Over the last decade a great deal of drug addiction research has focused attention on understanding the role of dopamine release from the ventral tegmental area (VTA) into the nucleus accumbens. One of the reasons for the special attention on the VTA has been the role that dopamine plays in encoding novel rewarding stimuli such as food, sex, and drugs with pleasurable side effects (Shultz, 2002). However, more recent imaging studies with drug using subjects have shown that brain regions other than the VTA and nucleus accumbens are involved in the addictive process. These brain regions showed changes in activity associated with chronic drug use and include the orbitofrontal cortex, cingulate gyrus, thalamus, amygdala, and hippocampus (for review see Volkow et al., 2004). Furthermore, transmitter systems other than dopamine appear to be altered by drug addiction, including the endogenous opioids, a group of peptides with rewarding properties that are associated with central nervous system pain suppression. In human clinical studies, opioid antagonists have been used to attenuate the rewarding effects of alcohol (see review Volkow and Li, 2004), and opioid peptides appear to be decreased in cocaine using subjects (Zubieta et al., 1996). It is probable that the mechanisms involved in the addictive process arise from changes in multiple brain circuits and transmitter systems; however, this review will focus on a specific subtype of opioid peptide receptor, the mu opioid receptors (MOR), and on its function in the hippocampus and potential role in opiate addiction.
Opiate addiction remains a considerable problem in the U.S.. Addiction to opiates may lead to compulsive drug use at the expense of everything in the drug user’s life. Regardless of the devastating effect chronic drug use has had on a recovered drug user; they nevertheless frequently relapse into a life of chronic opioid abuse. This relapse is often triggered by cravings produced by the exposure of the recovered drug user to cues that they had previously associated with drug use. Clearly, understanding how these associations are formed is crucial to determining the neural mechanisms that lead to addiction and relapse.
Hippocampal function is required for the formation of declarative long term memories. These are the types of memories where predictive relationships can be formed between an external environment and the presentation of a reward, such as an addictive drug. Therefore, it is not surprising that rodents with hippocampal lesions fail to learn to systemically self-administer morphine when presented with drug-associated cues (Olmstead & Franklin, 1997a). Furthermore, rodents can be trained to self-administer morphine directly into the hippocampus (Corrigall & Linesman, 1988; Steven et al., 1991; Self and Stein, 1993; but see Olmstead & Franklin, 1997b), suggesting that opioid receptors in the hippocampus may be at least part of the “first response” component of opioid addiction for these animals. Coupled with the fact that MORs are required for the addictive properties of opioids (Matthes et al., 1996), these behavioral studies suggest that the hippocampus is involved in the formation of memories that lead to addictive behavior and that MORs in the hippocampus itself may modulate the formation of memories associated with addiction.
Precisely how MOR activation affects behavior and hippocampal network function is not fully understood. However, it is known that the activation of MORs in area CA1 of the rat hippocampus can modulate both spatial learning and synaptic plasticity. Interestingly, the manner by which MOR activity modulates spatial learning and synaptic plasticity is dependent on the stage of drug dependence of the animal. In the drug naïve animal, the activation of MORs facilitates a long term decrease in excitatory synaptic transmission called long term depression (LTD, Wagner et al., 2001). However, when the animal is dependent on morphine, the activation of MORs facilitates the ability to produce a long term increase in excitatory synaptic transmission called long term potentiation (LTP) (Mansouri et al., 1997; 1999; Pourmotabbed et al., 1998). In contrast, when the animal is withdrawn from morphine, MOR activation inhibits that ability to induce LTP and also compromises spatial learning (Pu et al., 2002). In addition to modulating synaptic plasticity, MOR activation in the hippocampus may alter the coding of information in the hippocampus by disrupting the synchronous activity of populations of CA1 pyramidal cells (Whittington et al., 1998; Faulkner et al., 1998; 1999). It has been suggested that synchronous activity by groups of principle neurons in the hippocampus may be the neural representation of the sensory information perceived by the animal in navigating their environment. Therefore, depending on the drug experience of the animal, morphine activation of MOR in the hippocampus may be capable of differentially modulating memory processes, synaptic plasticity and the encoding of information. Exactly how the activation of MOR receptors in the hippocampus accomplishes this through the inhibition and activation of certain neuronal types is not completely understood.
