Elsevier

Brain Research

Volume 754, Issues 1–2, 18 April 1997, Pages 103-112
Brain Research

Research report
6-Hydroxydopamine lesion of ventral pallidum blocks acquisition of place preference conditioning to cocaine

https://doi.org/10.1016/S0006-8993(97)00059-0Get rights and content

Abstract

In parallel with nucleus accumbens (NAS), ventral pallidum (VP) also receives a dopaminergic projection from the ventral tegmental area (VTA). The present study examined the involvement of this mesopallidal dopaminergic system in the action of cocaine. In the first experiment, the effect of cocaine injections on VP dopamine was examined by microdialysis. Intraperitoneal (i.p.) injections of cocaine 5–20 mg/kg dose-dependently increased the extracellular dopamine level in VP 2.5–4.5-fold. In addition, intra-VP perfusion of 20 μM cocaine induced a 12-fold increase of dopamine locally. The second experiment examined the role of VP dopamine in cocaine-induced conditioned place preference (CPP) and locomotor activation. Rats received bilateral intra-VP injections of 3–4 μg 6-OHDA or ascorbic acid vehicle in 0.5 μl volume. Tissue assays indicated that the 6-OHDA-lesioned rats had significantly lowered dopamine concentration in VP, but not in NAS or striatum. As a group, 6-OHDA lesions blocked the development of CPP to 5 mg/kg cocaine but not to 10 mg/kg cocaine. However, rats with more than 60% depletion in VP dopamine did not develop CPP to cocaine at either dose. Preference for the cocaine-paired side correlated significantly with dopamine concentration in VP, but not in NAS or striatum. It was concluded that VP dopamine may play a critical role in the initial rewarding effect of cocaine. 6-OHDA lesions also blocked locomotor activation induced by 5 mg/kg cocaine but had no effect on 10 mg/kg cocaine-induced locomotion. Dopamine concentration in VP did not correlate with the locomotor activation response to cocaine at either dose. These findings further establish the involvement of the mesopallidal dopaminergic system in the action of cocaine.

Introduction

A considerable research effort is now being expended to understand the neurobiological mechanisms of cocaine addiction. On the cellular level, the action of cocaine has been attributed to its ability to block the reuptake of dopamine [37]. On the system level, the mesolimbic dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens septi (NAS) has received the most attention with respect to its involvement in cocaine reward 23, 26. However, behavioral and pharmacological data do not consistently support NAS as the neural site mediating cocaine reward 7, 12, 43. Thus, the investigation of other neural areas with respect to cocaine reward processes is an important area of investigation.

In parallel with the NAS, medial prefrontal cortex (mPFC) is a major recipient of dopaminergic projections from the VTA [3]. Rats will self-administer cocaine into mPFC 7, 8and ablations of mPFC reduce i.p. cocaine-induced CPP [19]. However, 6-OHDA lesions of mPFC fail to block either i.p. cocaine-induced CPP [13]or intravenous (i.v.) cocaine self-administration [24]. Indeed, these lesions have been reported to increase the reward efficacy of low dose i.v. cocaine 25, 42. As a result, the role of mPFC dopamine in cocaine reward is not clear.

Recent studies have suggested a role for ventral pallidum (VP) in psychostimulant reward and locomotion. Lesions of VP cell bodies have been shown to attenuate cocaine and heroin self-administration 18, 40, block the development of place preference conditioning to amphetamine [15], and reduce apomorphine-induced locomotor activation and CPP in NAS dopamine-depleted rats 45, 46. These and other data have led researchers to emphasize VP as an important output `relay' of NAS in mediating locomotor activating and rewarding effects of psychostimulants 22, 23, 36.

This serially connected VTA-NAS-VP model of psychostimulant reward has limitations. It has recently been demonstrated that VP receives a direct `mesopallidal' DA projection from VTA 21, 29, and that NAS is not necessary for the normal VP neuronal response to systemic treatments of apomorphine or cocaine 20, 28. Therefore, anatomical and physiological data suggest VTA can directly activate VP through the mesopallidal dopamine projection. Consistent with this suggestion, intra-VP injections of dopamine or dopamine agonists have been found to increase locomotor activity 9, 21, 27and induce CPP [9]. In addition, results of previously mentioned lesion studies 15, 18, 40, 45, 46are compatible with an action of cocaine and apomorphine at the level of VP.

