Inactivation of the paraventricular thalamus abolishes the expression of cocaine conditioned place preference in rats

doi:10.1016/j.drugalcdep.2013.09.021

Drug and Alcohol Dependence

Volume 134, 1 January 2014, Pages 387-390

https://doi.org/10.1016/j.drugalcdep.2013.09.021 Get rights and content

Abstract

Background

The paraventricular thalamus (PVT) is rapidly becoming recognized as part of the addiction circuitry. In addition to its strong anatomical connection to most of the brain regions underlying addiction, such as the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus, the PVT has recently been shown to contribute to cocaine sensitization and reinstatement. In the present study, we examined the role of the PVT in the expression of cocaine conditioned place preference (CPP).

Methods

We tested the impact of PVT inactivation by baclofen/muscimol (bac-mus) microinjection on the expression of cocaine-induced CPP in rats. Rats were implanted with guide cannulae into the PVT. Bac-mus (GABA_B–GABA_A agonists) or saline was injected into the PVT prior to CPP testing.

Results

Inactivation of the PVT by bac-mus prevented the expression of CPP, while placements outside the PVT did not affect CPP. Intra-PVT injections of bac-mus did not affect locomotor activity during the session.

Conclusions

In the present study, we contribute to the growing body of research supporting a role for the PVT in addiction by demonstrating that the PVT is necessary for the expression of cocaine CPP.

Introduction

Recently, it has been suggested that the PVT may play a critical role in addictive behaviors and thus should be included as part of the reward circuitry (James and Dayas, 2013, Martin-Fardon and Boutrel, 2012). Mounting evidence supports the role of the PVT in addictive behaviors. For example, the PVT sustains electrical self-stimulation (Clavier and Gerfen, 1982). Furthermore, Young and Deutch (1998) found that lesion of the PVT in rats prevents cocaine-induced locomotor sensitization. Also, lesion of the PVT inhibits context-dependent reinstatement of alcohol-seeking behavior using the self-administration paradigm (Hamlin et al., 2009), while injection of tetrodotoxin (TTX) into the PVT prevents cocaine-induced reinstatement of cocaine-seeking behavior (James et al., 2010). Recent studies support a role for CART, dynorphin and orexin in the reinstatement of drug-seeking by the PVT (James et al., 2010, Marchant et al., 2010, Martin-Fardon and Boutrel, 2012).

Although several studies have examined the role of the PVT in self-administration reinstatement, few have assessed the role of the PVT in CPP. One such study found that lesions of the entire medial dorsal thalamus, including the PVT, prevented the acquisition of sucrose CPP (McAlonan et al., 1993), but to our knowledge, no one has assessed the role of the PVT in the expression of CPP. In the present study, we assessed the role of the PVT in the expression of previously acquired cocaine-induced CPP in rats by temporarily inactivating the PVT with baclofen-muscimol (GABA_A & GABA_B agonists) prior to CPP testing.

Section snippets

Animals

Male Sprague Dawley rats (n = 29; Simonsen Laboratories, Gilroy, CA) weighing 300–350 g were individually housed in a reversed 12:12 light/dark cycle in a temperature- and humidity-controlled colony room at 21 ± 1 °C and were handled daily. Care of the animals was in accordance with the National Institute of Health guide for the care and use of laboratory animals, and all procedures were approved by the Institutional Animal Care and Use Committee of Washington State University. All efforts were made

Results

Inactivation of the PVT by the high dose of bac-mus completely inhibited the expression of cocaine CPP [F_(2,15) = 13.79, P ≤ 0.001] (Fig. 1A). CPP was not affected in animals with cannulae placements outside the PVT (Fig. 1B). Furthermore, locomotor activity was not affected by bac-mus injections into the PVT (Fig. 2A).

Discussion

In the present experiment, we add to the mounting evidence indicating a role for the PVT in addiction by determining that inactivation of the PVT completely abolishes cocaine CPP expression. To our knowledge, we are the first to demonstrate a role for the PVT specifically in the expression phase of previously acquired cocaine-induced CPP.

The contribution of the PVT to addiction is gaining interest, and it has been recently suggested that the PVT should be included as part of the addiction

Role of funding source

Funding for this study was provided by NIH Grant DA023202; the NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Jenny Browning and Barbara Sorg designed the study and wrote the protocol. Jenny Browning undertook the statistical analysis and wrote the first draft of the manuscript. Barbara Sorg and Heiko Jansen edited the manuscript prior to submission. All authors contributed to and have approved the final manuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

References (26)

S. Chen et al.
Afferent connections of the thalamic paraventricular and parataenial nuclei in the rat – a retrograde tracing study with iontophoretic application of Fluoro-Gold
Brain Res.
(1990)
M.J. Christie et al.
Excitatory amino acid projections to the nucleus accumbens septi in the rat: a retrograde transport study utilizing D[3H]aspartate and [3H]GABA
Neuroscience
(1987)
R.M. Clavier et al.
Intracranial self-stimulation in the thalamus of the rat
Brain Res. Bull.
(1982)
M.H. James et al.
Propensity to ‘relapse’ following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei
Neuroscience
(2011)
G.M. McAlonan et al.
Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: further evidence for the involvement of the ventral striatopallidal system in reward-related processes
Neuroscience
(1993)
T.M. Tzschentke
Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues
Prog. Neurobiol.
(1998)
C.D. Young et al.
The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization
Pharmacol. Biochem. Behav.
(1998)
M.T. Bardo et al.
Conditioned place preference: what does it add to our preclinical understanding of drug reward?
Psychopharmacology (Berl.)
(2000)
R.M. Cooper et al.
Thalamic reticular system and central grey: self-stimulation
Science
(1967)
J.L. Cornish et al.
Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction
J. Neurosci.
(2000)

A.Y. Deutch et al.

Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus

J. Neurosci.

(1998)

A.S. Hamlin et al.

Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking

Eur. J. Neurosci.

(2009)

M.H. James et al.

Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour

PLoS ONE

(2010)

Cited by (55)

Paraventricular thalamus to nucleus accumbens circuit activation decreases long-term relapse of alcohol-seeking behaviour in male mice
2024, Pharmacology Biochemistry and Behavior
Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction.
The chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP.
Our results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.
Histamine Regulates Accumbens Microcircuits: An Arousing Finding for Addiction Research
2023, Biological Psychiatry
Accumbal-thalamic connectivity and associated glutamate alterations in human cocaine craving: A state-dependent rs-fMRI and <sup>1</sup>H-MRS study
2023, NeuroImage: Clinical
Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm³) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.
The intersection of empathy and addiction
2023, Pharmacology Biochemistry and Behavior
Empathy, the ability to perceive the affective state of another, is a complex process that is integral to many of the prosocial behaviors expressed in humans and across the animal kingdom. Research into the behavioral and neurobiological underpinnings of empathic behaviors has increased in recent years. Growing evidence suggests changes in empathy may contribute to a myriad of psychiatric illnesses, including substance use disorder (SUD). Indeed, both clinical and preclinical research in SUD demonstrates a strong relationship between drug taking or relapse events and changes to empathic behavior. Further, there is significant overlap in the underlying neural substrates of these complex behaviors, including the insula, paraventricular nucleus of thalamus (PVT), and the paraventricular nucleus of the hypothalamus (PVN). In this review, we will discuss our current understanding of the interplay between empathic behaviors and SUD. We will also examine the underlying neurobiology that may regulate this interaction, focusing specifically on the insula, PVT, and PVN. Finally, we discuss the biologic and therapeutic importance of taking empathic processes into consideration when discussing SUD.
Regulation of cocaine-related behaviours by estrogen and progesterone
2022, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Finally, systemic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 10 min prior to or immediately following cocaine conditioning sessions inhibited the acquisition of cocaine CPP (Cervo and Samanin, 1995), possibly by acting in the NAc shell (Li et al., 2016) or in the hippocampus (McDonald et al., 2005) to disrupt cocaine-associated contextual memory consolidation. The expression of cocaine CPP involves input to the VTA from the paraventricular nucleus of the thalamus (PVT) and the ventral bed nucleus of the stria terminalis (BNST) (Browning et al., 2014; Sartor and Aston-Jones, 2012). Additionally, intra-VTA microinjections of SCH23390 inhibited the expression of cocaine CPP (Galaj et al., 2014).
Women are more sensitive to cocaine craving elicited by stimuli associated with relapse. Ovarian hormones modulate cocaine craving and may therefore function as risk factors or therapeutic agents for the development and treatment of cocaine use disorder, respectively. We review herein the neuropharmacological effects of the steroid hormones 17ß-estradiol, progesterone, and allopregnanolone, a progesterone metabolite, in relation to their effects on cocaine-induced locomotion, behavioural sensitization, conditioned place preference, and reinstatement of cocaine seeking. In general, the literature suggests that female rats are more sensitive to these cocaine-induced behaviours than males and that 17ß-estradiol facilitates the expression of these sex differences. Alternatively, in females, exogenous progesterone attenuates cocaine conditioned place preference, reinstatement, and possibly behavioural sensitization, either on its own or after conversion to allopregnanolone. These opposing effects of 17ß-estradiol and progesterone/allopregnanolone involve endocannabinoid, γ-aminobutyric acid, dopamine, and glutamate transmission in the medial prefrontal cortex and striatum. We conclude that 17ß-estradiol may be a risk factor for various components of cocaine use disorder in women, whereas progesterone and allopregnanolone may be potential treatment options.
Thalamic circuits
2022, Neurocircuitry of Addiction
The thalamus is a paired gray matter structure in the diencephalon in the brain (deep within the brain), located adjacent to the third ventricle that plays many essential roles in behavior and neural function. It is composed of various nuclei that each serve a unique role, ranging from relaying sensory and motor signals to regulating consciousness, alertness, sleep and wakefulness. The thalamus has traditionally been characterized by its relay functions and multinuclear structure. Abundant thalamic circuitries and its diverse functions suggest that this structure is involved in many physiological and pathological processes, including, most recently, those underlying addiction disorders. Indeed, the thalamus is considered an important relay between the ventral striato-pallidum and dorsal striatum and may contribute to the development and persistence of compulsive drug-seeking behavior and is therefore considered an integral structure within brain reward circuitry, and findings from both animal and human studies suggest that this brain region plays an important role in both drug self-administration and the reinstatement of drug-seeking behavior. This chapter will review clinical evidence supporting a critical role of the thalamus in addiction. We then present and examine the preclinical literature in rodents that demonstrate the involvement of the thalamus and thalamic circuits in animal models of drug addiction.

View all citing articles on Scopus

View full text

Published by Elsevier Ireland Ltd.

Short communicationInactivation of the paraventricular thalamus abolishes the expression of cocaine conditioned place preference in rats

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Animals

Results

Discussion

Role of funding source

Contributors

Conflict of interest

Brain Res.

Neuroscience

Brain Res. Bull.

Neuroscience

Neuroscience

Prog. Neurobiol.

Pharmacol. Biochem. Behav.

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

Psychopharmacology (Berl.)

Thalamic reticular system and central grey: self-stimulation

Science

Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction

J. Neurosci.

Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus

J. Neurosci.

Paraventricular thalamus mediates context-induced reinstatement (renewal) of extinguished reward seeking

Eur. J. Neurosci.

Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour

PLoS ONE

Short communication
Inactivation of the paraventricular thalamus abolishes the expression of cocaine conditioned place preference in rats