Dopamine D5 receptor localization on cholinergic neurons of the rat forebrain and diencephalon: A potential neuroanatomical substrate involved in mediating dopaminergic influences on acetylcholine release

132

In Alzheimer's disease (AD) patients dysfunction of cholinergic neurons is considered a typical hallmark, leading to a rationale for the pharmacological treatment in use based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine transmission, other neurotransmitter systems are involved in cognitive dysfunction leading to dementia. Among others, dopamine seems to be particularly involved in the regulation of cognitive processes, also having functional relationship with acetylcholine. To test whether cholinergic dysfunction can be modified by dopamine, we used short latency afferent inhibition (SLAI) as a neurophysiological tool. First, we tested the function of the cholinergic system in AD patients and in healthy subjects. Then, we tested whether a single L-dopa challenge was able to interfere with this system in both groups. We observed that SLAI was reduced in AD patients, and preserved in normal subjects. L-dopa administration was able to restore SLAI modification only in AD, having no effect in healthy subjects. We conclude that dopamine can modify SLAI in AD, thus confirming the relationship between acetylcholine and dopamine systems. Moreover, it is suggested that together with cholinergic, dopaminergic system alteration is likely to occur in AD, also. These alterations might be responsible, at least in part, for the progressive cognitive decline observed in AD patients.

Section: Discussionmentioning

confidence: 99%

Dopamine Modulates Cholinergic Cortical Excitability in Alzheimer's Disease Patients

Martorana

Mori

Esposito

et al. 2009

132

“…Synaptic communication within the reward circuit is conducted via DA (modulatory), acetylcholine (ACh, modulatory), glutamate (GLU, excitatory), and g-aminobutyric acid (GABA, inhibitory) neurotransmission. (Alcantara et al, 2003;Berlanga et al, 2005). Activation of the D 1 receptor subtypes stimulates, whereas that of D 2 receptor subtypes inhibits, striatal ACh release (Berlanga et al, 2005;Bertorelli and Consolo, 1990;Consolo et al, 1999;Drukarch et al, 1990;Stoof et al, 1987).…”

Section: Mesostriatal Cholinergic Neuronsmentioning

confidence: 99%

“…(Alcantara et al, 2003;Berlanga et al, 2005). Activation of the D 1 receptor subtypes stimulates, whereas that of D 2 receptor subtypes inhibits, striatal ACh release (Berlanga et al, 2005;Bertorelli and Consolo, 1990;Consolo et al, 1999;Drukarch et al, 1990;Stoof et al, 1987). Zhang et al (2002) have suggested that the offsetting action of the D 1 and D 2 receptor subtypes maintains the balance between ACh and DA.…”

Section: Mesostriatal Cholinergic Neuronsmentioning

confidence: 99%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

160

138

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

“…In addition, ACh and its target receptors are prominent in subcortical and cortical structures important to drug reward, self-administration, and the addictive use of substances. For example, the effect of ACh on reward-relevant processes is due, at least in part, to ACh projections on ventral tegmental area dopaminergic efflux (Clarke and Pert, 1985;Weiner et al, 1990) and the subsequent effect of dopamine (DA) release on striatal ACh interneurons (Berlanga et al, 2005;Consolo et al, 1999). Striatal cholinergic output then further modulates striatal DA efflux (Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Adinoff

Devous

Williams

et al. 2010

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1-to 6-week abstinent, cocaine-(and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (po0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.