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Opiate Influences on Nucleus Accumbens Neuronal Electrophysiology: Dopamine and Non-Dopamine Mechanisms

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Opiate Influences on Nucleus Accumbens Neuronal Electrophysiology: Dopamine and Non-Dopamine Mechanisms The Journal of Neuroscience, October 1969, 9(10): 35363546 Opiate Influences on Nucleus Accumbens Neuronal Electrophysiology: Dopamine and Non-Dopamine Mechanisms Ft. L. Hakan and S. J. Henriksen Department of Neuropharmacology, Research Institute of the Scripps Clinic, La Jolla, California 92037 Single-unit recordings of nucleus accumbens septi (NAS) abuse potential for humans such as the opiate alkaloids (Goeders neurons in halothane-anesthetized rats revealed that mi- et al., 1984; Vaccarino et al., 1985; Corrigal and Vaccarino, croinfusions of morphine into the ventral tegmental area (VTA) 1988; Koob and Goeders, 1989). Although there is controversy primarily inhibited spontaneously active NAS units. These regarding the precise neuropharmacological mechanism(s) un- inhibitory effects were reversed by alpha-flupenthixol (s.c.), derlying opiate actions on the NAS and on NAS-related brain suggesting a role for dopamine (DA) in the observed opiate- circuitry (e.g., see Wise, 1987), behavioral research has indicated induced effect. VTA opiate microinfusions also inhibited the that these drugs may exert pharmacological influence over NAS evoked (driven) responses of silent cells (spontaneously function via dopamine (DA)-dependent and DA-independent inactive) in the NAS elicited by stimulation of hippocampal projections from the DA containing cell bodies of the midbrain afferents to the NAS. In addition, this inhibition of driven ventral tegmental area (VTA) (Bozarth and Wise, 198 l), the response was reversed by naloxone (s.c.) but not by alpha- cellular origin of the DA-ergic input to the NAS (see Kelly et flupenthixol, implying a VTA-mediated non-DA mechanism. al., 1980; Stinus et al., 1980; Kalivas et al., 1983; Pettit et al., Morphine applied iontophoretically to cells within the NAS 1984; Amahic and Koob, 1985; Vaccarino et al., 1986; Wise, inhibited spontaneous activity but not fimbria-driven cellular 1987; Di Chiara and Imperato, 1988; Koob and Goeders, 1989). activity, suggesting that the systemic effects of opiates on Electrophysiological studies have shown that morphine will NAS activity can be mediated directly in the NAS as well as excite VTA-DA projection neurons when administered either through VTA afferents. Moreover, since VTA-induced inhi- systemically (Nowycky et al., 1978; Glysing and Wang, 1983) bition of fimbria-driven activity was reversed by systemic or electrophoretically onto identified VTA-DA neurons (Hu and opiates, opiates also can exert effects through other, as yet Wang, 1984; Mathews and German, 1984). Moreover, exci- unidentified NAS afferent systems. tation of NAS activity by hippocampal or amygdala stimulation is inhibited by VTA conditioning stimulation, and this effect is The nucleus accumbens septi (NAS) is a basal forebrain struc- mimicked by the actions of iontophoretically applied dopamine ture that can be distinguished in part from adjacent brain regions in the NAS (Yim and Mogenson, 1982; Yang and Mogenson, (e.g., the caudate nucleus) by its differential patterns of neural 1984; but see Akaike et al., 1981). Finally, opioid receptors connectivity (Heimer and Wilson, 1975; Swanson and Cowan, primarily of the p-receptor subtype exist in the NAS (Wamsley 1975; Powell and Leman, 1976; Williams et al., 1977; Nauta et al., 1980; Herkenham et al., 1984; Unterwald et al., 1986) et al., 1978; Troiano and Siegel, 1978; Groenwegen et al., 1980; providing a substrate for direct action of opioids on NAS neu- Newman and Winans, 1980; Chronister and De France, 198 1; rons. Kelley and Domesick, 1982; Kelley and Stinus, 1984; Phillipson Recently, the electrophysiological effects of systemically ad- and Griffiths, 1985). The NAS receives substantial input from ministered opiates on NAS single-units have been described limbic structures (e.g., hippocampus, amygdala, septal nuclei, (Hakan and Henriksen, 1987). While systemically administered cingulate cortex, mammillary bodies) and projects to nuclei me- opiate alkaloids inhibited the majority of single-cells recorded diating extrapyramidal motor functions (the ventral pallidal re- (55%), significant numbers ofother NAS cells were either excited gion). Thus, some researchers have suggested the NAS serves (19%) or unaffected (25%). It is possible that the heterogeneity to integrate motivation-related inputs that are vital to goal- of NAS responses to systemically administered opiates is a con- seeking behaviors (Beninger, 1983; Mogenson, 1987). More- sequence of combined direct opiate effects in the NAS as well over, the NAS also seems critical for the locomotor stimulant as indirect opiate effects mediated by NAS afferents such as the effects elicited by many drugs of abuse (Pigenberg and Van mesolimbic DA projections originating from the VTA. The Rossum, 1973; Kelly et al., 1975; Jones and Mogenson, 1980; present experiments