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S A Deadwyler

Publications and source records attributed to S A Deadwyler.

At least 19 recordsLinked to original sources
PubMed2005

Behaviorally relevant endocannabinoid action in hippocampus: dependence on temporal summation of multiple inputs.

Endocannabinoids have been shown to mediate depolarization-induced suppression of GABAergic inhibition (DSI), possibly via release and retrograde diffusion following moderate to severe depolarization of hippocampal pyramidal neurons. However, it is not clear how hippocampal neurons, which have relatively low firing rates in vivo, achieve the degree of depolarization required to release endocannabinoids. Here it is demonstrated that DSI is not dependent on the occurrence of action potentials in the postsynaptic neuron, but is mediated by depolarization-induced calcium entry via voltage-controlled calcium channels (VCCs). The optimal level of calcium entry, and subsequent DSI, are directly related to the frequency of depolarizing pulses, which differs between immature and adult hippocampus. However, it is shown via modeled spike train inputs that the frequency dependence of DSI is overcome if two or more convergent spike trains from different neurons with normal in vivo firing rates converge and overlap in time. In these modeled circumstances, endocannabinoid-mediated DSI occurs most often when converging synaptic inputs from multiple neurons fire in synchrony to allow temporal summation of local membrane events in postsynaptic cells to exceed threshold for calcium entry. It is therefore possible that such suppression of inhibition would only occur during the time that recipient hippocampal neurons receive multiple coincident excitatory synaptic inputs.

Action Potentials↗
PubMed2002

Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance.

Arc (also termed activity-regulated cytoskeleton-associated protein or Arg3.1), is an effector immediate early gene whose upregulation has been demonstrated during events of synaptic plasticity. In the present study, the possibility that Arc would be specifically upregulated in rats during the acquisition of a quickly learned behavioral task but not in overtrained animals was investigated. Three groups of rats, pseudotrained, newly trained and overtrained, were examined with respect to Arc expression following training on a simple operant lever-pressing task. Newly trained animals were killed 30 min following the session in which they demonstrated acquisition of the task, and overtrained animals were trained on the same task for 13-14 days and then killed. Relative to base level measures taken 6 h following the session, all three groups demonstrated significant levels of induction of Arc mRNA; however, newly trained animals exhibited heightened induction of Arc mRNA relative to both pseudotrained and overtrained animals. The increased levels of Arc mRNA in newly trained animals were located in the CA1 and CA3 fields of hippocampus, the subiculum, and the anterior cingulate, piriform, infra/prelimbic, perirhinal and entorhinal cortical areas. Additionally, Arc mRNA was expressed differentially across the above anatomic structures in a relative pattern that was the same in all three groups. Finally, levels of Arc mRNA in specific brain regions of newly trained animals correlated negatively with the rate of task acquisition, such that slow learners exhibited higher levels of Arc mRNA than fast learners. From these results we suggest that Arc is upregulated in an experience-dependent manner, with higher levels of induction occurring during the initial stage of learning. Furthermore, the finding of increased Arc levels in slow versus fast learners indicates that Arc expression may be associated with the length of time required to: (1) form new associations or (2) remodel existing connections. These results confirm other reports that Arc is a critical substrate for the synaptic plasticity underlying the acquisition of new behaviors.

Animals↗
PubMed2001

Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy.

The underlying cause of neocortical involvement in temporal lobe epilepsy (TLE) remains a fundamental and unanswered question. Magnetic resonance imaging has shown a significant loss in temporal lobe volume, and it has been proposed that neocortical circuits are disturbed functionally because neurons are lost. The present study used design-based stereology to estimate the volume and cell number of Brodmann's area 38, a region commonly resected in anterior temporal lobectomy. Studies were conducted on the neocortex of patients with or without hippocampal sclerosis (HS). Results provide the surprising finding that TLE patients have significant atrophy of neocortical gray matter but no loss of neurons. Neurons are also significantly larger, dendritic trees appear sparser, and spine density is noticeably reduced in TLE specimens compared with controls. The increase in neuronal density we found in TLE patients is therefore attributable to large neurons occupying a much smaller volume than in normal brain. Neurons in the underlying white matter are also increased in size but, in contrast to other reports, are not significantly elevated in number or density. Neuronal hypertrophy affects HS and non-HS brains similarly. The reduction in neuropil and its associated elements therefore appears to be a primary feature of TLE, which is not secondary to cell loss. In both gray and white matter, neuronal hypertrophy means more perikaryal surface area is exposed for synaptic contacts and emerges as a hallmark of this disease.