MOR Distribution and Synaptic Inhibition
The anatomical localization of MORs in hippocampal CA1 can provide insight into the mechanisms by which MOR activation modulates the CA1 network. Autoradiography and immunohistochemical studies have shown that MORs are found in moderate concentrations in hippocampal CA1. Within this area, MORs are concentrated in the principle neuron cell body layer, the stratum pyramidale (SP), although there are significant amounts of MORs in the layer containing the distal apical dendrites of CA1 pyramidal cells, the stratum lacunosum-moleculare (SLM) (Atweh & Kuher, 1977; Herkenham & Pert, 1980; Crain et al., 1986; McLean et al., 1987; Mansour et al., 1987, 1994, 1995; Arvidsson et al., 1995; Bausch & Chavkin, 1995; Ding et al., 1996). The autoradiography and immunohistochemical studies have been confirmed and extended by in situ hybridization studies that demonstrated the presence of MOR mRNA in neurons located primarily in SP and the output layer, stratum oriens (SO) (Thompson et al., 1993; Mansour et al., 1994; Delfs et al., 1994; Stumm et al., 2004). Furthermore, MOR mRNA was found largely in interneurons that contained parvalbumin, a marker for interneurons that synapse on pyramidal cell bodies, and also in somatostatin interneurons, a marker for interneurons that primarily project to the distal dendrites of CA1 pyramidal cells (Stumm et al., 2004). However, MOR mRNA was also found in interneurons that were found near the border of the proximal dendritic layer, stratum radiatum (SR), and the distal dendritic layer, SLM. This smaller population of interneurons often contained calretinin, which is a marker for interneurons that primarily innervate other interneurons (Stumm et al., 2004). Higher resolution light and electron microscopy studies have confirmed these in situ studies by demonstrating that MOR-like immunoreactivity (MOR-ir) exclusively localized to axons, terminals, dendrites and somata of GABAergic interneurons (Kalyuzhny et al., 1997; Drake & Milner, 1999, 2002). Furthermore, MOR-ir was found to be preferentially localized to interneurons that innervated pyramidal neuron cell bodies; however, there was also a significant amount of MOR-ir found on interneurons that innervated the distal dendrites of CA1 pyramidal cells in the SLM, the area that receives cortical inputs from the entorhinal cortex as well as from the thalamus (Drake & Milner, 2002). Therefore, based on anatomical evidence alone, it appears that MOR activation primarily affects the hippocampal CA1 network by modulating inhibitory interneurons that influence the output of CA1 pyramidal cells with perhaps a small additional effect on the inputs to their distal dendrites.
Direct and indirect recording of interneuron activity supports the anatomical data suggesting that MOR activation modulates interneuron function in hippocampal CA1. MOR agonists have been shown to both hyperpolarize inhibitory interneurons (Madison & Nicoll 1988; Wimpey & Chavkin 1991; Svoboda & Lupica 1998; Svoboda et al. 1999) and presynaptically inhibit the release of GABA from interneuron terminals (Nicoll et al. 1980; Masukawa & Prince 1982; Swearengen & Chavkin, 1989; Wimpey et al., 1990; Cohen et al. 1992; Lupica et al. 1992; Capogna et al. 1993; Rekling 1993; Lupica 1995). Furthermore, morphological reconstruction of interneurons in SO showed that nearly all of the recorded interneurons that project to the somata of pyramidal neurons were hyperpolarized by MOR agonists whereas less than half of the interneurons that project to the dendritic fields of pyramidal cells were hyperpolarized by MOR activation (Svoboda et al., 1999). These findings are in agreement with the anatomical data and suggest that MOR activation primarily increases the output of CA1 pyramidal neurons by suppressing inhibition at their somata.
MOR Activation and CA1 Network Activity
Neuronal network activity can be assessed in a number of ways. Studies examining the effects of MOR activation on CA1 hippocampal network activity have measured the excitability of CA1 pyramidal cells, the resting membrane potential of CA1 pyramidal cells and the efficacy of excitatory synaptic inputs onto CA1 pyramidal cells. As would be expected from the anatomical localization of MORs in hippocampal CA1, MOR agonists had no direct effect on the resting membrane potential or firing properties of CA1 pyramidal cells, presumably because CA1 pyramidal cells do not express MORs (Nicoll et al., 1980; Dingledine 1981; Siggins & Zieglgansberger 1981; Sweargengen & Chavkin, 1989; Lupica et al., 1992). However, MOR activation did increase the number of action potentials observed in CA1 pyramidal cells in response to excitatory synaptic stimulation (Martinez et al., 1979; Corrigall & Linesman, 1980; Haas and Ryall, 1980; Nicoll et al., 1980; Dingledine, 1981; Lynch et al., 1981; Masukawa & Prince, 1982; Neumaier et al., 1988; Swearengen & Chavkin, 1989). Interestingly, this increased response of CA1 pyramidal cell firing to excitatory synaptic input was not accompanied by an increase in synaptic responses measured in the dendritic field of CA1 pyramidal cells (Martinez et al., 1979; Corrigall & Linesman, 1980; Haas & Ryall, 1980; Dingledine, 1981; Lynch et al., 1981; Masukawa & Prince, 1982). Taken together, these data suggest that MOR activation increases the output of CA1 pyramidal cells by suppressing synaptic inhibition at the somata of CA1 pyramidal cells, whereas the inputs to CA1 pyramidal cells and dendritic integration within CA1 pyramidal cells are unaffected.
