The Effects of Thalamic Paraventricular Nucleus Lesions on Cocaine-Induced Locomotor Activity and Sensitization

doi:10.1016/S0091-3057(98)00051-3

Pharmacology Biochemistry and Behavior

Volume 60, Issue 3, June 1998, Pages 753-758

https://doi.org/10.1016/S0091-3057(98)00051-3 Get rights and content

Abstract

The brain circuitry that subserves the augmented locomotor response to repeated psychostimulant administration has been the subject of intense scrutiny. The dopaminergic innervation of the nucleus accumbens is critically involved in psychostimulant-elicited behavioral sensitization, and recent studies suggest that lesions of structures that send glutamatergic projections to the nucleus accumbens alter the acquisition or expression of psychostimulant-elicited sensitization. Although certain thalamic nuclei provide a major glutamatergic input to the striatum, the involvement of the thalamus in psychostimulant-elicited sensitization has not been investigated. We therefore examined the effects of lesions of the thalamic paraventricular nucleus, which projects to the shell of the nucleus accumbens, on cocaine-elicited locomotor sensitization. Lesions of the paraventricular nucleus did not alter basal locomotor activity, but significantly enhanced the acute locomotor response to cocaine. In contrast, repeated cocaine administration did not progressively augment locomotor activity in lesioned rats, but did so in sham-lesioned animals. The thalamic lesions also blocked the conditioned locomotor response to the environment in which the cocaine injections took place. These data suggest that the thalamic paraventricular nucleus may be an integral part of extended circuitry that subserves both the conditioned and nonconditioned components of psychostimulant-induced behavioral sensitization.

Section snippets

Subjects

Adult male Sprague–Dawley rats (CAMM, Wayne, NJ) were group housed under temperature- and humidity-controlled conditions on a 12 L:12 D schedule (lights on at 07 00 h). Food and water were available ad lib. The studies reported were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institute of Health.

Surgery

Rats were randomly assigned to undergo either electrolytic lesions of the PV (n = 16) or sham lesions (n = 12). Rats

Baseline Ambulation

PV lesions did not alter baseline locomotor activity relative to sham-lesioned rats, nor did activity levels in vehicle-injected lesioned rats differ from those seen in vehicle-injected sham-lesioned rats on any of the test days (Fig. 1).

Cocaine-Elicited Locomotor Activity

PV-lesioned rats showed a significantly greater increase in activity on the first day of cocaine administration than did sham-lesioned rats administered cocaine, F(1, 13) = 8.07, p = 0.01 (see Fig. 1). However, cocaine-elicited activity levels in the

Discussion

Baseline locomotor activity was not affected by lesions of the PV, but PV-lesioned rats were significantly more responsive to acute cocaine administration. Despite the greater sensitivity to cocaine on day 1, activity levels in PV-lesioned rats did not progressively augment with daily cocaine injections. Similarly, PV-lesioned rats did not exhibit significant contextual conditioning to the locomotor apparatus. These data suggest that the PV may be an important site in the extended circuitry

Acknowledgements

We appreciate the generous equipment loan and assistance of Drs. Bryan Horger and Jane Taylor. This work was supported in part by MH-45124.