were designed to assess electrophysiologi- Wise, 1984; Swerdlow et al., 1986; Ksir and Kline, 1987; Mo- tally the roles of DA-dependent and DA-independent processes genson, 1987). For example, animal studies suggest that the NAS underlying opiate actions on NAS neurons. is critical for supporting the self-administration of drugs having Materials and Methods Male Sprague-Dawley rats weighing 250-350 gm were osed in these Received Feb. 10, 1989; accepted Mar. 9, 1989. experiments. Subjects were housed 3 per cage and allowed free access This research was supported by PHS grants DA03665 and AA06420 (Johnson to food and water. The animal housing facility was maintained at a and Johnson Publication BCR55 15). constant temperature (2 l-23oC) and normal lighting cycle. The subjects Correspondence should be addressed to Dr. Steven Henriksen, Research Insti- were tested during the light phase. tute ofthe Scripps Clinic,BCR-1, 10666 N. Torrey Pines Rd., La Jolla, CA 92037. Individual rats were prepared for acute electrophysiological record- Copyright 0 1989 Society for Neuroscience 0270-6474/89/103538-09$02.00/O ings in the following manner: Subjects were first anesthetized with 2% The Journal of Neuroscience, October 1999, 9(10) 3539 halothane in air; a tracheotomy was performed, and the rats were then TABLE 1. THE EFFECTS OF FIMBRIA STIMULATION ON NAS SINGLE placed in a stereotaxic holder (Kopf). Body temperature was monitored UNIT ACTIVITY by rectal probe and maintained at 36°C by a thermostatically controlled abdominal heating pad. Light anesthesia was maintained with O&0.8% halothane in air delivered to the subiect through the implanted tracheal tube. A craniotomy was performed to allow insertion of a bipolar con- centric stimulating electrode (Rhodes Medical, SNE- 100) in the fimbria TOTAL # OF NAS CELLS RECORDED _ 372 (A 2.0 mm, L 2.0 mm from bregma and DV -4.0 to -5.0 mm from TOTAL #OF (QUIET) DRIVEN CELLS -118 (32%) brain surface; Paxinos and Watson, 1982) and to allow placement of a single or a multibarrel glass micropipette used for recording unit activity TOTAL # OF SLOW CELLS -149 (40%) and “population” field responses evoked by fimbria stimulation. Single- barrel micropipettes (9-50 MR resistance) or one of the barrels of the TOTAL # OF FAST CEL~I S -105 (28%) multibarrel micropipettes (1 O-25 MQ) were backfilled with Pontamine sky blue (PSB) in 0.5 M sodium acetate and lowered with a microdrive unit (Narishige) into the NAS (A + 1.1 to 2.2 mm, L - 1.1 to - 1.7 mm EFFECTS OF STIMULATION ON from bregma, and DV - 5.7 to - 7.3 mm from brain surface) ipsilateral SPONTANEOUSLY ACTIVF NAS CFI LS to the stimulating electrode. A 23 gauge cannula (10 mm long) prefit with a 30 gauge stylet to prevent plugging of the tip was inserted 1.5 SLOW CELLS FAST CELLS mm above the ipsilateral VTA (A -5.0 mm, L -.0.8 mm from bregma, EXCITED 22 15 and DV -6.5 mm from brain surface). Both stimulatina electrode and recording electrode coordinates were adjusted as necessary to maximize INHIBITED 31 25 NAS field responses to fimbria stimulation (De France and Yoshihara, 1975; Hakan and Henriksen, 1987) as well as to discriminate single- DRIVEN 56 18 unit activity. (wlspont.) Single square-wave monophasic current pulses (0.15 msec duration and aonroximatelv 100-600 UA intensitv) were delivered to the iosi- COMPLEX 20 29 lateral hmbria at 0.1 Hz by a’ stimulus generator (Grass S-88) coupled NO EFFECT 20 to an optically isolated stimulus isolation unit. Amplified electrical sig- 18 nals from the recording electrode were either unfiltered (for field poten- -----_____~~~~~---_~________________ tial recording) or filtered (l-20 kHz for single-unit activity) and dis- ____~---~------___--________________ played on oscilloscopes. Randomly encountered single-unit ‘potentials AVERAGE LATENCIES OF Al I DRIVFN CFI I S were separated from background noise by a voltage-gated window dis- criminator (Neurolog systems), and the discriminated output was re- 5-12 ms 13-25 ms BOTH OTHER layed to a chart recorder (Gould) and to a computer (MINC, digital Equipment) for spike-train analysis. Systemically administered nalox- 70 66 41 15 one (4.0 mg/kg), alpha-flupenthixol(O.5 mg/kg), or heroin (0.5 mgkg) were administered in a volume of 1 mg/ml through a subcutaneous The data reflect the single-cell electrophysiological profile of the NAS region and the variety of effects fimbria stimulation exerts on NAS cellular activity. Fimbria injection needle inserted into the flank region. Prior to isolation of NAS stimulation-evoked cellular responses from quiet cells (driven), slow (24 Hz) and single-unit activity, the cannula stylet was replaced by a 30 gauge in- fast (>4 Hz) NAS cellular activity were encountered throughout the NAS with jection needle (11.0 mm in length) connected to PE-10 tubing so that essentially equal probability (see text for further details). Fimbria stimulation morphine (2.5 pg in 1 ~1) could be later infused (over 1 min) to the VTA would typically drive NAS silent cells (but also some spontaneously active cells) with the aid ofa 5.0 ~1 Hamilton syringe and syringe pump.
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