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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Animal studies have shown that, in common with classical depressant
drugs, volatile solvents have biphasic effects on motor activity, disrupt
psychomotor performance, have anticonvulsant effects, produce biphasic
drug-like effects on rates of schedule-controlled operant behaviour, increase
rates of punished responding, serve as reinforcers in self-administration
studies and share discriminative stimulus effects with barbiturates and
ethanol (Evans & Balster, 1991). Toluene is self-administered in primates
(Weiss, Wood & Macys, 1979), and has biphasic effects on intracranial self-
stimulation, increasing the frequency of self-stimulation at lower
concentrations and decreasing it at higher concentrations. Several solvents
contained in glue vapours, including toluene, induce conditioned place
preference and activate the brain reward system in intracranial self-
stimulation in rats, predicting the dependence-producing potential of volatile
solvents (Yavich & Patkina, 1994; Yavich & Zvartau, 1994).

Mechanism of action
Little is known about the mechanism of action of the solvents, and they have
received far less attention in research than other psychoactive substances. Most
reviews consider the nature of the acute effects of volatile organic solvents by
comparing their actions to those of classical depressant drugs such as the
barbiturates, benzodiazepines and ethanol. Based on their physical effects it
is assumed that solvents induce similar biochemical changes as ethanol and
anaesthetics, and therefore the search for a GABAergic mechanism of action
has been pursued. In mice, the discriminative stimulus effects of ethanol may
be substituted for several volatile anaesthetics, toluene and other volatile
solvents (Bowen & Balster, 1997). Acquisition of toluene discrimination by rats
and mice, generalizes for GABAergic agents such as barbiturates and
benzodiazepines, suggesting that toluene may have drug dependence potential
of the CNS-depressant type (Knisely, Rees & Balster, 1990).
The commonly used solvents, including toluene, also affect ligand-gated
ion channel activity. Toluene, similar to ethanol, reversibly enhances GABA(A)
receptor-mediated synaptic currents. Therefore, the molecular sites of action
of these compounds may overlap with those of ethanol and the volatile
anaesthetics (Beckstead et al., 2000). Toluene has excitatory and inhibitory
biphasic effects on neurotransmission that are related to GABAergic neuro-
transmission.
Dopamine in the nucleus accumbens is closely related to substance
dependence for all psychoactive substances (Chapter 3). Acute inhalation of
toluene by rats results in an increase in extracellular dopamine levels in the
striatum (Stengard, Hoglund & Ungerstedt, 1994), and changes in neuronal
firing of dopamine neurons of the VTA (Riegel & French, 1999). Therefore,
this electrophysiological study suggests that mesolimbic dopamine
neurotransmission can be changed by toluene exposure, pointing towards
the same conclusion as the neurochemical studies.

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