Biomedical subjects

Alexander F Hoffman

Publications and source records attributed to Alexander F Hoffman.

7 recordsLinked to original sources

PubMed2007

Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation.

Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Delta(9)-THC for hippocampal function are poorly understood. Rats were injected with Delta(9)-THC (10 mg/kg, i.p., q.d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, Delta(9)-THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high-frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d Delta(9)-THC-treated animals. Delta(9)-THC also blocked HFS-LTP after 3 d, but not 1 d of treatment. The complete blockade of LTP persisted for 3 d after the last Delta(9)-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Delta(9)-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Delta(9)-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Delta(9)-THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated Delta(9)-THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.

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PubMed2006

Visualizing cannabinoid effects using brain slice imaging and electrophysiological approaches.

The use of electrophysiological recordings in brain slices is now routinely used to assess the actions of cannabinoid ligands within various central nervous system nuclei. In this chapter we describe common protocols involving both intracellular and extracellular recording techniques in the hippocampus, where the presynaptic modulatory effects of cannabinoid receptor activation have been studied in detail. In addition to describing the basic electrophysiological setup needed for these recordings, we will address common technical problems and limitations involved in working with highly lipophilic compounds, such as the cannabinoid ligands, in brain slices.

Animals↗

PubMed2005

Species and strain differences in the expression of a novel glutamate-modulating cannabinoid receptor in the rodent hippocampus.

A novel, non-CB1 cannabinoid receptor has been defined by the persistence of inhibition of glutamatergic EPSPs by the cannabinoid receptor agonist WIN55,212-2 in mice lacking the cloned CB1 receptor (CB1-/-) (Hajos et al., 2001). This novel receptor was also distinguished from CB1 by its sensitivity to the antagonist SR141716A and its insensitivity to the antagonist AM251 (Hajos & Freund, 2002). We have chosen to refer to this putative receptor as CBsc due to its identification on Schaffer collateral axon terminals in the hippocampus. We examined properties of CBsc receptors in Sprague Dawley (SD) rats and two strains of wild-type (WT) mice (C57BL/6J and CD1) used as backgrounds for two independent lines of CB1-/- mice (Ledent et al., 1999; Zimmer et al., 1999). The inhibition of synaptic glutamate release by WIN55,212-2 was observed in hippocampal slices from WT CD1 mice and SD rats but was absent in WT C57 mice. We also found that AM251 and SR141716A antagonized the effect of WIN55,212-2 in hippocampal slices from CD1 mice and SD rats demonstrating a lack of selectivity of these ligands for CB1 and CBsc receptors in these animals. The results indicate that the glutamate-modulating CBsc cannabinoid receptor is present in the hippocampi of CD1 mice and SD rats but not in C57BL/6J mice. Thus, we have identified animal models that may permit the study of cannabinoids independently of the novel CBsc receptor (C57CB1+/+), the CBsc receptor independently of the cloned CB1 receptor (CD1CB1-/-), or in the absence of both receptors (C57CB1-/-).

Adenosine↗

PubMed2004

Marijuana and cannabinoid regulation of brain reward circuits.

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

Animals↗

PubMed2003

Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure.

The rewarding properties of the psychoactive constituents of marijuana, termed "cannabinoids," may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Delta9-tetrahydrocannabinol (THC), or the cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slices from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the mu-opioid agonist Tyr-D-Ala2, N-CH3-Phe4,Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Delta9-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids.

Animals↗

PubMed2003

Synthesis, structure-activity relationship, and evaluation of SR141716 analogues: development of central cannabinoid receptor ligands with lower lipophilicity.

Exploration of the central CB1 cannabinoid receptors using positron emission tomography (PET) will allow for an understanding of the pharmacological and physiological role played by these receptors in the CNS. Current tracers are highly lipophilic compounds that exhibit very high nonspecific to specific binding ratios and as a result are inapt for use in humans. We have synthesized a series of less lipophilic analogues of SR141716 to serve as potential radioligands. Binding affinities of the series and a functional electrophysiological assay of three of our compounds have been presented.

Animals↗

PubMed2003

Functional localization of cannabinoid receptors and endogenous cannabinoid production in distinct neuron populations of the hippocampus.

The possible localization of cannabinoid (CB) receptors to glutamatergic and GABAergic synaptic terminals impinging upon GABAergic interneurons in the CA1 region of the rat hippocampus was examined using the electrophysiological measurement of neurotransmitter release in brain slices. Whereas activation of cannabinoid receptors via the application of the cannabinoid agonist WIN55,212-2 significantly and dose-dependently reduced evoked IPSCs recorded from interneurons possessing somata located in the stratum radiatum (S.R.) and stratum oriens (S.O.) lamellae, evoked glutamatergic EPSCs were unaffected in both neuronal populations. However, in agreement with previous reports, WIN55,212-2 significantly reduced EPSCs recorded from CA1 pyramidal neurons. Additional experiments confirmed that the effects of WIN55,212-2 on IPSCs were presynaptic and that they could be blocked by the CB1 receptor antagonist SR141716A. The involvement of endogenous cannabinoids in the presynaptic inhibition of GABA release was also examined in the interneurons and pyramidal cells using a depolarization-induced suppression of inhibition (DSI) paradigm. DSI was observed in CA1 pyramidal neurons under control conditions, and its incidence was greatly increased by the cholinergic agonist carbachol. However, DSI was not observed in the S.R. or S.O. interneuron populations, in either the presence or absence of carbachol. Whereas DSI was not present in these interneurons, the inhibitory inputs to these cells were modulated by the synthetic cannabinoid WIN55,212-2. These data support the hypothesis that cannabinoid receptors are located on inhibitory, but not excitatory, axon terminals impinging upon hippocampal interneurons, and that CA1 pyramidal neurons, and not interneurons, are capable of generating endogenous cannabinoids during prolonged states of depolarization.

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