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The paraventricular nucleus of the thalamus (PVT) is a midline thalamic brain region that has emerged as a critical circuit node in the regulation of behaviors across domains of affect and motivation, stress responses, and alcohol- and drug-related behaviors. The influence of the PVT in this diverse array of behaviors is a function of its ability to integrate and convey information about salience and valence through its connections with cortical, hypothalamic, hindbrain, and limbic brain regions. While understudied to date, recent studies suggest that several PVT efferents play critical and complex roles in drug and alcohol-related phenotypes. The PVT is also the site of signaling for many neuropeptides released from the synaptic terminals of distal inputs and local neuropeptidergic neurons within. While there is some evidence that neuropeptides including orexin, neurotensin, substance P, and cocaine and amphetamine-related transcript (CART) signal in the PVT to regulate alcohol/drug intake and reinstatement, there remains an overall lack of understanding of the roles of neuropeptides in the PVT in addiction-related behaviors, especially in a circuit-specific context. In this review, we present the current status of preclinical research regarding PVT circuits and neuropeptide modulation of the PVT in three aspects of the addiction cycle: reward/acquisition, withdrawal, and relapse, with a focus on alcohol, opioids (particularly morphine), and psychostimulants (particularly cocaine). Given the PVT's unique position within the broader neural landscape, we further discuss the potential ways in which neuropeptides may regulate these behaviors through their actions upon PVT circuits.
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Drug addiction is a chronic relapsing brain disease characterized by compulsive, out-of-control drug use and the appearance of negative somatic and emotional consequences when drug access is prevented. The limited efficacy of treatment urges researchers toward a deeper understanding of the neural mechanism of drug addiction. Brain circuits that regulate reward and motivation are considered to be the neural substrate of drug addiction. An increasing body of literature indicates that the paraventricular thalamic nucleus (PVT) could serve as a key node in the neurocircuits that control goal-directed behaviors. In this review, we summarize the anatomical and functional evidence that the PVT regulates drug-related behaviors. The PVT receives extensive inputs from the brainstem and hypothalamus, and is reciprocally connected with the limbic system. Neurons in the PVT are recruited by drug exposure as well as cues and context associated with drug taking. Pathway-specific perturbation studies have begun to decipher the precise role of PVT circuits in drug-related behaviors. We also highlight recent findings about the involvement of neural plasticity of the PVT pathways in drug addiction and provide perspectives on future studies.
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Addicted individual compulsively use drug despite its negative consequences. This often originates from exacerbated motivation for the drug and impaired behavioral control over its use. Although they share commonalities, these two processes can involve various cerebral structures. To date, the emphasis has been made on the exacerbated motivation for the drug and therefore most studies from animal models to human studies have been focused on the reward circuit. The present chapter will not only review the various surgical interventions that have been carried out in the structures of the classical circuit but will also propose a more recent view of this circuit that includes the subthalamic nucleus (STN), a cerebral structure involved in both motivation and inhibitory control. We will thus also review the various results obtained after manipulation of the STN on motivational processes and addiction-related behaviors. The surgical strategy raises several issues, but in extreme cases when no treatment has proven efficacy, as for certain forms of addiction, surgery can be the best option. We will however also review here the noninvasive strategies developed in the recent years.
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Citation Excerpt :
Indeed, more recent studies have identified important roles for the PVT in various behavioral features of drug addiction. Early work showed that the PVT was important for locomotor responses to cocaine because electrolytic PVT lesions increased the acute locomotor responses to cocaine and prevented locomotor sensitization (Young and Deutch, 1998). There has been relatively little investigation of the role of the PVT in self-administration behavior and the available evidence is conflicting.
This chapter reviews the anatomical and functional evidence demonstrating the contribution of the paraventricular thalamic nucleus (PVT) to appetitive motivation, food intake control, and drug-seeking behaviors. We first consider the anatomical properties of the PVT to highlight its relevance in the control of appetitive motivation, feeding, and drug seeking. This is followed by a review of the available literature on PVT neurocircuitry, PVT involvement in food intake control, animal models of drug self-administration, withdrawal, and relapse. We show that PVT occupies a strategic position as a major thalamic interface between hindbrain and hypothalamic regions for viscerosensation and energy states; and between amygdala, cortical, and ventral striatal regions for motivation, reward, and learning. Understanding the precise anatomical and functional organization of these trans-PVT pathways remains a key challenge. Nonetheless, we show that PVT may be profitably viewed as the thalamic gateway to appetitive motivation, feeding, and drug addiction allowing both bottom-up (from brainstem and hypothalamus) and top-down (from cortex) control over reward and motivation.

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ArticlesThe Effects of Thalamic Paraventricular Nucleus Lesions on Cocaine-Induced Locomotor Activity and Sensitization

Abstract

Section snippets

Subjects

Surgery

Baseline Ambulation

Cocaine-Elicited Locomotor Activity

Discussion

Acknowledgements

Brain Res.

Life Sci.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Neuroscience

Brain Res.

Brain Res.

Neuroscience

Trends Neurosci.

Brain Res.

Drug Alcohol Depend.

Brain Res. Rev.

Drug Alcohol Depend.

Behav. Brain Res.

Brain Res. Rev.

Brain Res. Bull.

Neurosci. Lett.

Behav. Brain Res.

Neuroscience

Life Sci.

Pharmacol. Biochem. Behav.

Amphetamine-induced conditioned activity in ratsComparison with novelty-induced activity and role of the basolateral amygdala

Behav. Neurosci.

The thalamostriatal projection in the cat

J. Comp. Neurol.

Pimozide blocks the establishment but not expression of amphetamine-produced environmental-specific conditioning

Science

Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum

J. Comp. Neurol.

Electron-microscopic characterization of adrenergic axon terminals in the diencephalon of the rat

Cell Tissue Res.

The afferent innervation of the core and shell of the accumbens part of the rat ventral striatumImmunohistochemical detection of retrogradely transported Fluoro-gold

J. Comp. Neurol.

Articles
The Effects of Thalamic Paraventricular Nucleus Lesions on Cocaine-Induced Locomotor Activity and Sensitization