# Presentation: 402126

## Solvent Research in Animal Models of Abuse: A Review of Mechanistic and Behavioral Studies 

**Silvia L. Cruz, PhD**
**Department of Pharmacobiology**
**Cinvestav Mexico**

## Why solvents?

- Solvents are legal, widely available and inexpensive.
- They can be found in household and industrial products: paint thinners, dry-cleaning fluids, degreasers, gasoline, glues, correction fluids, and permanent markers.

## Solvent abuse is a worldwide problem

- 1988

- 1993

**Solvent abuse is a worldwide problem**

## In some countries, solvent abuse accounts for more than 80% of the cases of inhalant abuse

- http://international.drugabuse.gov/downloads/Inhalant_Summary.pdf

## Solvent exposure

- WHO?
-  young children or older adults.
- WHERE?
- At school, at home, in the streets.

## Solvent exposure

- HOW?
- Occupational exposure to low levels of solvents for extended periods of time.

## Solvent exposure

- HOW?
- Intentional exposure: binge patterns, i.e., high concentrations for short periods of time.

## Why animal research?

- “The neurochemical action of the inhalants largely remains a mistery”
- Dinwiddie, 1984
- There are many remaining questions which can be answered by animal research:
**What are the cellular bases for their reinforcing effects?**
- Do they produce tolerance/sensitization and/or dependence?
- Balster, 1997

## Experimental approaches

- Static exposure chambers for brief exposures to high concentrations (6000 ppm toluene for 30 min)
- Dynamic exposure chambers for chronic exposures (100 ppm, 8h/day for 2 weeks)
- Other routes of administration

## Xenopus oocytes

***Xenopus***** oocytes**

## Effects of solvents on ligand-gated ion channels

- GABAA
- NMDA
- Glycine
- 5-HT3
- nAChR

## Effects of toluene on ligand-gated ion channels

## Increased Inhibition

- Decreased
- Excitation

- Abused Solvents...

## Brain-Imaging Study Offers Clues to Inhalant Abuse

**Brain-Imaging Study Offers Clues to Inhalant Abuse**

- http://www.bnl.gov/bnlweb/pubaf/pr/2002/bnlpr041502.htm

**The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons.**
- _[Riegel](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Riegel%20AC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)__[ AC](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Riegel%20AC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_, _[Zapata A](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Zapata%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_, _[Shippenberg](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shippenberg%20TS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)__[ TS](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Shippenberg%20TS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_, _[French](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22French%20ED%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)__[ ED](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22French%20ED%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_.

**The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons.**
- _[Riegel](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Riegel%20AC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)__[ AC](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Riegel%20AC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_, _[Zapata A](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Zapata%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus)_, **Shippenberg TS**, **French ED**. (1999)

## Behavioral Studies

- Reinforcing and discriminative stimulus
- Motor function
- Anticonvulsant effects
- Anti-anxiety effects
- Memory and learning impairment

## Effects of toluene on voltage-gated ion channels

***Na******+***
- K+
- Ca2+

## Effects of toluene on voltage-gated ion channels

**Effects of toluene on voltage-gated ion channels**

## ↓NMDA

**↓****NMDA**

**↑****GABA****A**** **

**↑****Glycine**

**nACh**

**↑****5-HT****3**

**↓****Na****+**** channels**

**K****+**** channels **

**Ca****2+**** channels **

**100 mM**

**10**** **

**1**** **

**(-) (+)**

**(-)**

**Toluene**

**Ethanol**

- (Cruz, SL)

## Prenatal exposure to solvents

- Children are exposed to solvents in uterus
- A fetal solvent syndrome, very similar to the fetal alcohol syndrome has been described
- Animal models can reproduce binge patterns of exposure to study the effects of solvents during pregnancy and after birth
- Exposure: GD 8- GD20; PN 4-7

## Inhalant abuse in pregnancy.

**Inhalant abuse in pregnancy.**
**Jones HE**, **Balster RL, ****1998**.

## Evidence from animal studies suggests that a number of commonly abused volatile solvents and anesthetic gases have neurobehavioral effects and mechanisms of action similar to those produced by CNS depressants, which include alcohol and medications such as sedatives and anesthetics.

## Curr Opin Psychiatry. 2005 May;18(3):243-7.                       

- Curr Opin Psychiatry. 2005 May;18(3):243-7.

## Other unanswered questions...

- What are the effects of combinations of inhalants?
- What are the effects of combined administration of inhalants and other drugs?
- Balster, 1997