The mesopallidal dopamine projection may not be just a dopamine projection in parallel with the mesoaccumbens and mesocortical systems. The mesopallidal dopamine system may be critically important in the mediation of cocaine reward. A unique feature of VP is its response to cocaine injections. Unlike intra-NAS injections of cocaine, which induce robust locomotor activity but not CPP [12], intra-VP injections of cocaine produce robust CPP but rather weak locomotor activation [9]. This almost opposite behavior profile seen after intra-VP and intra-NAS cocaine injections further establishes mesopallidal dopamine and mesoaccumbens dopamine as separate systems that may play different roles in mediating the action of cocaine.

Another unique property of VP is its sensitivity to psychostimulants. It was found that, compared to NAS, VP regional cerebral blood flow increased in response to a much lower dose of i.v. cocaine [44]. Electrophysiological studies have shown that the cocaine-sensitive VP neurons have an ED50 about 10 times less than those in NAS or VTA 14, 20. Behaviorally, it was reported that intra-VP injections as low as 0.01 μg dopamine increase locomotor activity [27].

In summary, accumulating evidence from neuroanatomical and behavioral studies suggests that the VP may play an important role in cocaine reward. An understanding of the role of VP dopamine in the action of cocaine may provide new insights into the cocaine reward mechanism. Therefore, the aim of this study was to answer the following questions: (1) Does the extracellular dopamine level in VP increase in response to systemic injection of cocaine? and (2) Does 6-OHDA lesion of dopaminergic terminals in VP affect systemic cocaine-induced CPP and locomotion?

Section snippets

Subjects

Male Sprague–Dawley rats (Harlan/Sprague–Dawley) weighing 275–325 g at the time of surgery were used. Animals were housed two/three per cage and maintained on a 12 h normal phase light-dark cycle (lights on 07.00 h) with food and water continuously available. Experimentation took place during the light phase of the cycle. All animal procedures adhered strictly to institutional and national ethical guidelines.

Microdialysis surgery

Rats in the microdialysis experiment were anesthetized with Nembutal® (50 mg/kg i.p.),

Microdialysis

Fig. 1 shows the location of the dialysis probes in the animals used in the microdialysis studies. Only rats with proper probe location were included in Fig. 1 and later data analysis. Basal output of dopamine (1.27 nM) and dopamine response to cocaine injection did not correlate with the antero-posterior location of the probe.

Effects of cocaine injection on VP dopamine measured by microdialysis with HPLC are depicted in Fig. 2. Basal output of dopamine was not significantly different across

VP dopamine in response to cocaine

I.p. injections of cocaine (5–20 mg/kg) dose-dependently increased the extracellular dopamine level in VP 2.5–4.5-fold. The two doses of cocaine used to induce CPP were found to induce an immediate increase of dopamine in VP. In addition, intra-VP perfusion of 20 μM cocaine induced a 12-fold focal increase of dopamine locally, which is also consistent with the fact that intra-VP cocaine injection induces CPP [9]. These findings further establish the involvement of the mesopallidal dopaminergic

Acknowledgements

This work was supported in part by NSF Grant IBN-94021104 (J.B.J., D.B.N.), NIDA Research Scientist Award DA 00179 (J.B.J.) and National Research Service Award DA 05707 (W.G.).

References (46)

  • Bardo, M.T., Rowlett, J.K. and Harris M.J., Conditioned place preference using opiate and stimulant drugs: a...
  • Bechara, A., Harrington, F., Nader, K. and van der Kooy, D., Neurobiology of motivation: double dissociation of two...
  • Berger, A., Thierry, A.M., Tassin, J.P. and Moyne, M.A., Dopaminergic innervation of the rat prefrontal cortex: a...
  • Bungay, P.M., Smith, A.D., Olson-Cosford, R.J., Newton, P. and Justice, J.B. Jr., Soc. Neurosci. Abstr., 19 (1993)...
  • Delfs, J.M., Schreiber, L. and Kelley, A.E., Microinjection of cocaine into the nucleus accumbens elicits locomotor...
  • Gerrits, M.A.F.M. and van Ree, J.M., Effect of nucleus accumbens dopamine depletion on motivational aspects involved in...
  • Goeders, N.E. and Smith, J.E., Cortical dopaminergic involvement in cocaine reinforcement, Science, 221 (1983)...
  • Goeders, N.E. and Smith, J.E., Reinforcing properties of cocaine in the medial prefrontal cortex: primary action on...
  • Gong, W., Neill, D.B. and Justice, J.B. Jr., Conditioned place preference and locomotor activation produced by...
  • Gong, W., Neill, D.B. and Justice, J.B. Jr., Locomotor response to novelty does not predict cocaine place preference...
  • Hemby, S.E., Jones, G.H., Hubert, G.W., Neill, D.B. and Justice, J.B. Jr., Assessment of the relative contribution of...
  • Hemby, S.E., Jones, G.H., Justice, J.B. Jr. and Neill, D.B., Conditioned locomotor activity but not conditioned place...
  • Hemby, S.E., Jones, G.H., Neill, D.B. and Justice, J.B. Jr., 6-Hydroxydopamine lesions of the medial prefrontal cortex...
  • Henry, D.J. and White, F.J., Electrophysiological correlates of psychomotor stimulant-induced sensitization, Ann. NY...
  • Hiroi, N. and White, N.M., The ventral pallidum area is involved in the acquisition but not expression of the...
  • Hooks, M.S., Duffy, P., Caryn, S. and Kalivas, P.W., Behavioral and neurochemical sensitization following cocaine...
  • Horger, B.A., Shelton, K. and Schenk, S., Preexposure sensitizes rats to the rewarding effects of cocaine, Pharmacol....
  • Hubner, C.B. and Koob, G.F., The ventral pallidum plays a role in mediating cocaine and heroin self-administration in...
  • Isaac, W.L., Nonneman, A.J., Neisewander, J., Landers, T. and Bardo M.T., Prefrontal cortex lesions differentially...
  • Johnson, P. and Napier, T.C., Contribution of the nucleus accumbens to cocaine-induced responses of ventral pallidal...
  • Klitenick, M.A., Deutch, A.Y., Churchill, L. and Kalivas, P.W., Topography and functional role of dopaminergic...
  • Koob, G.F. and Swerdlow, N.R., Functional output of the mesolimbic dopamine system, Ann. NY Acad. Sci., 537 (1988)...
  • Koob, G.F., Drugs of abuse: anatomy, pharmacology and function of reward pathways, Trends Pharmacol. Sci., 13 (1992)...
  • Cited by (94)

    • Regulation of cocaine-related behaviours by estrogen and progesterone

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      These specific projections from the NAc to the VP are not involved in acute cocaine-induced locomotion (Creed et al., 2016; Farrell et al., 2019). Cocaine may act directly in the VP to activate locomotion in a dopamine-dependent manner (Gong et al., 1997, 1996). Cocaine functions in the mPFC and in the VTA to induce behavioural sensitization (Kalivas and Weber, 1988; Li et al., 1999).

    • Midbrain (VTA) circuits

      2022, Neurocircuitry of Addiction
    • Ventral pallidum cellular and pathway specificity in drug seeking

      2021, Neuroscience and Biobehavioral Reviews
    • Role of D2 dopamine receptors of the ventral pallidum in inhibitory avoidance learning

      2017, Behavioural Brain Research
      Citation Excerpt :

      This is confirmed by the fact that place preference can be induced by the administration of the indirect DA agonists cocaine and amphetamine into the VP [8], and the formation of the cocaine-induced place preference is blocked by the 6-hydroxidopamine lesion of the dopaminergic nerve endings in VP [9]. Furthermore, it has been shown that the cocaine remarkably increases the DA level in the VP [9]. The DA receptors can be grouped in two major families (i.e. the D1- and the D2-subtype) [10–12], and in the VP, applying autoradiography [13,14] and mRNA immunhistochemistry [15,16] both DA receptor subtypes have been detected.

    View all citing articles on Scopus
    View full text