Adolescent↗
PubMed2000

Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats.

The memory-disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and the synthetic cannabinoid WIN 55,212-2 (WIN-2) were assessed in rats exposed to varying doses of each drug (Delta(9)-THC, 0.5-2.0 mg/kg; WIN-2, 0.25-0.75 mg/kg) during performance of a delayed nonmatch to sample (DNMS) task. Cannabinoids affected performance in a dose x delay-dependent manner, with WIN-2 showing a potency more than four times that of Delta(9)-THC. These effects on DNMS performance were eliminated if the cannabinoid CB1 receptor antagonist SR141617A (Sanofi Research Inc.) was preadministered, but doses of the antagonist alone had no effect on performance. Simultaneous recording from ensembles of hippocampal neurons revealed that both WIN-2 and Delta(9)-THC produced dose-dependent reductions in the frequency (i.e., "strength") of ensemble firing during the sample phase of the task to the extent that performance was at risk for errors on >70% of trials as a function of delay. This decrease in ensemble firing in the Sample phase resulted from selective interference with the activity of differentiated hippocampal functional cell types, which conjunctively encoded different combinations of task events. A reduction in ensemble firing strength did not occur in the nonmatch phase of the task. The findings indicate that activation of CB1 receptors renders animals at risk for retention of item-specific information in much the same manner as hippocampal removal.

Action Potentials↗
PubMed2000

Firing rate of nucleus accumbens neurons is dopamine-dependent and reflects the timing of cocaine-seeking behavior in rats on a progressive ratio schedule of reinforcement.

The progressive ratio (PR) schedule of reinforcement is used to determine the reinforcing properties of rewards such as drugs of abuse. In this schedule, the animal is required to press a lever a progressively increasing number of times to receive a reward; the highest ratio obtained before the animal ceases responding is termed "breakpoint." We recorded neuronal spike activity from cells in the nucleus accumbens (NAc) of rats responding on a PR schedule for cocaine reinforcement. A common subtype of NAc cells demonstrated firing rates that varied according to the time between cocaine deliveries. The firing rate was inversely related to the NAc cocaine level predicted by a pharmacokinetic model. At higher response-to-reward ratios, inter-reward intervals were increased, resulting in a decrease in modeled cocaine level and a concomitant increase in firing rate over the session. The final increase in firing rate above a threshold value suggests a neural correlate of breakpoint. The effects of preadministration of dopamine D1 or D2 antagonists on the animals' behavior were similar in that both reduced breakpoint; however, each antagonist had markedly different effects on NAc cell firing. The D1 antagonist SCH23390 reduced firing rates, even at low cocaine levels, whereas the D2 antagonist eticlopride induced a rightward shift in the dose dependence of NAc cell firing relative to modeled cocaine level. Our results suggest that the firing of NAc cells reflects changes in cocaine levels and thereby contributes to the temporal spacing of self-administration and to the cessation of responding at breakpoint.

Animals↗
PubMed2000

Cannabinoid receptor activation in CA1 pyramidal cells in adult rat hippocampus.

Intracellular assessments of the physiological actions of cannabinoid receptor agonists and antagonists on adult hippocampal CA1 pyramidal cells in the in vitro slice preparation were performed using current clamp and conventional sharp-electrode intracellular recording procedures. Several manipulations were performed to delineate putative currents and conductance mechanisms affected by the cannabinoid receptor agonist WIN 55,212-2 (WIN-2). This compound produced a tonic hyperpolarization of the pyramidal cell membrane that was bicuculline sensitive, reversed by changing the chloride gradient, and abolished by the addition of TTX to the bathing medium. Instantaneous membrane input resistance, computed from hyperpolarizing current pulses (peak R(in)) was also reduced significantly in the presence of WIN-2 and was accompanied by enhancement of a superimposed slow depolarization that reduced steady-state R(in) (SSR(in)); both effects were resistant to barium. Intracellular perfusion of cesium acetate (CsAc) and the sodium/potassium channel blocker, QX314, each blocked the effect of WIN-2 on R(in) and SSR(in). WIN-2 also reduced input resistance calculated from depolarizing current injections (R(d)). This effect was also blocked by atropine, as well as media containing TTX or low Ca(2+). Each of the above effects of WIN-2 was blocked by the cannabinoid receptor antagonist SR141716A, showing a dependence on CB1 cannabinoid receptors. Several known pre- and postsynaptic processes in adult pyramidal cells are discussed which could be responsible for these cannabinoid-produced changes in membrane resistances.

Action Potentials↗
PubMed2000

Protein kinase-dependent phosphorylation and cannabinoid receptor modulation of potassium A current (IA) in cultured rat hippocampal neurons.

The potent cannabinoid receptor agonist WIN 55,212-2 produces positive shifts in steady-state inactivation of the potassium A current (IA) in rat hippocampal neurons via an adenosine 3',5'-cyclic monophosphate (cAMP)-, protein kinase A (PKA)-dependent process. This effect is probably mediated by phosphorylation or dephosphorylation of the IA channel protein. The role of protein phosphorylation in this cascade was tested by testing cannabinoid actions in cultured hippocampal neurons (pyramidal cells) that were exposed also to either the catalytic subunit of PKA (PKAc), a PKA-specific phosphorylation inhibitor (IP-20, Walsh peptide), or a potent protein phosphatase inhibitor (okadaic acid). Cannabinoids such as WIN 55,212-2 produce a positive (rightwards) shift in the steady-state inactivation of IA, thus providing increased current at a given membrane voltage. Cells dialyzed with PKAc showed a negative shift in IA inactivation, opposite to that produced by cannabinoids, and similar to that produced by increased levels of cAMP. In addition, PKAc completely blocked the positive shift produced by WIN 55,212-2. In contrast, dialysis of cells with IP-20 produced a positive shift in steady state inactivation of IA, similar to that produced by WIN, but the effects were not additive with cannabinoid receptor activation. The phosphatase inhibitor, okadaic acid produced a small negative shift in IA steady-state inactivation when administered alone, and blocked the positive shift produced by WIN 55,212-2. Okadaic acid also enhanced the negative shift in IA inactivation when co-administered with forskolin. The effects of okadaic acid and WIN 55,212-2 were not additive, suggesting a common pathway. These results demonstrate that IA is altered by direct manipulations of the phosphorylation status of the channel protein, and that cannabinoid effects on IA are probably mediated by dephosphorylation of the IA channel.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Differential information processing by hippocampal and subicular neurons.

It has been known for some years that hippocampal neurons are critically involved in processing of information necessary for encoding memories. What is less understood is the role of the subiculum in this process. We describe here differential response characteristics of subicular and hippocampal neurons in rats during execution of a delayed-nonmatch-to-sample short-term memory task. Subicular neurons, unlike hippocampal neurons, fire primarily in the delay interval of the task and appear to provide a temporal linkage between events encoded in hippocampus during the sample and nonmatch phases. Indeed, a large proportion of subicular neurons fire robustly for the entire duration of the delay only. Further analyses using electrical activation methods indicate that subicular neurons that receive short latency inputs from the anterior thalamus and do not project to cingulate cortex are the most responsive to stimuli with behavioral significance.

Afferent Pathways↗
PubMed2000

Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons.

The current study showed that potassium K current (I(K)), which is evoked at depolarizing potentials between -30 and +40 mV in cultured hippocampal neurons, was significantly reduced by exposure to the CB1 cannabinoid receptor agonist WIN 55,212-2 (WIN-2). WIN-2 (20-40 nM) produced an average 45% decrease in I(K) amplitude across all voltage steps, which was prevented by SR141716A, the CB1 receptor antagonist. The cannabinoid receptor has previously been shown to be G(i/o) protein-linked to several cellular processes; however, the decrease in I(K) was unaffected by modulators of G(i/o) proteins and agents that alter levels of protein kinase A. In contrast, CB1 receptor-mediated or direct activation of G(s) proteins with cholera toxin (CTX) produced the same decrease in I(K) amplitude as WIN-2, and the latter was blocked in CTX-treated cells. G(s) protein inhibition via GDPbetaS also eliminated the effects of WIN-2 on I(K). Consistent with this outcome, activation of protein kinase C (PKC) by arachidonic acid produced similar effects to WIN-2 and CTX. Kappa opioid receptor agonists, which also reduce I(K) amplitude via G(s) proteins, were compared with WIN-2 actions on I(K.) The kappa receptor agonist U50,488 reduced I(K) amplitude in the same manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased I(K) amplitude and significantly reduced the effect of co-administered WIN-2. The results indicate that CB1 and kappa receptor activation is additive with respect to I(K) amplitude, suggesting that CB1 and kappa receptors share a common G(s) protein signaling pathway involving PKC.

Analgesics↗
PubMed1999

Distribution of spatial and nonspatial information in dorsal hippocampus.

The hippocampus in the mammalian brain is required for the encoding of current and the retention of past experience. Previous studies have shown that the hippocampus contains neurons that encode information required to perform spatial and nonspatial short-term memory tasks. A more detailed understanding of the functional anatomy of the hippocampus would provide important insight into how such encoding occurs. Here we show that hippocampal neurons in the rat are distributed anatomically in distinct segments along the length of the hippocampus. Each longitudinal segment contains clusters of neurons that become active when the animal performs a task with spatial attributes. Within these same segments are ordered arrangements of neurons that encode the nonspatial aspects of the task appropriate to those spatial features. Thus, anatomical segregation of spatial information, together with the interleaved representation of nonspatial information, represents a structural framework that may help to resolve conflicting views of hippocampal function.

Animals↗
PubMed1999

Effects of ibotenate hippocampal and extrahippocampal destruction on delayed-match and -nonmatch-to-sample behavior in rats.

The effects of ibotenate lesions of the hippocampus (HIPP) or hippocampus plus collateral damage to extrahippocampal structures (HCX) were investigated in rats trained to criterion on spatial versions of either a delayed-match (DMS) or delayed-nonmatch-to-sample (DNMS) task. After recovery from surgery, animals were retrained at "0" sec delays, then assessed at 0-30 sec delays for 15 d, retrained again at 0 sec delays, and retested for another 25 d on 0-30 sec delays. Pretrained HIPP-lesioned animals showed marked delay-dependent deficits in both tasks that never recovered. Detailed examination of within- and between-trial performance factors, including changes in response preferences, length of previous trial delay, and sequential dependencies, revealed important factors operating in lesioned animals that were either absent or insignificant before the lesion. Pretrained HCX-lesioned animals showed deficits similar to those of HIPP animals, with the noticeable exception of a strong "recency" influence of the previous trial. Another group of HIPP- and HCX-lesioned animals trained on the tasks after the lesion showed reduced impairments of the type described above, suggesting that extrahippocampal structures trained after the lesion can assume the role of the hippocampus to some degree. The findings indicate that both the type of lesion and the previous history of the animal determine the postlesion DMS and DNMS performance of animals suffering damage to the hippocampus and/or related structures.

Animals↗
PubMed1999

Anatomic model of hippocampal encoding of spatial information.