Although there appears to be overwhelming evidence suggesting that MOR activation selectively suppresses interneurons that inhibit the somata of pyramidal neurons, there are also some inconsistencies in the evidence that question this hypothesis. Although the anatomical evidence suggests that most of the MORs in hippocampal CA1 were associated with interneurons that innervate pyramidal neuron cell bodies, they were also shown to be expressed in a significant number of interneurons that innervate the dendritic fields of CA1 pyramidal cells (Kalyuzhny et al., 1997; Drake & Milner, 1999, 2002). Furthermore, although MOR agonists hyperpolarized a larger proportion of interneurons that innervated pyramidal cell bodies compared to interneurons that innervate the dendritic fields, these studies were not able to measure the effect of MORs on the axon terminals (Svoboda et al., 1999). Because these studies were performed using patch clamp recordings in the soma, it is possible that the effect of MORs on responsive interneurons projecting to the dendritic fields of CA1 pyramidal cells could have been underestimated. Finally, although excitatory synaptic potentials in the dendritic field of CA1 pyramidal cells was not increased by MOR agonists, care must be taken in interpreting field excitatory postsynaptic potential (fEPSP) data. In CA1, fEPSPs are not electrical potentials but rather are the result of the generation of a current associated with the activation of glutamatergic synaptic conductances in the dendrites of pyramidal cells. Thus fEPSPs can be altered in one of two ways: (i) by changing the number of receptors activated (i.e. increasing the amount of glutamate released or increasing the number of postsynaptic receptors available) or (ii) by changing the driving force for the current (i.e. changing the resting membrane potential). A change in input resistance of the neuron will not change the current flow through the postsynaptic glutamate receptors. However, the membrane potential generated by the synaptic currents will be changed by a change in input resistance. This is because the flow of current through the cell membrane must follow Ohm’s law (V=I*R). If the synaptic current (I) is the same, but the input resistance (R) is changed, then the resulting voltage response (V) must change proportionally to the change in the input resistance. This is what may occur in the dendrite when inhibitory synaptic inputs are suppressed. Because the reversal potential of GABAA receptors is close to the resting membrane potential, the suppression of inhibitory inputs results in a decrease in the number of GABAA receptors activated, and thus an increase in the input resistance of the dendrites without a significant change in the driving force for synaptic glutamate currents. Under these conditions, the fEPSP will be unchanged even though there is an increase in the amplitude of the excitatory synaptic potential in the dendrites. Therefore, MOR agonist suppression of dendritic synaptic inhibition may change the dendritic postsynaptic potentials without changing the measured fEPSP.
MOR Activation Disinhibits CA1 Pyramidal Cell Dendrites
Two approaches can be taken to directly measure membrane potential changes in the dendrites of CA1 pyramidal cells. First, patch clamp recordings from the dendrites of CA1 pyramidal cells can be performed; however, this approach only records from a small region of the dendritic tree. Furthermore, recording from the smaller secondary and tertiary processes, where the synapses are located, is extremely difficult with this technique. A second more dynamic method available to measure dendritic changes is voltage-sensitive dye (VSD) imaging, a technique that can measure changes in the membrane potential of pyramidal cells throughout the entire somatodendritic axis simultaneously. Unlike patch clamp, VSD recordings can measure responses in a large area of the dendritic tree in hippocampal CA1.
In hippocampal slices, VSD imaging is performed by staining with a VSD (i.e. NK3630, Hayashibara Biochemical Laboratories, Japan) and measuring changes in light transmittance following the electrical stimulation of synapses within the slice (Jin et al., 2002). The VSD is incorporated into the lipid plasma membranes of cells where it absorbs transmitted light passing through the slice. The amount of light absorbed is linearly proportional to the membrane potential, with a depolarization resulting in a decrease in the amount of light being absorbed (for review see Zochowski et al., 2000). Changes in synaptic activity are recorded as sub-millisecond changes in absorption. These events are measured with a photodiode array that permits the measurement of very high light levels (Jin et al., 2002). A typical measurement is shown in Figure 1.
