Jakie McGinty, Ph.D.
BS, 1972, Connecticut College
Ph.D., 1978, SUNY Downstate Medical Center
My research focuses on (1) the effects of drugs of abuse on neurotransmitter release and gene expression in the rat brain and (2) the effects of methamphetamine neurotoxicity in neurotrophic factor knockout mice during aging. Using in vivo microdialysis, my lab has demonstrated that endogenous opioid and muscarinic systems decrease the psychostimulant-induced release of neurotransmitters such as dopamine and glutamate in the striatum. By affecting intracellular kinase cascades in neurons which express dopamine and glutamate receptors, we have demonstrated that psychostimulants change the activity of nuclear transcription factors and the expression of their target genes.
Currently we are using cDNA microarray technology, in situ hybridization, immunoblotting, and immunohistochemistry to characterize changes in gene expression that may signify longterm neuroadaptations in the brain thought to underlie drug addiction and neurotoxicity during aging.
Project: Changes in Gene and Protein Expression
during different phases of cocaine self administration, abstinence, and relapse. We use Affymetrix GeneChips and quantitative PCR and in situ hybridization to characterize the gene changes followed by immunoblotting to see whether there are similar changes in the encoded proteins. Ultimately, the goal is to re-introduce the gene /protein candidates back into the animal model by knockdown and/or overexpression methods (Kalivas lab) to investigate whether they affect cocaine seeking.
Altered expression of prefrontal cortical genes three weeks after cessation of cocaine self-administration. J. L. Peters, W. J. Berglind, S. Jani, G. Page, J. F. McGinty. Dept. of Neurosciences, Med Univ of SC, Charleston, SC, USA
The dorsal medial prefrontal cortex (dmPFC) is critical for relapse to cocaine-seeking after periods of withdrawal from cocaine. To examine large-scale gene expression patterns within dmPFC, a microarray approach was used to screen for genes that are altered 3 weeks after cessation of cocaine self-administration. Rats (n=10) self-administered cocaine for 10 days and then underwent a 3-week period of abstinence in the home cage. A control group of rats (n=10) received yoked-saline infusions in the operant environment instead of cocaine. The cDNA from dmPFC of saline and cocaine animals was hybridized to high-density Affymetrix U230A GeneChipsTM. Robust multichip averaging (RMA) was used to process the data and individual genes were analyzed at a p<0.01 cutoff and false discovery rate of <0.25. Gene ontology analyses revealed changes in patterns of gene expression between saline and cocaine groups. Neurogenesis- and synaptic plasticity-related genes, such as AMPA receptor alpha subunit, Arc, synaptophysin, neuronatin and neurochondrin were predominantly upregulated by cocaine. There was also a global upregulation of ribonucleoproteins and a small subset of ribonucleoprotein genes that were downregulated in cocaine self-administering animals. Several MAP kinase-related genes were altered including MAPK1 and JNK/SAPK-associated protein 1 (down) and TAO2 and JunD (up). In addition to the AMPA receptor, other specific receptors were significantly upregulated by cocaine. These included the GABAB receptor, somatostatin receptor 2, GDNF receptor alpha2, serotonin receptor 1A, metabotropic glutamate receptor 1, and sigma opioid receptor 1; whereas the muscarinic cholinergic receptor 5 was downregulated. Several kinase and phosphatase-related enzymes were also significantly altered by cocaine. Individual genes of interest will be examined by RT-PCR and/or in situ hybridization to verify positive gene candidates.
Supported by DA15369 (JFM) and T32 DA 07288 (JFM).
Theme: Disorders of the Nervous Systems
Topic: 11. Addiction and Drugs of Abuse
Bilateral BDNF Infusions into the Prefrontal Cortex During Cocaine Self-Administration Attenuates Cue and Cocaine-Induced Reinstatements in Rats.
W.J. Berglind*;R.K. Branham; R.A. Fuchs, R.E. See, J.F. McGinty. Department of Neurosciences, Med. Univ. of SC, Charleston, SC, USA
Chronic exposure to cocaine induces long-lasting neuro-adaptations within the mesocorticolimbic reward pathway that are thought to underlie the emergence of addictive behaviors. Infusion of brain derived neurotrophic factor (BDNF) within the nucleus accumbens (NAcc) as well as the ventral tegmental area (VTA) has been demonstrated to augment cocaine reinforcement and the reinstatement of cocaine-seeking behavior (Horger et al., 1999; Grimm et al., 2003, Lu et al., 2004). However, less is known about the role of BDNF within the corticostriatal pathway, including projections from the prefrontal cortex (PFC) to the NAC, which are critical in relapse behaviors (Kalivas, 2004). In the present study, rats self-administered cocaine (0.2 mg/inf) on an FR1 schedule of reinforcement, with contingent presentation of a light+tone CS, for 10 days. Immediately after the 10th self-administration session, rats received intra-PFC infusions of BDNF (0.75mg/0.5ml/side) or vehicle (PBS, 0.5ml). Following 7 days of abstinence in the home cage, rats were re-exposed to the self-administration environment in the response-contingent presence of the CS during a 2-hour session. Rats that had received intra-PFC infusions of BDNF exhibited less active lever responding during this test relative to vehicle-treated rats. Similarly, rats that received intra-PFC infusions of BDNF exhibited less lever responding following a cocaine challenge (10 mg/kg, i.p.). This evidence sharply contrasts with other studies that have measured the effect of intra-VTA or intra-NAcc infusions of BDNF on reinstatement of cocaine seeking (Lu et al., 2004; Graham and Self, 2004). The mechanisms underlying this effect remain to be investigated, but have significant implications in elucidating both the role of BDNF within the PFC, and the role of the PFC itself in modulating relapse to cocaine-seeking.
Support: DA15369 (JFM), and DA07288 (WJB)
Keywords: growth factors, psychostimulants, addiction, reward
Theme F: Disorders of the nervous system
11. Addiction and Drugs of abuse
Topic: g. cocaine