Place cells were recorded simultaneously from identified locations along the longitudinal axis of the CA3 and CA1 subregions of hippocampus with a sixteen site electrode array while rats performed a simple pellet chasing task (Deadwyler et al., J Neurosci 1996;16:354-372; Hampson et al., Hippocampus 1996;6:281-293). Cells in CA3 or CA1, separated by 100-300 microm (two electrode locations), exhibited high cross-correlations with respect to place field firing in a given location in the chamber. This pattern of co-activity changed abruptly to low cross-correlations when the longitudinal distance between recording sites increased to 400-1,000 microm. Surprisingly, cells located 1,200-1,400 microm apart again exhibited similar place fields, suggesting a repeating pattern of place field representation within hippocampus. These features were used to construct a model of hippocampal place cell activation using known anatomic connections and projections between CA3 as well as CA1 pyramidal cells. The model provides a topographic representation in hippocampus of the animals' movements around the chamber as different place cells become activated. The model utilizes key landmarks (i.e., corners and walls) to define the animals' movement trajectories through successive place fields and to construct corresponding patterns of place cell firing in hippocampus. This is accomplished via a topological transformation of the chamber's key landmarks projected onto the anatomy of the CA3 and CA1 subregions. The primary feature of the model is that it can, within limited capacity, accurately encode where the animal has been, rather than where it is going. The model, therefore, appears to be more appropriate for memory required to return to particular locations than for initial guidance into those locations.

Animals↗
PubMed1999

Cannabinoids, hippocampal function and memory.

Prior studies from this laboratory have shown that the psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC), interferes with short-term memory (1-3) in both delayed match and nonmatch to sample tasks (DMS/DNMS). Recent experiments have shown that other cannabinoids such as the potent CB1 receptor agonist, WIN 55,212-2 produces a delay-dependent deficit in the DNMS task at a dose range (0.10-0.50 mg/kg) well below that of delta9-THC which was blocked by the CB11 receptor antagonist SR141716A (Sanofi Inc). The effects of WIN 55,212-2 at low doses were similar to those of isolated lesions of the hippocampus, whereas high doses (0.50 mg/kg, i.p.) produced effects similar to lesions of both hippocampus and surrounding retrohippocampal areas. The low dose effect was delay-dependent while the high dose introduced an additional deficit at short delays that was sensitive to both SR141716A and the GABA(B) receptor antagonist, phaclofen. Comparison of lesion vs. cannabinoid effects on DNMS performance suggests that CB1 receptors on hippocampal neurons interfere with the processing of DNMS task-specific information within a trial. CB1 receptors on hippocampal GABAergic interneurons and in retrohippocampal areas appear to influence the ability to maintain segregation of information between trials in the task.

Animals↗
PubMed1999

Examination of factors mediating the transition to behaviorally correlated nucleus accumbens cell firing during cocaine self-administration sessions in rats.

We have previously reported that at the initiation of cocaine self-administration sessions, neurons in the nucleus accumbens (NA) exhibit a spontaneous transition in firing rate from activity unrelated to the reinforced response, to one of four types of patterned discharges (Carelli RM, King VC, Hampson RE, Deadwyler SA. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res 1993;626:14-22; Carelli RM, Deadwyler SA. Dose-dependent transitions in nucleus accumbens cell firing and behavioral responding during cocaine self-administration sessions in rats. J Pharm Exp Ther 1996;277(1):385 393; Carelli RM, Deadwyler SA. Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals. Pharmacol Biochem Behav 1997;57:(2)1-10). This transition in NA cell firing is cocaine dose-dependent and is accompanied by a shift from high response rates at the start of the session ('Load-up' behavior) to a lower steady rate of responding thereafter (termed 'Session' phase responding). Two experiments were conducted to examine further factors that may mediate this process. Experiment 1 examined the effects of pre-session, response-independent delivery of cocaine on behavioral/neural transitions. Results revealed an absence of Load-up responding and the immediate onset of NA patterned activity at the start of the session. Experiment 2 examined the involvement of dopamine D1 versus D2 receptors in mediating the corresponding behavioral/neural transitions. Animals were pretreated with either saline, the dopamine D1 receptor antagonist SCH23390 (2.5-20 microg/kg, s.c.), or the dopamine D2 receptor antagonist eticlopride (2.5-20 microg/kg, s.c.) 30 min prior to the cocaine (0.33 mg/inf) self-administration session. SCH23390 significantly increased the number of Load-up responses at 10 and 20 microg/kg and the number of responses following the Load-up phase (i.e. during the Session phase) at 5, 10, and 20 microg/kg. Eticlopride increased the number of Session responses (5, 10, and 20 microg/kg), but did not alter the number of Load-up responses at any dose tested. The transition in NA cell firing corresponded with the shift in behavioral responding and was delayed within the session following SCH23390 but not eticlopride pretreatment. These findings support the notion that cocaine self-administration sessions in rats consists of two distinct behavioral phases that are mediated by different neurophysiological mechanisms operating in the NA.

Analysis of Variance↗
PubMed1999

Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain.

Chronic treatment of rats with delta9-tetrahydrocannabinol (delta9-THC) results in tolerance to its acute behavioral effects. In a previous study, 21-day delta9-THC treatment in rats decreased cannabinoid activation of G proteins in brain, as measured by in vitro autoradiography of guanosine-5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) binding. The present study investigated the time course of changes in cannabinoid-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding in both brain sections and membranes, following daily delta9-THC treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time-dependent decreases in WIN 55212-2-stimulated [35S]GTPgammaS and [3H]WIN 55212-2 binding in cerebellum, hippocampus, caudate-putamen, and globus pallidus, with regional differences in the rate and magnitude of down-regulation and desensitization. Membrane binding assays in these regions showed qualitatively similar decreases in WIN 55212-2-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding (using [3H]SR141716A), and demonstrated that decreases in ligand binding were due to decreases in maximal binding values, and not ligand affinities. These results demonstrated that chronic exposure to delta9-THC produced time-dependent and region-specific down-regulation and desensitization of brain cannabinoid receptors, which may represent underlying biochemical mechanisms of tolerance to cannabinoids.

Animals↗
PubMed1999

Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture.

Cannabinoid (CB(1)) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7-15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (I(A)) and D (I(D)) were isolated from a composite tetraethylammonium-insensitive current (I(comp)) by blockade with either 4-aminopyridine (500 microM) or dendrotoxin (2 microM) and subtraction of the residual I(A) from I(comp) to reveal I(D). The time constants of inactivation (tau) of I(A) and I(D) as determined in this manner were found to be quite different. The CB(1) agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of I(A) and a simultaneous voltage-independent reduction in the amplitude of I(D) in the same neurons. The EC(50) value for the effect of WIN 55,212-2 on I(D) amplitude (13.9 nM) was slightly lower than the EC(50) value for its effect on I(A) voltage dependence (20.6 nM). Pretreatment with either the CB(1) antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on I(A) and I(D), whereas cellular dialysis with guanosine-5'-O-(3-thio)triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on I(A) and I(D) were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate I(A) and I(D) channels and the contribution of each to composite voltage-gated potassium currents in these cells.

4-Aminopyridine↗
PubMed1998

Effects of long-term exposure to delta9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions.

The time course of changes across 21 days of continuous exposure to Delta9-tetrahydrocannabinol (Delta9-THC) was assessed for the level of cannabinoid receptor (CB1) mRNA expression in three different rat brain regions: cerebellum, hippocampus and corpus striatum. Expression levels of CB1 mRNA were determined using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) following a protocol which included a gene standard, 28S ribonucleic acid protein (rRNA), for normalization of levels of RNA in the three different brain regions. The levels of CB1 mRNA were assessed in four different rats at each of seven time points (6 h, and 1, 2, 3, 7, 14 and 21 days) during a 21-day Delta9-THC one dose day-1 (10 mg kg-1) treatment regimen. In the cerebellum and hippocampus, CB1 mRNA levels were increased above vehicle control animals at 7 and 14 days of treatment. In the striatum the levels of CB1 transcripts were severely reduced from days 2-14. CB1 message expression in all three brain areas returned to vehicle control levels by day 21 of Delta9-THC treatment, a time at which behavioral tolerance has been previously reported. An additional measure, receptor stimulated GTPgammaS binding, performed over the same time period revealed differential desensitization within the 3 brain areas as a function of chronic exposure to Delta9-THC. Hippocampus was the earliest to desensitize decreasing to 35% of control by treatment day 7, followed by a decrease in the cerebellum to that same level on day 14 of treatment. The striatum showed only half that degree of desensitization (65%) over the entire 21-day treatment period. Comparisons suggests that CB1 message may be regulated by different effector systems in each of the three areas during chronic Delta9-THC exposure.

Animals↗