Using VSD recordings in our lab, we were able to record excitatory postsynaptic potentials evoked in either SR, SO or SLM, and furthermore, we were able to follow their propagation through the CA1 neuronal network (Fig. 1A, McQuiston & Saggau, 2003). As expected, the synaptically generated excitatory activity decreased in amplitude as it propagated away from the site of stimulation, presumably due to the low pass filtering properties of the CA1 pyramidal cell dendrites (Fig. 1B, McQuiston & Saggau, 2003). When MOR agonists were applied by bath, the amplitude of the excitatory events increased in size in the SP and output layer (SO) of hippocampal CA1 as expected. However, MOR agonists also increased excitatory events in the input layers, including the SR (Fig. 1B), where previous studies had shown little to no effect on excitation by MOR activation. More interesting was the observation that the change in excitability produced by MOR agonists was proportionately larger as the excitatory event propagated away from the site of stimulation (Fig. 1D). The simplest interpretation of this latter observation is that as the excitatory event propagated through the circuit, there was less and less inhibition in each layer resulting in an increase in excitation. This explanation was supported by the observation that the MOR agonist effects were abolished in the presence of the GABAA receptor antagonist bicuculline and that pharmacologically isolated GABAA inhibitory events were suppressed by MOR agonists to an equivalent extent in each layer of CA1 (McQuiston & Saggau, 2003). Furthermore, synaptically stimulated excitatory events in surgically isolated dendritic fields of CA1 pyramidal cells (SR and SLM) were significantly increased in the presence of MOR agonists (McQuiston, Soc. Neurosci Abst, 2004). Taken together, these data suggest that MORs suppress the release of GABA onto all regions of CA1 pyramidal cells. In addition, not only is the output of CA1 pyramidal cells increased by MOR activation, but MOR activation also increased the inputs to and dendritic integration within CA1 pyramidal cells. Furthermore, this MOR-induced disinhibition also facilitated the propagation of excitatory activity between different compartments of CA1 pyramidal cells. The combination of these effects may allow associative interactions within distal regions of the dendritic tree of these neurons.
Chronic administration of opiates like morphine may change the firing and integrative properties of pyramidal cells in the long term by altering the properties of different types of interneurons innervating different regions of the pyramidal somatodendritic axis. The changes may not be simple, and not all of these interneurons may be altered in the same manner. Studies from other regions of the CNS suggest that chronic morphine has different effects in different regions of the brain. For example, acute withdrawal after chronic morphine has been shown to potentiate GABAergic synaptic transmission the ventral tegmental area (Bonci & Williams, 1997), nucleus accumbens (Chieng & Williams, 1998), raphe nucleus (Jolas et al., 2000) and periaqueductal gray (Chieng & Christie, 1996; Ingram et al., 1998) by a cAMP-dependent mechanism. However, glutamatergic synaptic transmission was unaffected by chronic morphine use in the ventral tegmental area (Manzoni & Williams, 1999). There have also been reports that in the shell of the nucleus accumbens, chronic morphine potentiated GABAergic synaptic transmission onto cholinergic interneurons but not onto medium spiny projection neurons (reviewed in Williams et al., 2001). Furthermore, chronic morphine changed the efficacy of MOR agonists in some neuron subtypes but not others (reviewed in Williams et al., 2001). Thus, given the different interneurons found in the hippocampus (Freund & Buzsaki, 1996), it is likely that chronic morphine and/or MOR agonists alter GABAergic interneuron synaptic transmission in a cell-specific manner, resulting in differential effects on pyramidal cell function. Because CA1 pyramidal cells are the primary output cells of the hippocampus, morphine and other MOR agonists may have profound effects on the relay of information to other brain areas. These effects and their relationship to opioid addiction, abstinence and relapse will be exciting areas of investigation for future research.
Conclusions
Previous anatomical and physiological studies have supported the hypothesis that MOR activity in area CA1 of the hippocampus primarily disinhibits the output of CA1 pyramidal cells. In addition, MOR agonists may also disinhibit distal cortical and thalamic inputs in SLM of hippocampal CA1. However, little evidence was available for an effect of MOR activation on proximal inputs and synaptic integration in the SR of hippocampal CA1. Despite the overwhelming data supporting this hypothesis, there remained observations describing MOR localized to GABAergic processes in all regions of CA1. Given the profound effect that an individual interneuron can have on the integration of excitatory activity in a single pyramidal cell (Miles et al., 1996; Larkum et al., 1999), there continued to be a possibility that MOR activity had significant effects in the proximal dendritic fields of CA1 pyramidal cells. Our VSD recordings have confirmed this and show that MOR activation not only facilitates the outputs of CA1 pyramidal cells, but MOR agonists also facilitate the inputs and propagation of excitatory activity within the dendritic tree of CA1 pyramidal cells.
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