Cocaine effects on striatal dynorphin and CART neuropeptides : association to mood disorder

People take cocaine to elevate mood, but with repeated use and subsequent development of dependence, in paradox, a negative mood state is induced. This may be one reason for the strong comorbidity between cocaine dependence and mood disorders. A common substrate implicated in both disorders is the neurotransmitter dopamine. Alterations of the dopamine system lead to neuroadaptations, such as modulations of gene transcription in postsynaptic neurons.

This thesis work involved examination of mRNA expression of neuropeptides in dopamine-related systems and their response to cocaine administration. Specifically, the opioid neuropeptide dynorphin involved in the regulation of emotion and motor function and the novel neuropeptide cocaine and amphetamine regulated transcript, CART, were studied. The focus was on the striatum, a brain region critical for limbic and motor functions, which is affected by cocaine. In addition, behavioral disturbances in relation to the comorbidity between cocaine and mood disorders were investigated.

We found CART mRNA expression in the human brain to be highly expressed in brain regions implicated in cocaine abuse, including most target regions of the mesocorticolimbic dopamine pathway and regions in the striatopallidal circuitry. These findings support a putative role of this neuropeptide in the effects of cocaine. In agreement, we found CART mRNA expression to be regulated by acute cocaine administration in the rat.

The well documented up-regulation of prodynorphin mRNA following cocaine exposure was confirmed and expanded in this thesis. We demonstrated dose-dependent and temporal elevation of the prodynorphin mRNA in the dorsal striatum of monkeys that had self-administered cocaine. The limbic-related patches/striosomes were initially more sensitive to the induction of the prodynorphin gene transcription with a progression to the sensorimotor-related matrix after long-term, high-dose, cocaine self-administration. In contrast, we found reductions of the striatal prodynorphin and dopamine D1 receptor mRNAs following 10 days abstinence from repeated cocaine injections in the rat, suggesting a long-lasting alteration in the striatonigral pathway following cocaine exposure. The observed suppressed striatal prodynorphin mRNA levels following cocaine abstinence was matched in a genetic animal model of depression, the Flinders Sensitive rat line (FSL). The FSL rats exhibited reduced prodynorphin mRNA levels in the caudal striatum during basal conditions. These results imply a low striatal dynorphin tone during a negative mood state, which may be related to psychomotor retardation.

The effects of cocaine on a depression genotype were investigated in the FSL rats. These animals acquired cocaine self-administration behavior at a similar rate as their controls, but we found a subtle reduction in cocaine reinforcement; cocaine intake was reduced at one dose in a dose-response curve. In addition, the FSL rats were low responders to novelty, which is associated with decreased vulnerability to addictive drugs. In contrast, the response to repeated cocaine administration indicated greater sensitivity to behavioral sensitization, as demonstrated by enhanced stereotyped behavior. Despite apparent motor differences the FSL rats showed a similar dopaminergic response in the nucleus accumbens shell to repeated cocaine administration, as measured by in vivo microdialysis. Taken together, the depression genotype was associated with behavioral differences in the response to cocaine. However, definite conclusions on the reinforcing efficacy of cocaine in the FSL rat will require further studies.

List of scientific papers

I. Hurd YL, Fagergren P (2000). Human cocaine- and amphetamine-regulated transcript (CART) mRNA is highly expressed in limbic- and sensory-related brain regions. J Comp Neurol. 425(4): 583-98.
https://pubmed.ncbi.nlm.nih.gov/10975881

II. Fagergren P, Hurd YL (1999). Mesolimbic gender differences in peptide CART mRNA expression: effects of cocaine. Neuroreport. 10(16): 3449-52.
https://pubmed.ncbi.nlm.nih.gov/10599860

III. Fagergren P, Smith HR, Daunais JB, Nader MA, Porrino LJ, Hurd YL (2003). Temporal upregulation of prodynorphin mRNA in the primate striatum after cocaine self-administration. Eur J Neurosci. [Accepted]

IV. Svensson P, Hurd YL (1998). Specific reductions of striatal prodynorphin and D1 dopamine receptor messenger RNAs during cocaine abstinence. Brain Res Mol Brain Res. 56(1-2): 162-8.
https://pubmed.ncbi.nlm.nih.gov/9602109

V. Fagergren P, Thorsell A, Moller C, Wiklund L, Heilig M, Hurd YL (2003). Cocaine abstinence in the rat is not associated with experimental anxiety on the plus-maze. [Manuscript]

VI. Fagergren P, Overstreet DH, Goiny M, Hurd YL (2003). Different cocaine responsivity in an animal model of depression. [Manuscript]