Dopamine Terminals

Several classes of drugs modulate the firing rates or patterns of midbrain dopamine neurons by direct, monosynaptic, or indirect, polysynaptic, inputs to the cell bodies within the ventral mesencephalon (i.e., nicotine and opiates). In contrast, amphetamine, cocaine, and methylphenidate act at the level of the dopamine terminal interfering with normal processes of transmitter packaging, release, reuptake, and metabolism. 

As pointed out before there are some major differences between the striatal and cortical dopamine terminals (Table 1). 

Pycock, CJ, Kerwin, RW and Carter, CJ (1980) Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 286 74-77. 

The motor activation produced by psychomotor stimulants has been long associated with the midbrain dopamine systems. While focused stereotyped behavior produced by high doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the corpus striatum (Creese and Iversen 1975), the locomotor activation produced by low doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the region of the nucleus accumbens (Kelly et al. 1975). This dopaminergic substrate for psychostimulant effects appears selective for the indirect sympathomimetics in that dopamine lesions to the region of the nucleus... 

The neuroehemical sites for psyehomotor stimulant reward are likely to be the presynaptic dopamine terminals located in the region of the nucleus aeeumbens, frontal cortex, and other forebrain structures that originate in the ventral tegmental area. Note, however, that intraeranial self-administration of eoeaine is elicited from the frontal cortex, but not from the nucleus aeeumbens (Goeders and Smith 1983). Thus, eoneomitant activation of structures other than the nucleus accumbens may be an important part of the circuitry involved in initiation of cocaine intravenous self-administration, as has been hypothesized for the opiates (Smith and Lane 1983 Smith et al. 1982). 

Investigation of the neurochemical substrates for the psychostimulant effects of MDMA suggests a role for the mesolimbic dopamine system. Destruction of dopamine terminal fields in the nucleus accumbens significantly attenuated the locomotor activation produced by MDMA. A similar blockade of amphetamine-induced locomotor hyperactivity is known and was observed following amphetamine injection in these same rats. Such results support the hypothesis that at least one component of MDMA-induced hyperactivity is dopamine mediated and suggest that mesolimbic dopamine specifically is the critical substrate. In this way, MDMA resembles other classical psychostimulants like amphetamine and cocaine. Interestingly, evidence for functional cross-sensitization was suggested in the study in which an injection of amphetamine followed MDMA injection. 

Eisch, A.J., Marshall, J.F. Methamphetamine neurotoxicity dissociation of striatal dopamine terminal damage from parietal cortical cell body injury. Synapse. 30 433, 1998. 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and ( -amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and ( -amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12— 2 and 12—3). These agents not only block the dopamine transporter but may actually... 

Wu LG, Betz WJ (1996) Nerve activity but not intracellular calcium determines the time course of endocytosis at the frog neuromuscular junction. Neuron 17 769-79 Zenisek D, Steyer JA, Feldman ME, Aimers W (2002) A membrane marker leaves synaptic vesicles in milliseconds after exocytosis in retinal bipolar cells. Neuron 35 1085-97 Zhou FM, Liang Y, Salas R, Zhang L, De Biasi M, Dani JA (2005) Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron 46 65-74 Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64 355—405... 

Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T (2005) Microglial activation and dopamine terminal loss in early Parkinson s disease. Ann. Neurol. 57 168-175. 

Stamford JA, Kruk ZL, Millar J. Striatal dopamine terminals release serotonin after 5-HTP pretreatment in vivo voltammetric data. Brain Res 1990 515 173-180. 

Rabinovic AD, Lewis DA, Hastings TG. 2000. Role of oxidative changes in the degeneration of dopamine terminals after injection of neurotoxic levels of dopamine. Neuroscience 101 67-76. 

Carr DB, Sesack SR (1996) Hippocampal afferents to the rat prefrontal cortex synaptic targets and relation to dopamine terminals. J Comp Neurol 369 1-15. 

It was thus concluded that D2R has a major role in regulating the size of the terminal arbor in dopamine neurons projecting from the SNpc to the CPu. This is consistent with the role of the D2 autoreceptor in regulating the delivery of dopamine. It suggests that this regulation is not only confined to dopamine storage, synthesis and turnover in the terminals but is also manifested in the density of dopamine terminals. 

Most, if not all, dopamine terminals in the striatum are newly formed when the CPu is re-innervated following an SNpc lesion and the ultrastructure of these terminals is altered, suggesting they may produce, store and release more dopamine than normal terminals (Finkelstein et al., 2000 Stanic et al., 2003a). These changes include increased terminal... 

Most animals with small lesions and many with intermediate lesions turned left or have only a modest tendency to turn toward the side of the lesion (right side). Only animals with large lesions persist in turning toward the lesioned side. Thus amphetamine induced turning provides a functional measure of the degree to which regenerated dopamine terminals can release dopamine. Amphetamine induced rotation is therefore a better measure of the degree of functional reinnervation rather than the size of a lesion. 

Garris PA, Walker QD, Wightman RM (1997) Dopamine release and uptake rates both decrease in the partially denervated striatum in proportion to the loss of dopamine terminals. Brain Res 753 225-234. 

Pickel VM, Johnson E, Carson M, Chan J (1992) Ultrastructure of spared dopamine terminals in caudate-putamen nuclei of adult rats neonatally treated with intranigral 6-hydroxydopamine. Brain Res Dev Brain Res... 

An alternative estimate of the density of dopamine terminals could, in principle, be obtained from counting varicosities and correcting for the fractions of varicosities without synapses, and the fraction of synapses not on varicosities. Doucet et al. (1986) estimated an average density of dopamine varicosities of 0.1 pm-3. This number is remarkably close to the density of synapses estimated above. 

Fig. 2. Relative abundance and close packing of different postsynaptic targets of dopaminergic synapses in the striatum. Note the termination of a dopamine (DA) and a glutamate (GLU) presynaptic terminal on the same postsynaptic spine in a minority of cases. Note also that the majority of glutamate synapses are within one or two synapses of a dopamine terminal. GABAergic (GABA) and unknown (UNK) terminals are also shown.

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