Using dopamine research to generate rational cannabinoid drug policy.

The recent rise in the recreational use of synthetic cannabinoids (e.g. 'K2' and 'Spice') has been accompanied by a corresponding increase in regulation. Besides prohibition of specific compounds and general class bans in over forty states, five synthetic cannabinoids (CB) are federally regulated under a 'temporary' ban and are currently under a formal review to determine whether to permanently schedule them. Whether through explicit prohibition of specific chemicals, or potential de facto bans of unofficially scheduled compounds through the analogue act, scheduling CBs may significantly impede researching their therapeutic utility and elucidating physiological roles of the endogenous CB system. We argue that a review of neuroscience research suggests that synthetic CBs that act like Δ9-tetrahydrocannabinol (THC) by directly binding to and stimulating CB receptors (i.e. direct agonists), as well as novel drugs that indirectly stimulate these receptors by increasing levels of endogenous CB neurotransmitters (i.e. indirect agonists) have therapeutic value. Specifically, neurochemical research into how CBs influence mesolimbic dopamine release, a reliable and consistent marker of drugs' rewarding/reinforcing effects, provides the most useful indication of CB abuse liability, and may have implications for the generation of rational drug policy. It demonstrates that direct CB receptor agonists, but not indirect agonists, increase mesolimbic dopamine release. Thus, while direct CB receptor agonists pose an abuse liability, indirect agonists do not. We recommend regulatory agencies revise policies that treat these separate CB classes similarly and to curb regulation aimed at any CB receptor agonists as Schedule I, as this ignores their medicinal properties.

Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.

Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1-knockout (Homer1-KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1-KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced 'behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1-KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder.