mGluR5 Involvement in Methamphetamine Reward and the Co-Morbidity of Schizophrenia and Stimulant Use Disorders
Methamphetamine (Meth) is a potent, widely-used stimulant. Stimulant abuse occurs more frequently in the schizophrenia patient population than the general population. The co-morbidity of stimulant use disorders and schizophrenia presents an understudied phenomenon and suggests overlapping brain states of these two pathologies. There are currently no FDA-approved pharmacotherapies for Meth addiction and relapse to Meth use remains a substantial challenge for abstinent Meth addicts. One factor that contributes to craving and relapse is exposure to environmental or contextual cues associated with Meth use. This effect is the consequence of associative learning that occurs between the rewarding properties of drugs and drug-related, contextual cues that become extremely salient to an individual. This drug-induced associative learning can be studied in the laboratory with humans and rodents using conditioned place preference (CPP). In the laboratory, repeated Meth administration also produces a progressive enhancement in motor activity termed motor sensitization. It is hypothesized that the neuronal adaptations associated with motor sensitization may model aspects of the brain changes that are associated with Meth abuse in humans. Schizophrenia patients and rodent models of the disorder demonstrate deficits in sensorimotor gating, or the inability to properly filter sensory information properly. Sensorimotor gating deficits are measured in the laboratory through the use of pre-pulse inhibition (PPI) of the acoustic startle response. PPI is defined as a normal suppression of the startle response when a weaker acoustic stimulus is presented before a louder startling acoustic stimulus. The current dissertation project utilized Meth-induced CPP, motor sensitization, and PPI to elucidate neuronal underpinnings of Meth addiction and schizophrenia / Meth addiction co-morbidity. The glutamate transmitter system is important for memory processing, addiction, and the neuropathology of schizophrenia. Glutamate activates both ionotropic and metabotropic receptors; the group I subtype 5 metabotropic glutamate receptor (mGluR5) is highly expressed in brain regions known to be important for stimulant reward. Thus, mGluR5 functions to fine tune neuronal excitability and modulate drug-induced behaviors. It is important, and clinically relevant, to study the neuronal adaptations that occur following repeated Meth administration in order to evaluate the ability of potential pharmacotherapy targets to influence Meth-induced behaviors in the general and schizophrenia patient population. The goal of this dissertation project was to elucidate the role of mGluR5 in different phases of Meth-induced associative learning in normal and schizophrenia-like rodents and to determine the correlation between deficits associated with schizophrenia and responding to the rewarding effects of Meth.
addiction, conditioned place preference, metabotropic glutamate receptor, methamphetamine, schizophrenia, Neuroscience and Neurobiology
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