for example, from patients with temporal lope epilepsy have a reduced density of inward rectifying K(+) (Kir) channels and thus a reduced K(+) buffering capacity. Evidence is accumulating that this downregulation of Kir channels could be implicated in epileptogenesis. In rat hippocampal brain slices, prolonged exposure to the nonselective Kir channel antagonist, Cs(+) (5 mM), gives rise to an epileptiform field potential (Cs-FP) in area CA1 composed of an initial positive (interictal-like) phase followed by a prolonged negative (ictal-like) phase. We have previously shown that the interictal-like phase depends on synaptic activation. The present study extends these findings by showing that the ictal-like phase of the Cs-FP is (i) sensitive to osmotic expansion of the extracellular space, (ii) reversed very quickly during wash out of Cs(+), and (iii) re-established in the presence of Ba(2+) (30-200 muM) or isosmotic low extracellular concentration of Na(+) ([Na(+)](o), 51.25 mM). The interictal-like phase showed less or no sensitivity to these treatments. In the complete absence of Cs(+), the Cs-FP could be fully reconstructed by the combined application of 4-aminopyridine (0.5 mM), an isosmotic high extracellular concentration of K(+) ([K(+)](o), 7 mM), and low [Na(+)](o) (51.25 mM). These results suggest that the interictal-like phase is initiated through synaptic activation and results from an unspecific increase in neuronal excitability, whereas the ictal-like phase is entirely dependent on blockade of Kir channels in CA1. We propose that glial dysfunction-related loss of Kir channels may not alone be sufficient for starting the induction process, but will likely increase the tendency of an epileptogenic process to proceed into seizure activity. (c) 2007 Wiley-Liss, Inc.

PMID: 17604346 [PubMed - as supplied by publisher]

Substance P and hypothalamus

Substance P targets sympathetic control neurons in the paraventricular nucleus.

Related Articles

Substance P targets sympathetic control neurons in the paraventricular nucleus.

Circ Res. 2007 Jun 8;100(11):1650-8

Authors: Womack MD, Morris R, Gent TC, Barrett-Jolley R

The paraventricular nucleus (PVN) contains spinally-projecting neurons implicated in fine-tuning the cardiovascular system. In vivo activity of "presympathetic" parvocellular neurons is suppressed by tonic inhibition from GABA-ergic inputs, inhibition of which increases sympathetic pressor activity and heart rate. Targeting of this specific neuronal population could potentially limit elevations of heart rate and blood pressure associated with disease. Here we show, for the first time, that "presympathetic" PVN neurons are disinhibited by the neuropeptide substance P (SP) acting via tachykinin NK1 receptor inhibition of GABA(A) currents. Application of SP to the paraventricular nucleus of rats increases heart rate and blood pressure. In in vitro brain slice experiments, in the presence of GABA, 1 micromol/L SP increased action current frequency by a factor of 2.7+/-0.6 (n=5, P< or =0.05, ANOVA). Furthermore, 1 micromol/L SP inhibited GABA(A) currents by 70+/-8% (n=8, P< or =0.005 paired t test). These effects were abolished by NK1 antagonists, but not NK2 and NK3 antagonists. GABA(A) inhibition was not reproduced by NK2 or NK3 agonists. The inhibition of parvocellular GABA(A) currents by SP was also abolished by a protein kinase C (PKC) inhibitor peptide and mimicked by application of phorbol-12-myristate-13-acetate (PMA), implicating a PKC-dependent mechanism. Single-channel analysis indicates that SP acts through reduction of channel mean open-time (cmot): GABA(A) cmot being reduced by approximately 60% by SP (P< or =0.05 ANOVA, Bonferroni). These data suggest that tachykinins mediate their pressor activity by increasing the excitability of spinally-projecting neurons and identifies NK1 receptors as potential targets for therapeutic modulation of the cardiovascular system.

PMID: 17495222 [PubMed - indexed for MEDLINE]

PC &amp; excitotoxicity

Olfactory system modulation of hippocampal cell death.

Related Articles

Olfactory system modulation of hippocampal cell death.

Neurosci Lett. 2007 Jun 14;

Authors: Pope K, Wilson DA

The hippocampal dentate gyrus is a major recipient of olfactory input in rodents, via connections from the olfactory (piriform) cortex and the olfactory bulb to the entorhinal cortex. Given this connectivity and the known role of activity in dentate gyrus granule cell survival, the present experiment examined the immediate effects of loss of olfactory input to the hippocampus on apoptosis. Adults rats underwent unilateral or bilateral olfactory bulb ablations (OBX), and allowed to recover 24-72h before the piriform cortex and hippocampal dentate gyrus were processed for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL] of apoptotic cells. OBX transiently increased TUNEL-positive cells in the ipsilateral piriform cortex and dentate gyrus. Increased TUNEL-labeling was apparent within 24h in both structures, but was more extensive and prolonged in piriform cortex. The results suggest a trans-synaptic regulation of cell survival through at least two synapses.

PMID: 17597296 [PubMed - as supplied by publisher]

PC, AC and RC

Olfactory information converges in the amygdaloid cortex via the piriform and entorhinal cortices: observations in the guinea pig isolated whole-brain preparation.

Related Articles

Olfactory information converges in the amygdaloid cortex via the piriform and entorhinal cortices: observations in the guinea pig isolated whole-brain preparation.

Eur J Neurosci. 2007 Jun;25(12):3648-58

Authors: Kajiwara R, Tominaga T, Takashima I

The amygdaloid cortex (AC) has reciprocal connections with the entorhinal cortex (EC) and also receives projections from the olfactory bulb and the piriform cortex (PC). To assess the possibility that the AC and EC represent functionally coupled structures in the olfactory stream of information, we investigated the propagation pattern of neural activity in olfactory cortices - PC, AC and EC - using optical recordings with voltage-sensitive dyes in the guinea pig in vitro isolated whole-brain preparation. We observed two distinct pathways that convey neural activation evoked by olfactory nerve stimulation: a medial pathway from the PC to the AC, and a lateral pathway from the PC to the lateral EC along the rhinal sulcus. Besides being activated directly via the medial pathway, the AC was activated a second time via activity that propagated from the lateral EC. Lesion experiments revealed that the lateral pathway close to the rhinal sulcus is crucial for neural activation of the EC. Consistent with this activation pattern, we observed two separate, sharp downward deflections in field potential recordings, and we recorded synaptic potentials with multiple peaks from single neurons in the AC. Our findings suggest that the AC and EC are functionally coupled during olfactory information processing, and that this functional linkage may allow the AC to integrate olfactory sensation with information retained or processed in the EC.

PMID: 17610584 [PubMed - in process]

CB1 and apoptosis

The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells.

Related Articles

The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells.

Int J Cancer. 2007 Jun 21;

Authors: Greenhough A, Patsos HA, Williams AC, Paraskeva C

Deregulation of cell survival pathways and resistance to apoptosis are widely accepted to be fundamental aspects of tumorigenesis. As in many tumours, the aberrant growth and survival of colorectal tumour cells is dependent upon a small number of highly activated signalling pathways, the inhibition of which elicits potent growth inhibitory or apoptotic responses in tumour cells. Accordingly, there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death. There is emerging evidence that cannabinoids, especially Delta(9)-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. THC-induced apoptosis was rescued by pharmacological blockade of the CB1, but not CB2, cannabinoid receptor. Importantly, THC treatment resulted in CB1-mediated inhibition of both RAS-MAPK/ERK and PI3K-AKT survival signalling cascades; two key cell survival pathways frequently deregulated in colorectal tumours. The inhibition of ERK and AKT activity by THC was accompanied by activation of the proapoptotic BCL-2 family member BAD. Reduction of BAD protein expression by RNA interference rescued colorectal cancer cells from THC-induced apoptosis. These data suggest an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy. (c) 2007 Wiley-Liss, Inc.

PMID: 17583570 [PubMed - as supplied by publisher]