Adolescent exposure to cannabinoids induces long-Lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons

doi:10.1016/j.biopsych.2004.05.006

Biological Psychiatry

Volume 56, Issue 2, 15 July 2004, Pages 86-94

https://doi.org/10.1016/j.biopsych.2004.05.006 Get rights and content

Abstract

Background

Recent studies have raised concerns about subtle long-lasting neurobiological changes that might be triggered by exposure to Cannabis derivatives, especially in a critical phase of brain maturation, such as puberty. The mesolimbic dopamine (DA) system, involved in the processing of drug-induced reward, is a locus of action of cannabinoids and endocannabinoids. Thus, we compared the effects of repeated cannabinoid administration in adolescent and adult rats on DA neuronal functions and responses to drugs of abuse.

Methods

Single-unit extracellular recordings from antidromically identified mesoaccumbens DA neurons and from their target cells in the nucleus accumbens were carried out in urethane-anesthetized rats. Animals were pretreated during adolescence or adulthood, for 3 days, with the cannabinoid agonist WIN55212.2 (WIN) or vehicle and allowed a 2-week interval.

Results

In cannabinoid-administered rats, DA neurons were significantly less responsive to the stimulating action of WIN, regardless of the age of pretreatment; however, in the adolescent group, but not in the adult, long-lasting cross-tolerance developed to morphine, cocaine, and amphetamine.

Conclusions

Our study suggests that an enduring form of neuronal adaptation occurs in DA neurons after subchronic cannabinoid intake at a young age, affecting subsequent responses to drugs of abuse.

Section snippets

Methods and materials

Male Sprague-Dawley rats (Harlan, Milan, Italy) were housed in groups of three to six in standard conditions of temperature and humidity under a 12 hours/12 hours light/dark cycle (lights on at 7:00 am), with food and water available ad libitum. After 3–4 days of habituation to the animal room, treatments began in two groups of animals of different ages: the “adolescent” group (aged 5–6 weeks) and the “adult” group (aged 8–9 weeks). Rats in each group received intraperitoneal (IP) injections

Results

A total of 107 DA neurons were included in this study. All neurons were identified by their well-established electrophysiologic features (see Methods and Materials) and by their antidromic response from the shell of the NAc. Additionally, all recording sites were located within the VTA, as confirmed by the histologic verification of pontamine sky blue dye. Treatment with cannabinoids and age of treatment had no effect on basal activity of DA neurons. Dopamine neurons in pooled vehicle-treated

Discussion

In this report we provide evidence for a long-lasting tolerance to acute cannabinoids in VTA DA neurons after administration of a cannabinoid agonist. When administered in periadolescent juvenile rats, this tolerance was not restricted to cannabinoids, but cross-tolerance developed to other drugs of abuse (morphine, cocaine, and amphetamine).

The hypothesis of differential effects of drugs of abuse exposure during adolescence or adulthood has been poorly investigated. However, evidence suggests

Acknowledgements

This work was partially supported by the grants of Assessorato Igiene e Sanità (Regime Autonoma della Sardegna) and Cofin 2003 (Ministero dell'Istruzione, dell'Università e della Ricerca).

We thank Mr. Stefano Aramo for his skilled technical assistance and Dr. Le Fur (Sanofi Recherche) for the generous gift of SR141716A.

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Original articleAdolescent exposure to cannabinoids induces long-Lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods and materials

Results

Discussion

Acknowledgements

Eur J Pharmacol

Eur J Pharmacol

Biol Psychiatry

Neuroscience

Brain Res Dev Brain Res

Eur J Pharmacol

Brain Res Dev Brain Res

Eur J Pharmacol

Neuroscience

Neuroscience

Brain Res

Brain Res

Curr Opin Neurobiol

Neuropharmacology

Neurosci Biobehav Rev

Pharmacol Biochem Behav

J Neurosci Methods

Neurosci Lett

Trends Pharmacol Sci

Neuroscience

Pharmacol Biochem Behav

Prog Neurobiol

Eur J Pharmacol

Brain Res

Brain Res Mol Brain Res

Neuron

Brain Res

Brain Res Dev Brain Res

Neurotoxicol Teratol

Neurosci Biobehav Rev

Brain Res Dev Brain Res

Brain Res

Brain Res

Brain Res

Neuroscience

Neuron

Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats

J Neurosci

Cannabis use in adolescence and risk for adult psychosisLongitudinal prospective study

BMJ

Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal periodImplications for the development of psychopathology

Cereb Cortex

Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice

Psychopharmacology (Berl)

Chronic treatment with CP 55,940 during the peri-adolescent period differentially affects the behavioural responses of male and female rats in adulthood

Psychopharmacology (Berl)

Chronic delta-9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain

J Neurochem

Behavioural sensitization after repeated exposure to Delta-9-tetrahydrocannabinol and cross-sensitization with morphine

Psychopharmacology (Berl)

Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

Psychopharmacology (Berl)

Ethanol inhibits single-unit responses in the nucleus accumbens evoked by stimulation of the basolateral nucleus of the amygdala

Alcohol Clin Exp Res

Cannabis and psychosis

Curr Psychiatry Rep

Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats

J Pharmacol Exp Ther

Electrophysiological effects of cocaine in the mesoaccumbens dopamine systemStudies in the ventral tegmental area

J Neurosci

Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats

Eur J Neurosci

Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamineCellular mechanisms of input selection

J Neurosci

Original article
Adolescent exposure to cannabinoids induces long-Lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons